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clinical studies

Independent ingredient review

There are a vast number of clinical studies over the last few decades that have shown the effectiveness of the ingredients found in Onco-V. Our clinical research team has compiled several of these studies with the results so that you can find out for yourself that the ingredients in Onco-V can help shield your cells from the damaging effects of common cancer-promoting triggers*.

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Boswellia (Boswellia Serrata) Gum Resin Extract CLINICAL STUDIES

Boswellia serrata extract attenuates inflammatory mediators and oxidative stress in collagen induced arthritis Umar S, et al. Boswellia serrata extract attenuates inflammatory mediators and oxidative stress in collagen induced arthritis. Phytomedicine. 2014 May 15;21(6):847-56. doi: 10.1016/j.phymed.2014.02.001. Epub 2014 Mar 22. PubMed PMID: 24667331. Rheumatoid arthritis (RA) is a chronic inflammatory disease which leads to destruction of joints. Current treatment modalities for RA either produce symptomatic relief (NSAIDs) or modify the disease process (DMARDs). Though effective, their use is also limited by their side effects. As a result, the interest in alternative, well tolerated anti-inflammatory remedies has re-emerged. Our aim was to evaluate the antioxidant and antiarthritic activity of Boswellia serrata gum resin extract (BSE) in collagen induced arthritis. Arthritis was induced in male Wistar rats by collagen induced arthritis (CIA) method. BSE was administered at doses of 100 and 200mg/kg body weight once daily for 21 days. The effects of treatment in the rats were assessed by biochemical (articular elastase, MPO, LPO, GSH, catalase, SOD and NO), inflammatory mediators (IL-1β, IL-6, TNF-α, IL-10, IFN-γ and PGE2), and histological studies in joints. BSE was effective in bringing significant changes on all the parameters (articular elastase, MPO, LPO, GSH, catalase, SOD and NO) studied. Oral administration of BSE resulted in significantly reduced levels of inflammatory mediators (IL-1β, IL-6, TNF-α, IFN-γ and PGE2), and increased level of IL-10. The protective effects of BSE against RA were also evident from the decrease in arthritis scoring and bone histology. The abilities to inhibit proinflammatory cytokines and modulation of antioxidant status suggest that the protective effect of Boswellia serrata extract on arthritis in rats might be mediated via the modulation of immune system.

Five Herbs Plus Thiamine Reduce Pain and Improve Functional Mobility in Patients With Pain: A Pilot Study Hedaya R. Five Herbs Plus Thiamine Reduce Pain and Improve Functional Mobility in Patients With Pain: A Pilot Study. Altern Ther Health Med. 2017 Jan;23(1):14-19. PubMed PMID: 28160759. A clinically significant reduction in perceived pain and improvement in functional mobility had occurred for the intervention group as related to their chronic joint, back, and muscle pain. The complex of 5 herbs, plus vitamin B1, was well tolerated, and the results suggest that the blend should be considered to be a valuable alternative treatment in the management of chronic musculoskeletal pain.

Boswellia Serrata, A Potential Antiinflammatory Agent: An Overview Siddiqui MZ. Boswellia Serrata, A Potential Antiinflammatory Agent: An Overview. Indian Journal of Pharmaceutical Sciences. 2011;73(3):255-261. doi:10.4103/0250-474X.93507. The resin of Boswellia species has been used as incense in religious and cultural ceremonies and in medicines since time immemorial. Boswellia serrata (Salai/Salai guggul), is a moderate to large sized branching tree of family Burseraceae (Genus Boswellia), grows in dry mountainous regions of India, Northern Africa and Middle East. Oleo gum-resin is tapped from the incision made on the trunk of the tree and is then stored in specially made bamboo basket for removal of oil content and getting the resin solidified. After processing, the gum-resin is then graded according to its flavour, colour, shape and size. In India, the States of Andhra Pradesh, Gujarat, Madhya Pradesh, Jharkhand and Chhattisgarh are the main source of Boswellia serrata. Regionally, it is also known by different names. The oleo gum-resins contain 30-60% resin, 5-10% essential oils, which are soluble in the organic solvents, and the rest is made up of polysaccharides. Gum-resin extracts of Boswellia serrata have been traditionally used in folk medicine for centuries to treat various chronic inflammatory diseases. The resinous part of Boswellia serrata possesses monoterpenes, diterpenes, triterpenes, tetracyclic triterpenic acids and four major pentacyclic triterpenic acids i.e. β-boswellic acid, acetyl-β-boswellic acid, 11-keto-β-boswellic acid and acetyl-11-keto-β-boswellic acid, responsible for inhibition of pro-inflammatory enzymes. Out of these four boswellic acids, acetyl-11-keto-β-boswellic acid is the most potent inhibitor of 5-lipoxygenase, an enzyme responsible for inflammation.

Natural anti-inflammatory agents for pain relief Maroon JC, Bost JW, Maroon A. Natural anti-inflammatory agents for pain relief. Surgical Neurology International. 2010;1:80. doi:10.4103/2152-7806.73804. The Boswellia species are trees located in India, Ethiopia, Somalia, and the Arabian Peninsula, and they produce a gum resin called olibanum, better known in the western world as frankincense. This resin possesses anti-inflammatory, anti-arthritic, and analgesic properties. Boswellia can inhibit the leukotriene biosynthesis in neutrophilic granulocytes by inhibiting 5-LOX, thus affecting various inflammatory diseases that are perpetuated by leukotrienes.[95] Clinically, the substance is used in the treatment of degenerative and inflammatory joint disorders. It reduces the total white blood cell count in joint fluid, and it also inhibits leukocyte elastase, which is released in rheumatoid arthritis. In one recent study, a statistically significant improvement in arthritis of the knee was shown after 8 weeks of treatment with 333 mg B. serrata extract taken three times a day. The treatment improved function, but radiographically there was no change in the affected joints.[62]

Systematic review of herbals as potential anti-inflammatory agents: Recent advances, current clinical status and future perspectives Beg S, Swain S, Hasan H, Barkat MA, Hussain MS. Systematic review of herbals as potential anti-inflammatory agents: Recent advances, current clinical status and future perspectives. Pharmacognosy Reviews. 2011;5(10):120-137. doi:10.4103/0973-7847.91102. A combination of Boswellia and curcumin showed superior efficacy and tolerability compared with nonsteroidal diclofenac for treating active osteoarthritis. Boswellia typically is given as an extract standardized to contain 30-40% boswellic acids (300-500 mg two or three times/day). Boswellia has been well tolerated in most studies, although some people may experience stomach discomfort, including nausea, acid reflux, or diarrhea.

Devils Claw CLINICAL STUDIES

Analgesic effect of Harpagophytum procumbens on postoperative and neuropathic pain in rats Lim DW, Kim JG, Han D, Kim YT. Analgesic effect of Harpagophytum procumbens on postoperative and neuropathic pain in rats. Molecules. 2014 Jan 16;19(1):1060-8. doi: 10.3390/molecules19011060. PubMed PMID: 24441655. Harpagophytum procumbens, also known as Devil's Claw, has historically been used to treat a wide range of conditions, including pain and arthritis. The study was designed to investigate whether H. procumbens extracts exhibit analgesic effects in plantar incision and spared nerve injury (SNI) rats. The whole procedure was performed on male SD rats. To evaluate pain-related behavior, we performed the mechanical withdrawal threshold (MWT) test measured by von Frey filaments. Pain-related behavior was also determined through analysis of ultrasonic vocalization (USVs). The results of experiments showed MWT values of the group that was treated with 300 mg/kg H. procumbens extract increased significantly; on the contrary, the number of 22-27 kHz USVs of the treated group was reduced at 6 h and 24 h after plantar incision operation. After 21 days of continuous treatment with H. procumbens extracts at 300 mg/kg, the treated group showed significantly alleviated SNI-induced hypersensitivity responses by MWT, compared with the control group. These results suggest that H. procumbens extracts have potential analgesic effects in the case of acute postoperative pain and chronic neuropathic pain in rats.

A review of the efficacy and safety of devil's claw for pain associated with degenerative musculoskeletal diseases, rheumatoid, and osteoarthritis Denner SS. A review of the efficacy and safety of devil's claw for pain associated with degenerative musculoskeletal diseases, rheumatoid, and osteoarthritis. Holist Nurs Pract. 2007 Jul-Aug;21(4):203-7. Review. PubMed PMID: 17627199. Harpagophytum procumbens, known as devil's claw, has been used traditionally for the treatment of pain, fevers, and dyspepsia. Recently, it has become popular for the treatment of rheumatoid and osteoarthritis. Studies have yet to establish a clear mechanism of action; however, current research is focusing on pro-inflammatory mediators as well as on potential antioxidant characteristics.

Analgesic, antiinflammatory and antidiabetic properties of Harpagophytum procumbens DC (Pedaliaceae) secondary root aqueous extract Mahomed IM, Ojewole JA. Analgesic, antiinflammatory and antidiabetic properties of Harpagophytum procumbens DC (Pedaliaceae) secondary root aqueous extract. Phytother Res. 2004 Dec;18(12):982-9. PubMed PMID: 15742343. South Africa is blessed with a rich floral biodiversity of medicinally useful plants. One such plant is Harpagophytum procumbens DC (Family: Pedaliaceae). H. procumbens is widely used in South African traditional medicine for the treatment, management and/or control of a variety of human ailments. In the present study, the analgesic effect of H. procumbens secondary root aqueous extract was evaluated in mice, using the 'hot-plate' and 'acetic acid' test methods; while the antiinflammatory and antidiabetic effects of the plant's secondary root extract were investigated in rats. Fresh egg albumin-induced pedal oedema and streptozotocin (STZ)-induced diabetes mellitus were used as experimental test models of inflammation and diabetes Diclofenac (DIC, 100 mg/kg i.p.) was used as a reference analgesic and antiinflammatory agent for comparison. Chlorpropamide (250 mg/kg p.o.) was used as a reference hypoglycaemic agent for comparison. H. procumbens root aqueous extract (HPE, 50-800 mg/kg i.p.) produced significant (p < 0.05-0.001) analgesic effects against thermally and chemically induced nociceptive pain stimuli in mice. H. procumbens root extract (HPE, 50-800 mg/kg i.p.) also produced dose-related, significant reductions (p < 0.05-0.001) of the fresh egg albumin-induced acute inflammation of the rat hind paw oedema. Furthermore, the plant extract (HPE, 50-800 mg/kg i.p.) produced dose-dependent, significant reductions (p < 0.05-0.001) in the blood glucose concentrations of both fasted normal and fasted diabetic rats. The results of this experimental animal study indicate that H. procumbens root aqueous extract possesses analgesic, antiinflammatory and hypoglycaemic properties, and lend pharmacological support to the suggested folklore uses of Harpagophytum procumbens root in the management and/or control of painful, arthritic and other inflammatory conditions, as well as for adult-onset, type-2 diabetes mellitus in some communities of South Africa.

Devil's claw extract as an example of the effectiveness of herbal analgesics. Chrubasik S. [Devil's claw extract as an example of the effectiveness of herbal analgesics]. Orthopade. 2004 Jul;33(7):804-8. Review. German. PubMed PMID: 15150687. Preparations from devil's claw differ in their content of active ingredients as assessed by the quantity of harpagoside present. The harpagoside content in the daily dose of Doloteffin (extraction solvent water) is double that of preparations extracted with 60% ethanol. Only preparations with proven effectiveness for painful lower back or arthrotic pain are an attractive alternative to synthetic analgesics, and are of substantial benefit in the treatment of chronic pain. From an evidence based view, extract with at least 50 mg harpagoside in the daily dose should be recommended for the treatment of pain. Treatment with devil's claw extract is associated with a lower risk of adverse events than treatment with synthetic analgesics, and may contribute in the majority of patients to the relief of pain.

Treatment of patients with arthrosis of hip or knee with an aqueous extract of devil's claw (Harpagophytum procumbens DC.). Wegener T, Lüpke NP. Treatment of patients with arthrosis of hip or knee with an aqueous extract of devil's claw (Harpagophytum procumbens DC.). Phytother Res. 2003 Dec;17(10):1165-72. PubMed PMID: 14669250. Preparations made from the secondary tubers of Devil's claw (Harpagophytum procumbens) are successfully used in patients with rheumatic diseases (arthrosis and low back pain). In order to add data on the efficacy and long-term safety of an aqueous extract (Doloteffin; 2400 mg extract daily, corresponding to 50 mg harpagoside), which has been tested successfully in patients with low back pain, an uncontrolled multicentre drug surveillance study for about 12 weeks was conducted in 75 patients with arthrosis of the hip or knee. To standardize the assessment of treatment effects, the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index (10 point scale) as well as the 10 cm VAS pain scale were used. The results of the study revealed a strong reduction of pain and the symptoms of osteoarthritis. There was a relevant improvement of each WOMAC subscale as well as of the total WOMAC index: 23.8% for the pain subscale, 22.2% for the stiffness subscale and 23.1% for the physical function subscale. The WOMAC total score was reduced by 22.9%. VAS pain scores were decreased by 25.8% for actual pain, 25.2% for average pain, 22.6% for worst pain and 24.5% for the total pain score. The physicians reported a continuous improvement in typical clinical findings such as 45.5% for pain on palpation, 35% for limitation of mobility and 25.4% for joint crepitus. Only two cases of possible adverse drug reactions were reported (dyspeptic complaints and a sensation of fullness). Although this was an open clinical study, the results suggest that this Devil's claw extract has a clinically beneficial effect in the treatment of arthrosis of the hip or knee.

Current nutraceuticals in the management of osteoarthritis: a review Akhtar N, Haqqi TM. Current nutraceuticals in the management of osteoarthritis: a review. Therapeutic Advances in Musculoskeletal Disease. 2012;4(3):181-207. doi:10.1177/1759720X11436238. Osteoarthritis (OA) is a progressive degenerative joint disease that has a major impact on joint function and quality of life. Nutraceuticals and dietary supplements derived from herbs have long been used in traditional medicine and there is considerable evidence that nutraceuticals may play an important role in inflammation and joint destruction in OA. We review the biological effects of some medicinal fruits and herbs – pomegranate, green tea, cat’s claw, devil’s claw, ginger, Indian olibaum, turmeric and ananas – in an attempt to understand the pivotal molecular targets involved in inflammation and the joint destruction process and to summarize their toxicities and efficacy for OA management. So far there is insufficient reliable evidence on the effectiveness of ginger, turmeric and ananas. Pomegranate and green tea only have preclinical evidence of efficacy due to the lack of clinical data. In vivo and clinical studies are required to understand their targets and efficacy in OA. Limited in vitro and in vivo evidence is available for cat’s claw and Indian olibaum. More extensive studies are required before long-term controlled trials of whole cat’s claw and Indian olibaum extracts, or isolated active compounds, are carried out in patients with OA to determine their long-term efficacy and safety. Devil’s claw has not been rigorously tested to determine its antiarthritic potential in in vitro and in vivo models. There is strong clinical evidence of the effectiveness of devil’s claw in pain reduction. However, high-quality clinical trials are needed to determine its effectiveness. No serious side effects have been reported for any fruits and herbs. Overall, these studies identify and support the use of nutraceuticals to provide symptomatic relief to patients with OA and to be used as adjunct therapy for OA management. More high-quality trials are needed to provide definitive answers to questions related to their efficacy and safety for OA prevention and/or treatment.

White Willow Bark Extract CLINICAL STUDIES

Medicinal potential of willow: A chemical perspective of aspirin discovery Mahdi JG. Medicinal potential of willow: A chemical perspective of aspirin discovery. Saudi Chem. Soc., 14, 317 – 322 (2010). The willow tree is a symbolic medicinal plant that has been associated with the discovery of aspirin, chemically known as acetylsalicylic acid, or salicylate, which still offers surprises as a revival drug. The philosophical perspective of the significance of the willow tree has been elaborated since the Assyrians (4000 BC) and Sumerians (3500 BC), who were aware of its medicinal merits. In 1838, the main pharmacologically active ingredient of willow, the salicin structure was elucidated by hydrolysis to comprise D-glucose and salicyl alcohol. These uncovered new perspectives, which eventually lead to the discovery of aspirin.

Herbal medicine for low-back pain Oltean H, et al. Herbal medicine for low-back pain. Cochrane Database Syst Rev. 2014 Dec 23;(12):CD004504. doi: 10.1002/14651858.CD004504.pub4. Review. PubMed PMID: 25536022. BACKGROUND: Low-back pain (LBP) is a common condition and imposes a substantial economic burden upon people living in industrialized societies. A large proportion of people with chronic LBP use complementary and alternative medicine (CAM), visit CAM practitioners, or both. Several herbal medicines have been purported for use in treating people with LBP. This is an update of a Cochrane Review first published in 2006. OBJECTIVES: To determine the effectiveness of herbal medicine for non-specific LBP. SEARCH METHODS: We searched the following electronic databases up to September 2014: MEDLINE, EMBASE, CENTRAL, CINAHL, Clinical Trials.gov, World Health Organization International Clinical Trials Registry Portal and PubMed; checked reference lists in review articles, guidelines and retrieved trials; and personally contacted individuals with expertise in this area. SELECTION CRITERIA: We included randomized controlled trials (RCTs) examining adults (over 18 years of age) suffering from acute, sub-acute, or chronic non-specific LBP. The interventions were herbal medicines which we defined as plants used for medicinal purposes in any form. Primary outcome measures were pain and function. DATA COLLECTION AND ANALYSIS: A library scientist with the Cochrane Back Review Group conducted the database searches. One review author contacted content experts and acquired relevant citations. We downloaded full references and abstracts of the identified studies and retrieved a hard copy of each study for final inclusion decisions. Two review authors assessed risk of bias, GRADE criteria (GRADE 2004), and CONSORT compliance and a random subset were compared to assessments by a third individual. Two review authors assessed clinical relevance and resolved any disagreements by consensus. MAIN RESULTS: We included 14 RCTs (2050 participants) in this review. One trial on Solidago chilensis M. (Brazilian arnica) (20 participants) found very low quality evidence of reduction in perception of pain and improved flexibility with application of Brazilian arnica-containing gel twice daily as compared to placebo gel. Capsicum frutescens cream or plaster probably produces more favourable results than placebo in people with chronic LBP (three trials, 755 participants, moderate quality evidence). Based on current evidence, it is not clear whether topical capsicum cream is more beneficial for treating people with acute LBP compared to placebo (one trial, 40 participants, low quality evidence). Another trial found equivalence of C. frutescens cream to a homeopathic ointment (one trial, 161 participants, very low quality evidence). Daily doses of Harpagophytum procumbens (devil's claw), standardized to 50 mg or 100 mg harpagoside, may be better than placebo for short-term improvements in pain and may reduce use of rescue medication (two trials, 315 participants, low quality evidence). Another H. procumbens trial demonstrated relative equivalence to 12.5 mg per day of rofecoxib (Vioxx®) but was of very low quality (one trial, 88 participants, very low quality). Daily doses of Salix alba (white willow bark), standardized to 120 mg or 240 mg salicin, are probably better than placebo for short-term improvements in pain and rescue medication (two trials, 261 participants, moderate quality evidence). An additional trial demonstrated relative equivalence to 12.5 mg per day of rofecoxib (one trial, 228 participants) but was graded as very low quality evidence. S. alba minimally affected platelet thrombosis versus a cardioprotective dose of acetylsalicylate (one trial, 51 participants). One trial (120 participants) examining Symphytum officinale L. (comfrey root extract) found low quality evidence that a Kytta-Salbe comfrey extract ointment is better than placebo ointment for short-term improvements in pain as assessed by VAS. Aromatic lavender essential oil applied by acupressure may reduce subjective pain intensity and improve lateral spine flexion and walking time compared to untreated participants (one trial, 61 participants,very low quality evidence). No significant adverse events were noted within the included trials. AUTHORS' CONCLUSIONS: C. frutescens (Cayenne) reduces pain more than placebo. Although H. procumbens, S. alba, S. officinale L., S. chilensis, and lavender essential oil also seem to reduce pain more than placebo, evidence for these substances was of moderate quality at best. Additional well-designed large trials are needed to test these herbal medicines against standard treatments. In general, the completeness of reporting in these trials was poor. Trialists should refer to the CONSORT statement extension for reporting trials of herbal medicine interventions.

Efficacy and Safety of White Willow Bark (Salix alba) Extracts Shara M, Stohs SJ. Efficacy and Safety of White Willow Bark (Salix alba) Extracts. Phytother Res. 2015 Aug;29(8):1112-6. doi: 10.1002/ptr.5377. Epub 2015 May 22. Review. PubMed PMID: 25997859. Willow bark extract has been used for thousands of years as an anti-inflammatory, antipyretic, and analgesic. In spite of its long history of use, relatively few human and animal studies have been published that confirm anecdotal observations. A small number of clinical studies have been conducted that support the use of willow bark extracts in chronic lower back and joint pain and osteoarthritis. Willow bark extracts also are widely used in sports performance and weight loss products presumably because of anti-inflammatory and analgesic activities, although no human studies have been published that specifically and directly document beneficial effects. In recent years, various in vitro and animal studies have demonstrated that the anti-inflammatory activity of willow bark extract is associated with down regulation of the inflammatory mediators tumor necrosis factor-α and nuclear factor-kappa B. Although willow bark extracts are generally standardized to salicin, other ingredients in the extracts including other salicylates as well as polyphenols, and flavonoids may also play prominent roles in the therapeutic actions. Adverse effects appear to be minimal as compared to non-steroidal anti-inflammatory drugs including aspirin. The primary cause for concern may relate to allergic reactions in salicylate-sensitive individuals.

Natural anti-inflammatory agents for pain relief Maroon JC, Bost JW, Maroon A. Natural anti-inflammatory agents for pain relief. Surgical Neurology International. 2010;1:80. doi:10.4103/2152-7806.73804. The use of both over-the-counter and prescription nonsteroidal medications is frequently recommended in a typical neurosurgical practice. But persistent long-term use safety concerns must be considered when prescribing these medications for chronic and degenerative pain conditions. This article is a literature review of the biochemical pathways of inflammatory pain, the potentially serious side effects of nonsteroidal drugs and commonly used and clinically studied natural alternative anti-inflammatory supplements. Although nonsteroidal medications can be effective, herbs and dietary supplements may offer a safer, and often an effective, alternative treatment for pain relief, especially for long-term use.

Curcumin CLINICAL STUDIES

Effects of turmeric curcuminoids and metformin against central sensitivity to pain in mice Vermaa S, Mundkinajeddub D, Agarwalb A, Chatterjeecd SS, Kumar V. Effects of turmeric curcuminoids and metformin against central sensitivity to pain in mice. Journal of Trad and Compl Med. 2017 Apr. 7(2); 145-51. The reported experimental study was conducted to compare the effects of repeated daily oral doses of curcuminoids (CLE) with metformin as potential antidepressants and analgesics. Effects of a single and ten daily oral doses of CLE (5, 20, 80 mg/kg/day) and of 50 mg/kg/day metformin (MET) were compared in mice hot plate test (HPT) for analgesics. On the 11th treatment day, all animals were subjected to foot shock stress triggered hyperthermia test, and on the 12th treatment day to tail suspension test (TST) for antidepressants. Immediately thereafter, their blood levels of glucose, insulin and cortisol were quantified. Dose dependent analgesic activity of CLE was observed in HPT, whereas the metformin dose tested suppressed only pain hypersensitivity in the test. But statistically significant effects of both of them were observed in TST, and both of them also afforded protections against body weight loss and slight elevation in core temperatures induced by daily handling and repeated testing. CLE or metformin had no significant effects in foot shock stress triggered transient hyperthermic responses or on blood glucose, insulin and cortisol levels. Reported results reveal that curcuminoids as well as metformin are stress response modifiers with antidepressants like activities, but only low dose curcuminoids possess centrally acting analgesics like activities. They suggest that the bio-assay system used in this study is well suited for identifying curcuminoids like plant metabolites with analgesic and anti-stress activities, and that low dose curcuminoids are more effective as analgesics than low dose metformin.

The spice for joint inflammation: anti-inflammatory role of curcumin in treating osteoarthritis Chin K-Y. The spice for joint inflammation: anti-inflammatory role of curcumin in treating osteoarthritis. Drug Design, Development and Therapy. 2016;10:3029-3042. doi:10.2147/DDDT.S117432. Osteoarthritis is a degenerative disease of the joint affecting aging populations worldwide. It has an underlying inflammatory cause, which contributes to the loss of chondrocytes, leading to diminished cartilage layer at the affected joints. Compounds with anti-inflammatory properties are potential treatment agents for osteoarthritis. Curcumin derived from Curcuma species is an anti-inflammatory compound as such. This review aims to summarize the antiosteoarthritic effects of curcumin derived from clinical and preclinical studies. Many clinical trials have been conducted to determine the effectiveness of curcumin in osteoarthritic patients. Extracts of Curcuma species, curcuminoids and enhanced curcumin, were used in these studies. Patients with osteoarthritis showed improvement in pain, physical function, and quality of life after taking curcumin. They also reported reduced concomitant usage of analgesics and side effects during treatment. In vitro studies demonstrated that curcumin could prevent the apoptosis of chondrocytes, suppress the release of proteoglycans and metal metalloproteases and expression of cyclooxygenase, prostaglandin E-2, and inflammatory cytokines in chondrocytes. These were achieved by blocking the activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) system in the chondrocytes, by preventing the activation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha, phosphorylation, and translocation of the p65 subunit of NF-κB complexes into the nucleus. In conclusion, curcumin is a potential candidate for the treatment of osteoarthritis. More well-planned randomized control trials and enhanced curcumin formulation are required to justify the use of curcumin in treating osteoarthritis.

Antinociceptive effects of curcumin in a rat model of postoperative pain Zhu Q, Sun Y, Yun X, Ou Y, Zhang W, Li J-X. Antinociceptive effects of curcumin in a rat model of postoperative pain. Scientific Reports. 2014;4:4932. doi:10.1038/srep04932. Curcumin is a principal ingredient of traditional Chinese medicine, Curcuma Longa, which possesses a variety of pharmacological activities including pain relief. Preclinical studies have demonstrated that curcumin has antinociceptive effects for inflammatory and neuropathic pain. This study examined the effects of curcumin in a rat model of postoperative pain. A surgical incision on the right hind paw induced a sustained mechanical hyperalgesia that lasted for 5 days. Acute curcumin treatment (10–40 mg/kg, p.o) significantly and dose dependently reversed mechanical hyperalgesia. In addition, repeated curcumin treatment significantly facilitated the recovery from surgery. In contrast, repeated treatment with curcumin before surgery did not impact the postoperative pain threshold and recovery rate. All the doses of curcumin did not significantly alter the spontaneous locomotor activity. Combined, these results suggested that curcumin could alleviate postoperative pain and promote recovery from the surgery, although there was no significant preventive value. This study extends previous findings and supports the application of curcumin alone or as an adjunct therapy for the management of peri-operative pain.

Natural anti-inflammatory agents for pain relief Maroon JC, Bost JW, Maroon A. Natural anti-inflammatory agents for pain relief. Surgical Neurology International. 2010;1:80. doi:10.4103/2152-7806.73804. The use of both over-the-counter and prescription nonsteroidal medications is frequently recommended in a typical neurosurgical practice. But persistent long-term use safety concerns must be considered when prescribing these medications for chronic and degenerative pain conditions. This article is a literature review of the biochemical pathways of inflammatory pain, the potentially serious side effects of nonsteroidal drugs and commonly used and clinically studied natural alternative anti-inflammatory supplements. Although nonsteroidal medications can be effective, herbs and dietary supplements may offer a safer, and often an effective, alternative treatment for pain relief, especially for long-term use.

Meriva®+Glucosamine versus Condroitin+Glucosamine in patients with knee osteoarthritis: an observational study Belcaro G, et al. Meriva®+Glucosamine versus Condroitin+Glucosamine in patients with knee osteoarthritis: an observational study. Eur Rev Med Pharmacol Sci. 2014;18(24):3959-63. PubMed PMID: 25555891. OBJECTIVE: Osteoarthritis (OA) is a major cause of physical disability and impaired quality of life. Non-steroidal anti-inflammatory drugs are the most used treatment for OA, but they are frequently associated to adverse events. Alternative therapies are under investigation for the treatment of OA. Meriva® is a lecithin delivery form of curcumin, a powerful promoter of anti-oxidant response studied in a number of conditions related to chronic inflammation and pain. PATIENTS AND METHODS: This 4-month observational study, conducted in a 'real-life' scenario, compares the association of Meriva and glucosamine (n=63) with chondroitin sulphate+glucosamine (n=61) in 124 patients with grade 1-2 OA of the knee. RESULTS: Patients treated with Meriva+glucosamine had significantly higher Karnofsky Index and WOMAC score (both in the physical and emotional domains), compared to those in the chondroitin+glucosamine group. Noteworthy, the walking distance at the treadmill test after 1 month was also significantly higher in the meriva+glucosamine group; this advantage was sustained until the end of the study. Although the need for concomitant drugs and medical attention decreased in both groups, this reduction was more evident for patients treated with Meriva+glucosamine. CONCLUSIONS: Taken together, the results of this study shows that the 4-month administration of the association of Meriva and glucosamine can result in a faster onset of action and improved outcomes than the administration of an association of chondroitin sulphate and glucosamine in patients with OA.

Bromelain CLINICAL STUDIES

Therapeutic uses of pineapple-extracted bromelain in surgical care - A review Muhammad ZA, Ahmad T. Therapeutic uses of pineapple-extracted bromelain in surgical care - A review. J Pak Med Assoc. 2017 Jan;67(1):121-125. PubMed PMID: 28065968. Bromelain is an extract obtained from the pineapple plant and is used as a traditional folk remedy for several ailments. In this review, a comprehensive electronic database search was carried out to compile available literature on therapeutic implications of bromelain. Pharmaceutical value of bromelain has been demonstrated in different surgical sub-specialties. Diverse biological processes like anti-inflammatory, anti-oedematous, analgesic, anti-thrombotic, exfoliation etc. are involved in bromelain's therapeutic actions, mediated through the kallikrein-kinin and arachidonic acid pathways as well as through effects on cell mediated immunity. Bromelain equals non-steroidal anti-inflammatory drugs as an anti-inflammatory agent, but has been shown to have fewer side effects. In Europe it is approved for oral and topical use, mainly for surgical wounds, inflammation due to trauma and surgery, and debridement of deep burns. Literature suggests a promising role of bromelain in surgical care. More clinical trials to establish its utility as an anti-inflammatory agent in surgical care are recommended.

Properties and Therapeutic Application of Bromelain: A Review Pavan R, Jain S, Shraddha, Kumar A. Properties and Therapeutic Application of Bromelain: A Review. Biotechnology Research International. 2012;2012:976203. doi:10.1155/2012/976203. Bromelain belongs to a group of protein digesting enzymes obtained commercially from the fruit or stem of pineapple. Fruit bromelain and stem bromelainare prepared differently and they contain different enzymatic composition. “Bromelain” refers usually to the “stem bromelain.” Bromelain is a mixture of different thiol endopeptidases and other components like phosphatase, glucosidase, peroxidase, cellulase, escharase, and several protease inhibitors. In vitro and in vivo studies demonstrate that bromelain exhibits various fibrinolytic, antiedematous, antithrombotic, and anti-inflammatory activities. Bromelain is considerably absorbable in the body without losing its proteolytic activity and without producing any major side effects. Bromelain accounts for many therapeutic benefits like the treatment of angina pectoris, bronchitis, sinusitis, surgical trauma, and thrombophlebitis, debridement of wounds, and enhanced absorption of drugs, particularly antibiotics. It also relieves osteoarthritis, diarrhea, and various cardiovascular disorders. Bromelain also possesses some anticancerous activities and promotes apoptotic cell death. This paper reviews the important properties and therapeutic applications of bromelain, along with the possible mode of action.

Bromelain as a Treatment for Osteoarthritis: a Review of Clinical Studies Brien S, Lewith G, Walker A, Hicks SM, Middleton D. Bromelain as a Treatment for Osteoarthritis: a Review of Clinical Studies. Evidence-based Complementary and Alternative Medicine. 2004;1(3):251-257. doi:10.1093/ecam/neh035. Bromelain, an extract from the pineapple plant, has been demonstrated to show anti-inflammatory and analgesic properties and may provide a safer alternative or adjunctive treatment for osteoarthritis. All previous trials, which have been uncontrolled or comparative studies, indicate its potential use for the treatment of osteoarthritis. This paper reviews the mechanism of its putative therapeutic actions, those clinical trials that have assessed its use in osteoarthritis to date, as well as considering the safety implications of this supplement for osteoarthritis and reviewing the evidence to date regarding the dosage for treating this condition. The data available at present indicate the need for trials to establish the efficacy and optimum dosage for bromelain and the need for adequate prospective adverse event monitoring in such chronic conditions as osteoarthritis.

A complex of three natural anti-inflammatory agents provides relief of osteoarthritis pain. Conrozier T, Mathieu P, Bonjean M, Marc JF, Renevier JL, Balblanc JC. A complex of three natural anti-inflammatory agents provides relief of osteoarthritis pain. Altern Ther Health Med. 2014 Winter;20 Suppl 1:32-7. PubMed PMID: 24473984. Devil's claw (Harpagophytum procumbens), turmeric (Curcuma longa), and bromelain are nutraceuticals that have demonstrated anti-inflammatory and analgesic properties and may be potential solutions in the treatment of acute or chronic joint pain. Their analgesic effect, however, is generally considered mild to moderate, and the relevance of their clinical use remains subject to discussion. The aim of the study was to evaluate the clinical relevance of the efficacy of a marketed complex of 3 plant extracts-H procumbens, C longa, and bromelain (AINAT, 650 mg)-in the treatment of degenerative joint pain The improvement of joint pain was clinically relevant in patients treated with AINAT for both acute and chronic OA pain. Considering its excellent tolerance profile, the tested complex of 3 plant extracts with antiinflammatory properties may be a valuable and safe alternative to NSAIDs in patients suffering from degenerative joint diseases.

Vitamin C (Ascorbic Acid) CLINICAL STUDIES

Effect of vitamin C on prevention of complex regional pain syndrome type I in foot and ankle surgery Besse JL, Gadeyne S, Galand-Desmé S, Lerat JL, Moyen B. Effect of vitamin C on prevention of complex regional pain syndrome type I in foot and ankle surgery. Foot Ankle Surg. 2009;15(4):179-82. doi: 10.1016/j.fas.2009.02.002. Epub 2009 Apr 5. PubMed PMID: 19840748. BACKGROUND: The public health cost impact of complex regional pain syndrome type I (CRPS I) is considerable in both emergency and scheduled orthopaedic surgery. We proposed to assess the effectiveness of vitamin C in prevention of CRPS I in foot and ankle surgery. METHODS: We carried out a "before-after" quasi-experimental study comparing two chronologically successive groups without (Group I: July 2002-June 2003) and with (Group II: July 2003-June 2004) preventive 1g daily vitamin C treatment. All patients having surgery on the foot or ankle were enrolled, with the exception of diabetic foot cases. Several factors were analysed: sex, age, type of pathology, history of CRPS I, psychological context, tourniquet time, and cast immobilisation time. RESULTS: 420 feet (392 patients) were included in the study: 185 in Group I, 235 in Group II. CRPS I occurred in 18 cases in Group I (9.6%) and 4 cases in Group II (1.7%) (p<10(-4)), with history of CRPS I as a significantly correlated factor (relative risk=10.4). The psychological context (anxio-depressive state) showed a (sub-significant) tendency to increase the risk of CRPS I (relative risk=2.6). CONCLUSION: Vitamin C has been shown to be effective in preventing CRPS I secondary to wrist fracture, but few data are available with respect to foot and ankle cases. The present study demonstrates the effectiveness of vitamin C in preventing CRPS I of the foot and ankle-a frequent complication in our control group (9.6%). The authors recommend preventive management by vitamin C.

Plantar Fasciitis: A Case Review Ross C, Prousky J. Plantar Fasciitis: A Case Review. 2016. Journal of Ortho Med. 16 (1). Supporting the integrity of the fascia by supplying copper and vitamin C may re-regulate disordered fibroblastic activity by promoting healthy connective tissue formation. Improving fibroblastic activity may be a factor in alleviating fibrosis formation and/or the pain associated with plantar fasciitis.

The role of vitamin C in the treatment of pain: new insights Carr AC, McCall C. The role of vitamin C in the treatment of pain: new insights. J Transl Med. 2017 Apr 14;15(1):77. doi: 10.1186/s12967-017-1179-7. Review. PubMed PMID: 28410599; PubMed Central PMCID: PMC5391567. The vitamin C deficiency disease scurvy is characterised by musculoskeletal pain and recent epidemiological evidence has indicated an association between suboptimal vitamin C status and spinal pain. Furthermore, accumulating evidence indicates that vitamin C administration can exhibit analgesic properties in some clinical conditions. The prevalence of hypovitaminosis C and vitamin C deficiency is high in various patient groups, such as surgical/trauma, infectious diseases and cancer patients. A number of recent clinical studies have shown that vitamin C administration to patients with chronic regional pain syndrome decreases their symptoms. Acute herpetic and post-herpetic neuralgia is also diminished with high dose vitamin C administration. Furthermore, cancer-related pain is decreased with high dose vitamin C, contributing to enhanced patient quality of life. A number of mechanisms have been proposed for vitamin C's analgesic properties. Herein we propose a novel analgesic mechanism for vitamin C; as a cofactor for the biosynthesis of amidated opioid peptides. It is well established that vitamin C participates in the amidation of peptides, through acting as a cofactor for peptidyl-glycine α-amidating monooxygenase, the only enzyme known to amidate the carboxy terminal residue of neuropeptides and peptide hormones. Support for our proposed mechanism comes from studies which show a decreased requirement for opioid analgesics in surgical and cancer patients administered high dose vitamin C. Overall, vitamin C appears to be a safe and effective adjunctive therapy for acute and chronic pain relief in specific patient groups.

Vitamin D (Cholecalciferol) CLINICAL STUDIES

Vitamin D supplementation for patients with chronic pain Kragstrup TW. Vitamin D supplementation for patients with chronic pain. Scandinavian Journal of Primary Health Care. 2011;29(1):4-5. doi:10.3109/02813432.2010.530738. A study in a previous issue of the Scandinavian Journal of Primary Health Care (SJPHC) adds to the growing list of publications on vitamin D as a possible treatment for chronic pain. It describes a high prevalence of hypovitaminosis D in patients with non-specific musculoskeletal pain, headache, and fatigue. The conclusion is that general practitioners should maintain awareness of hypovitaminosis D in these patients. The authors are, however, aware that firm conclusions regarding cause and effect cannot be based on a cross-sectional study, which leaves plenty of room for confounding. Vitamin D supply is defined by sun exposure and dietary intake, which may be affected by work, economy, culture, diseases etc. Similarly, chronic pain may be affected by work, economy, culture, diseases etc. It seems reasonable to use vitamin D supplementation (with or without previous measurement of the vitamin D status) with up to 50 μg (2.000 IU) daily for patients with chronic pain. The supplement may not be a cure for the pain, but the study in the SJPHC demonstrates that low levels of vitamin D are common in this group of patients. The treatment is cheap, relatively safe, and there is emerging evidence that vitamin D supplementation has positive effects on public health. Underlying conditions causing the chronic pain should be diagnosed irrespective of vitamin D status.

Vitamin D Deficiency and Pain: Clinical Evidence of Low Levels of Vitamin D and Supplementation in Chronic Pain States Shipton EE, Shipton EA. Vitamin D Deficiency and Pain: Clinical Evidence of Low Levels of Vitamin D and Supplementation in Chronic Pain States. Pain and Therapy. 2015;4(1):67-87. doi:10.1007/s40122-015-0036-8. A number of studies suggest a link between low levels of 25-hydroxy vitamin D and incidence of acute and chronic pain. Clinical studies of vitamin D supplementation in patients with known vitamin D deficiency have shown mixed results in improving pain scores. There remains a growing body of both clinical and laboratory evidence pointing to a potential relationship between low levels of 25-hydroxy vitamin D and a variety of chronic pain states. More focused research involving large RCTs is necessary.

Vitamin D Deficiency, Prevention and Treatment Iraj B, Ebneshahidi A, Askari G. Vitamin D Deficiency, Prevention and Treatment. International Journal of Preventive Medicine. 2012;3(10):733-736. Case Study Result: The serum of 25 (OH) D was 42 ng/ml and the PTH was 70 Pg/ml. As it is known, the secondary hyperparathyroidism due to vitamin D deficiency improves after 6-12 months of treatment with vitamin D. Therefore, the serum PTH level in this patient is not worrisome. Therefore, the maintenance therapy in this patient continued and after 3 months of the treatment the patient reported sense of wellbeing and the low back pain and the throbbing bone pain totally resolved.

Unrecognised severe vitamin D deficiency Sievenpiper JL, McIntyre EA, Verrill M, Quinton R, Pearce SHS. Unrecognised severe vitamin D deficiency. BMJ : British Medical Journal. 2008;336(7657):1371-1374. doi:10.1136/bmj.39555.820394.BE. Although persistent, non-specific musculoskeletal pains and weakness may represent a unifying set of features, this overlap with other rheumatological conditions, as well as depression, necessitates a high index of suspicion in the diagnosis of hypovitaminosis D.

Vitamin D Deficiency Promotes Skeletal Muscle Hypersensitivity and Sensory Hyperinnervation Tague SE, et al. Vitamin D Deficiency Promotes Skeletal Muscle Hypersensitivity and Sensory Hyperinnervation. The Journal of Neuroscience. 2011;31(39):13728-13738. doi:10.1523/JNEUROSCI.3637-11.2011. Musculoskeletal pain affects nearly half of all adults, most of whom are vitamin D deficient. Previous findings demonstrated that putative nociceptors (“pain-sensing” nerves) express vitamin D receptors (VDRs), suggesting responsiveness to 1,25-dihydroxyvitamin D. In the present study, rats receiving vitamin D-deficient diets for 2– 4 weeks showed mechanical deep muscle hypersensitivity, but not cutaneous hypersensitivity. Muscle hypersensitivity was accompanied by balance deficits and occurred before onset of overt muscle or bone pathology. Hypersensitivity was not due to hypocalcemia and was actually accelerated by increased dietary calcium. Morphometry of skeletal muscle innervation showed increased numbers of presumptive nociceptor axons (peripherin-positive axons containing calcitonin gene-related peptide), without changes in sympathetic or skeletal muscle motor innervation. Similarly, there was no change in epidermal innervation. In culture, sensory neurons displayed enriched VDR expression in growth cones, and sprouting was regulated by VDR-mediated rapid response signaling pathways, while sympathetic outgrowth was not affected by different concentrations of 1,25-dihydroxyvitamin D. These findings indicate that vitamin D deficiency can lead to selective alterations in target innervation, resulting in presumptive nociceptor hyperinnervation of skeletal muscle, which in turn is likely to contribute to muscular hypersensitivity and pain.

Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study Kanzaki N, Ono Y, Shibata H, Moritani T. Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study. Clin Interv Aging. 2015 Oct 28;10:1743-53. doi: 10.2147/CIA.S93077. eCollection 2015. PubMed PMID: 26604721; PubMed Central PMCID: PMC4631410. BACKGROUND: The aim of this study was to investigate the ability of a glucosamine-containing supplement to improve locomotor functions in subjects with knee pain. METHODS: A randomized, double-blind, placebo-controlled, parallel-group comparative study was conducted for 16 weeks in 100 Japanese subjects (age, 51.8±0.8 years) with knee pain. Subjects were randomly assigned to one of the two supplements containing 1) 1,200 mg of glucosamine hydrochloride, 60 mg of chondroitin sulfate, 45 mg of type II collagen peptides, 90 mg of quercetin glycosides, 10 mg of imidazole peptides, and 5 μg of vitamin D per day (GCQID group, n=50) or 2) a placebo (placebo group, n=50). Japanese Knee Osteoarthritis Measure, visual analog scale score, normal walking speed, and knee-extensor strength were measured to evaluate the effects of the supplement on knee-joint functions and locomotor functions. RESULTS: In subjects eligible for efficacy assessment, there was no significant group × time interaction, and there were improvements in knee-joint functions and locomotor functions in both groups, but there was no significant difference between the groups. In subjects with mild-to-severe knee pain at baseline, knee-extensor strength at week 8 (104.6±5.0% body weight vs 92.3±5.5% body weight, P=0.030) and the change in normal walking speed at week 16 (0.11±0.03 m/s vs 0.05±0.02 m/s, P=0.038) were significantly greater in the GCQID group than in the placebo group. Further subgroup analysis based on Kellgren-Lawrence (K-L) grade showed that normal walking speed at week 16 (1.36±0.05 m/s vs 1.21±0.02 m/s, P<0.05) was significantly greater in the GCQID group than in the placebo group in subjects with K-L grade I. No adverse effect of treatment was identified in the safety assessment. CONCLUSION: In subjects with knee pain, GCQID supplementation was effective for relieving knee pain and improving locomotor functions.

Vitamin B12 (Methylcobalamin) CLINICAL STUDIES

Sustained-release pregabalin with methylcobalamin in neuropathic pain: an Indian real-life experience Dongre YU, Swami OC. Sustained-release pregabalin with methylcobalamin in neuropathic pain: an Indian real-life experience. International Journal of General Medicine. 2013;6:413-417. doi:10.2147/IJGM.S45271. Introduction Neuropathic pain is intense in nature and difficult to manage. Thus, the primary goal is maximum relief from pain. The aim of this study was to assess the efficacy and safety of a fixed-dose combination of sustained-release pregabalin and methylcobalamin in reducing neuropathic pain in Indian patients, in the real-life situation. Methods This was a multicenter, prospective, open-labeled, single-arm, observational, 14-day study. Patients received fixed dose combination of 75 or 150 mg sustained-release pregabalin combined with 1500 mcg immediate release methylcobalamin, depending on the clinical requirement. Data was collected for pain reduction and other positive and negative symptoms associated with neuropathy, including hyperesthesia, paresthesia, numbness/tingling, burning sensation, muscle weakness, sleep disturbances, and impairment of movement. Pain intensity was measured on a ten-point visual analog scale (VAS) (0 represented “no pain,” and 10 represented “worst pain ever”). The safety of the drug was also evaluated throughout the study duration. Data was analyzed using appropriate statistical methods. Results The overall reduction in mean VAS score over 14 days was 72.3%. The reduction in mean VAS score was significant as early as the first week. Both positive and negative symptoms of peripheral neuropathy were significantly improved in >50% patients within the 2 weeks. Giddiness (4.7%), followed by sedation (3.6%), dizziness (2.9%), drowsiness (2.3%), and nausea (2.3%) were the most commonly observed adverse effects. The overall efficacy and tolerability was rated as good to excellent by >95% of the investigators and patients. Conclusion Fixed dose combination of sustained-release pregabalin and methylcobalamin significantly reduced neuropathic pain, with significant improvement in both the positive and negative symptoms associated with neuropathy, in Indian patients and was well tolerated.

Methylcobalamin: A Potential Vitamin of Pain Killer Zhang M, Han W, Hu S, Xu H. Methylcobalamin: A Potential Vitamin of Pain Killer. Neural Plasticity. 2013;2013:424651. doi:10.1155/2013/424651. Methylcobalamin (MeCbl), the activated form of vitamin B12, has been used to treat some nutritional diseases and other diseases in clinic, such as Alzheimer's disease and rheumatoid arthritis. As an auxiliary agent, it exerts neuronal protection by promoting regeneration of injured nerves and antagonizing glutamate-induced neurotoxicity. Recently several lines of evidence demonstrated that MeCbl may have potential analgesic effects in experimental and clinical studies. For example, MeCbl alleviated pain behaviors in diabetic neuropathy, low back pain and neuralgia. MeCbl improved nerve conduction, promoted the regeneration of injured nerves, and inhibited ectopic spontaneous discharges of injured primary sensory neurons. This review aims to summarize the analgesic effect and mechanisms of MeCbl at the present.

B complex vitamins for analgesic therapy Gazoni FM, Malezan WR, Santos FC. B complex vitamins for analgesic therapy. 2016. Revista Dor, 17(1), 52-56. https://dx.doi.org/10.5935/1806-0013.20160013 The B complex vitamins have been used as single therapy or combined to other drugs, such as anti-inflammatory drugs, in different clinical situations, such as degenerative spinal diseases, rheumatologic diseases, polyneuropathies and in different postoperative situations. This study aimed at identifying in the scientific literature most recent evidences of the use of B complex vitamins as analgesic therapy and at describing clinical situations where their analgesic action could be observed. Existing studies, although scarce and heterogeneous, have shown that B complex vitamins have analgesic effect. They are considered safe and have low cost and have shown to be a good option as adjuvant analgesic therapy.

Magnesium Bisglycinate Chelate CLINICAL STUDIES

Randomised, cross-over, placebo controlled trial of magnesium citrate in the treatment of chronic persistent leg cramps Roffe C, Sills S, Crome P, Jones P. Randomised, cross-over, placebo controlled trial of magnesium citrate in the treatment of chronic persistent leg cramps. Med Sci Monit. 2002 May;8(5):CR326-30. PubMed PMID: 12011773. BACKGROUND: Nocturnal leg cramps are common and distressing. The only treatment of proven effectiveness is quinine, but this has a number of side effects. Magnesium salts have been shown to reduce leg cramp distress in pregnancy. This study tests whether magnesium citrate is effective in the treatment of leg cramps in non-pregnant individuals by conducting in a randomised, double-blind, cross-over placebo-controlled trial. MATERIAL/METHODS: Volunteers suffering regular leg cramps were recruited. Magnesium citrate equivalent to 300 mg magnesium and matching placebo were given for 6 weeks each. The number of cramps recorded in the cramp diary during the final 4 weeks of magnesium and placebo treatment, severity and duration of cramps and the participants' subjective assessment of effectiveness were analysed. RESULTS: In subjects who started with placebo (n=29) the median (95% CI) number of cramps was 9 (6-17) on placebo and 5 (4-8) on magnesium. For the group starting with magnesium (n=17) the median no of cramps was 9 (5-13) on magnesium and 8 (4-14) on placebo. There was no significant carry-over effect (p=0.88), but a highly significant period effect (p=0.008). There was a trend towards less cramps on magnesium (p=0.07). There was no difference in cramp severity and duration between the groups. Significantly more subjects thought that the treatment had helped after magnesium than after placebo 36 (78%) and 25 (54%) respectively, (p=0.03). Diarrhoea was recorded as a side effect of magnesium. CONCLUSIONS: The results suggest that magnesium may be effective in treatment of nocturnal leg cramps. Further evaluation is recommended.

Supplementation with alkaline minerals reduces symptoms in patients with chronic low back pain. Vormann J, Worlitschek M, Goedecke T, Silver B. Supplementation with alkaline minerals reduces symptoms in patients with chronic low back pain. J Trace Elem Med Biol. 2001;15(2-3):179-83. PubMed PMID: 11787986. The cause of low back pain is heterogeneous, it has been hypothesised that a latent chronic acidosis might contribute to these symptoms. It was tested whether a supplementation with alkaline minerals would influence symptoms in patients with low back pain symptoms. In an open prospective study 82 patients with chronic low back pain received daily 30 g of a lactose based alkaline multimineral supplement (Basica) over a period of 4 weeks in addition to their usual medication. Pain symptoms were quantified with the "Arhus low back pain rating scale" (ARS). Mean ARS dropped highly significant by 49% from 41 to 21 points after 4 weeks supplemention. In 76 out of 82 patients a reduction in ARS was achieved by the supplementation. Total blood buffering capacity was significantly increased from 77.69 +/- 6.79 to 80.16 +/- 5.24 mmol/L (mean +/- SEM, n = 82, p < 0.001) and also blood pH rose from 7.456 +/- 0.007 to 7.470 +/- 0.007 (mean +/- SEM, n = 75, p < 0.05). Only intracellular magnesium increased by 11% while other intracellular minerals were not significantly changed in sublingual tissue as measured with the EXA-test. Plasma concentrations of potassium, calcium, iron, copper, and zinc were within the normal range and not significantly influenced by the supplementation. Plasma magnesium was slightly reduced after the supplemenation (-3%, p < 0.05). The results show that a disturbed acid-base balance may contribute to the symptoms of low back pain. The simple and safe addition of an alkaline multimineral preparate was able to reduce the pain symptoms in these patients with chronic low back pain..

MAGnesium-oral supplementation to reduce PAin in patients with severe PERipheral arterial occlusive disease: the MAG-PAPER randomised clinical trial protocol Venturini MA, Zappa S, Minelli C, et al. MAGnesium-oral supplementation to reduce PAin in patients with severe PERipheral arterial occlusive disease: the MAG-PAPER randomised clinical trial protocol. BMJ Open. 2015;5(12):e009137. doi:10.1136/bmjopen-2015-009137. Magnesium exerts analgaesic effects in several animal pain models, as well as in patients affected by acute postoperative pain and neuropathic chronic pain. There is no evidence that magnesium can modulate pain in patients with peripheral arterial occlusive disease (PAOD). We describe the protocol of a single-centre randomised double-blind clinical trial aimed at assessing the efficacy of oral magnesium supplementation in controlling severe pain in patients with advanced PAOD.

Manganese Bisglycinate Chelate (TRAACS) CLINICAL STUDIES

Retooling Manganese(III) Porphyrin-Based Peroxynitrite Decomposition Catalysts for Selectivity and Oral Activity: A Potential New Strategy for Treating Chronic Pain Rausaria S, Ghaffari MME, Kamadulski A, et al. Retooling Manganese(III) Porphyrin-Based Peroxynitrite Decomposition Catalysts for Selectivity and Oral Activity: A Potential New Strategy for Treating Chronic Pain. Journal of medicinal chemistry. 2011;54(24):8658-8669. doi:10.1021/jm201233r. Redox-active metalloporphyrins represent the most well characterized class of catalysts capable of attenuating oxidative stress in vivo through the direct interception and decomposition of superoxide and peroxynitrite. While many interesting pharmacological probes have emerged from these studies, few catalysts have been developed with pharmaceutical properties in mind. Herein we describe our efforts to identify new Mn(III)-porphyrin systems with enhanced membrane solubilizing properties. To this end seven new Mn(III)-tetracyclohexenylporphyin (TCHP) analogues 7, 10, 12, 15, 16a–c have been prepared in which the beta-fused cyclohexenyl rings provide a means to shield the charged metal center from the membrane during passive transport. Compounds 7, 15, and 16a–c have been shown to be orally active and potent analgesics in a model of carrageenan-induced thermal hyperalgesia. In addition oral administration of compound 7 (10–100 mg/kg, n = 5) has been shown to dose dependently reverse mechano-allodynia in the CCI model of chronic neuropathic pain.

Zinc Glycinate Chelate (TRAACS) CLINICAL STUDIES

Zinc alleviates pain through high-affinity binding to the NMDA receptor NR2A subunit Nozaki C, Vergnano AM, Filliol D, et al. Zinc alleviates pain through high-affinity binding to the NMDA receptor NR2A subunit. Nature neuroscience. 2011;14(8):1017-1022. doi:10.1038/nn.2844. Zinc is abundant in the central nervous system and regulates pain, but the underlying mechanisms are unknown. In vitro studies have shown that extracellular zinc modulates a plethora of signaling membrane proteins, including NMDA receptors containing the NR2A subunit, which display exquisite zinc sensitivity. We created NR2A-H128S knock-in mice to investigate whether Zn2+–NR2A interaction influences pain control. In these mice, high-affinity (nanomolar) zinc inhibition of NMDA currents was lost in the hippocampus and spinal cord. Knock-in mice showed hypersensitivity to radiant heat and capsaicin, and developed enhanced allodynia in inflammatory and neuropathic pain models. Furthermore, zinc-induced analgesia was completely abolished under both acute and chronic pain conditions. Our data establish that zinc is an endogenous modulator of excitatory neurotransmission in vivo and identify a new mechanism in pain processing that relies on NR2A NMDA receptors. The study also potentially provides a molecular basis for the pain-relieving effects of dietary zinc supplementation.

Hyaluronic acid (from Sodium Hyaluronate) CLINICAL STUDIES

The effects of an oral preparation containing hyaluronic acid (Oralvisc®) on obese knee osteoarthritis patients determined by pain, function, bradykinin, leptin, inflammatory cytokines, and heavy water analyses Nelson FR, et al. The effects of an oral preparation containing hyaluronic acid (Oralvisc®) on obese knee osteoarthritis patients determined by pain, function, bradykinin, leptin, inflammatory cytokines, and heavy water analyses. Rheumatol Int. 2015 Jan;35(1):43-52. doi: 10.1007/s00296-014-3047-6. Epub 2014 Jun 5. Erratum in: Rheumatol Int. 2015 Jan;35(1):53. PubMed PMID: 24899570. The purpose of this study was to determine the effects of an oral preparation containing hyaluronic acid on osteoarthritic knee joint pain and function as well as changes in inflammatory cytokines, bradykinin, and leptin. We also used heavy water to determine the turnover rates of glycosaminoglycans in synovial fluid. This was a double-blind, randomized, placebo-controlled study of 40 subjects over a period of 3 months. Visual analog scale, Western Ontario McMaster pain, and WOMAC function scores were recorded. Serum and synovial fluid were measured by enzyme-linked immunosorbent assays for inflammatory cytokines, bradykinin, and leptin. In 20 subjects, terminal heavy water ingestion was used for spectral analyses of serum and joint fluid samples. There were statistically significant improvements in pain and function. Both serum and synovial fluid samples showed significant decreases for a majority of inflammatory cytokines, leptin, and bradykinin in the oral hyaluronic acid preparation group. Heavy water analyses revealed a significant decrease in hyaluronic acid turnover in the synovial fluid of the treatment group. A preparation containing hyaluronic acid and other glycosaminoglycans holds promise for a safe and effective agent for the treatment for patients with knee osteoarthritis and who are overweight. Further studies will be required to see whether this is a disease-modifying agent.

The effectiveness of hyaluronic acid intra-articular injections in managing osteoarthritic knee pain Trigkilidas D, Anand A. The effectiveness of hyaluronic acid intra-articular injections in managing osteoarthritic knee pain. Ann R Coll Surg Engl. 2013 Nov;95(8):545-51. doi: 10.1308/003588413X13629960049432. Review. PubMed PMID: 24165334; PubMed Central PMCID: PMC4311527. INTRODUCTION: Knee osteoarthritis (OA) is a common and progressive joint disease. Treatment options for knee OA vary from simple analgesia in mild cases to knee replacement for advanced disease. Knee pain due to moderate OA can be targeted with intra-articular injections. Steroid injections have been used widely in managing acute flare-ups of the disease. In recent years, viscosupplementation has been used as a therapeutic modality for the management of knee OA. The principle of viscosupplementation is based on the physiological properties of the hyaluronic acid (HA) in the synovial joint. Despite a sound principle and promising in vitro studies, clinical studies have been less conclusive on the effectiveness of HA in managing osteoarthritic knee pain. The aim of this systematic review was to assess the effectiveness of HA intra-articular injections in the management of osteoarthritic knee pain. METHODS: A systematic review of the literature was performed using MEDLINE®, Embase™ and CINAHL® (Cumulative Index to Nursing and Allied Health Literature). The databases were searched for randomised controlled trials available on the effectiveness of HA intra-articular injections in managing osteoarthritic knee pain. RESULTS: The search yielded 188 studies. Of these, 14 met the eligibility criteria and were reviewed in chronological order. CONCLUSIONS: HA intra-articular injections have a modest effect on early to moderate knee OA. The effect peaks at around 6-8 weeks following administration, with a doubtful effect at 6 months.

MSM (Methyl Sulfonyl Methane) CLINICAL STUDIES

Effects of MSM on exercise-induced muscle and joint pain: a pilot study Withee ED, Tippens KM, Dehen R, Hanes D. Effects of MSM on exercise-induced muscle and joint pain: a pilot study. Journal of the International Society of Sports Nutrition. 2015;12(Suppl 1):P8. doi:10.1186/1550-2783-12-S1-P8. Exercise-induced muscle pain and joint pain increase within 15 minutes of completing a half-marathon, continue through the following day, and diminish approximately two days post-race. Three weeks of MSM supplementation at 3g/day attenuated post-exercise muscle and joint pain at clinically significant levels compared to placebo. However, the pain reductions did not reach statistical significance, warranting further research on MSM and post-exercise pain among larger samples.

Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial Kim LS, Axelrod LJ, Howard P, Buratovich N, Waters RF. Efficacy of methylsulfonylmethane (MSM) in osteoarthritis pain of the knee: a pilot clinical trial. Osteoarthritis and Cartilage. 2006 Mar. 14(3); 286-94. MSM (3 g twice a day) improved symptoms of pain and physical function during the short intervention without major adverse events. The benefits and safety of MSM in managing OA and long-term use cannot be confirmed from this pilot trial, but its potential clinical application is examined. Underlying mechanisms of action and need for further investigation of MSM are discussed.

Evaluation of the Effect of Mega MSM on Improving Joint Function in Populations Experiencing Joint Degeneration Xu G, et al. Evaluation of the Effect of Mega MSM on Improving Joint Function in Populations Experiencing Joint Degeneration. Int J Biomed Sci. 2015 Jun;11(2):54-60. PubMed PMID: 26199577; PubMed Central PMCID: PMC4502733. Joint degeneration has become a commonplace problem in aging populations. The main clinical manifestations include joint pain, joint stiffness and joint swelling with functional disorder. Mega MSM is a nutritional supplement that may provide potential relief for joint problems associated with joint degeneration. The current experiment performed was a 12-week, randomized, double-blind, controlled study conducted on populations in China experiencing joint degeneration. The objective of the study was to determine whether the daily use of Mega MSMcapsules could improve joint function, relieve symptoms of joint degeneration and improve the quality of life in aging populations. A total of 100 male and female participants over 50 years old who had at least one of the related symptoms of joint degeneration (joint pain, joint stiffness, joint swelling, difficulty walking, difficulty getting up from bed and difficulty going down stairs) were recruited and their symptoms of joint degeneration before and after the intervention were recorded. In this study, Mega MSM shows positive effects in improving joint function, relieving symptoms associated with joint degeneration and improving the quality of life in aging populations.

Hydrolyzed Collagen CLINICAL STUDIES

Daily oral consumption of hydrolyzed type 1 collagen is chondroprotective and anti-inflammatory in murine posttraumatic osteoarthritis Dar QA, et al. Daily oral consumption of hydrolyzed type 1 collagen is chondroprotective and anti-inflammatory in murine posttraumatic osteoarthritis. PLoS One. 2017 Apr 6;12(4):e0174705. doi: 10.1371/journal.pone.0174705. eCollection 2017. PubMed PMID: 28384173; PubMed Central PMCID: PMC5383229. Osteoarthritis (OA) is a degenerative joint disease for which there are no disease modifying therapies. Thus, strategies that offer chondroprotective or regenerative capability represent a critical unmet need. Recently, oral consumption of a hydrolyzed type 1 collagen (hCol1) preparation has been reported to reduce pain in human OA and support a positive influence on chondrocyte function. To evaluate the tissue and cellular basis for these effects, we examined the impact of orally administered hCol1 in a model of posttraumatic OA (PTOA). In addition to standard chow, male C57BL/6J mice were provided a daily oral dietary supplement of hCol1 and a meniscal-ligamentous injury was induced on the right knee. At various time points post-injury, hydroxyproline (hProline) assays were performed on blood samples to confirm hCol1 delivery, and joints were harvested for tissue and molecular analyses were performed, including histomorphometry, OARSI and synovial scoring, immunohistochemistry and mRNA expression studies. Confirming ingestion of the supplements, serum hProline levels were elevated in experimental mice administered hCol1. In the hCol1 supplemented mice, chondroprotective effects were observed in injured knee joints, with dose-dependent increases in cartilage area, chondrocyte number and proteoglycan matrix at 3 and 12 weeks post-injury. Preservation of cartilage and increased chondrocyte numbers correlated with reductions in MMP13 protein levels and apoptosis, respectively. Supplemented mice also displayed reduced synovial hyperplasia that paralleled a reduction in Tnf mRNA, suggesting an anti-inflammatory effect. These findings establish that in the context of murine knee PTOA, daily oral consumption of hCol1 is chondroprotective, anti-apoptotic in articular chondrocytes, and anti-inflammatory. While the underlying mechanism driving these effects is yet to be determined, these findings provide the first tissue and cellular level information explaining the already published evidence of symptom relief supported by hCol1 in human knee OA. These results suggest that oral consumption of hCol1 is disease modifying in the context of PTOA.

Effects of Native Type II Collagen Treatment on Knee Osteoarthritis: A Randomized Controlled Trial Bakilan F, et al. Effects of Native Type II Collagen Treatment on Knee Osteoarthritis: A Randomized Controlled Trial. Eurasian J Med. 2016 Jun;48(2):95-101. doi: 10.5152/eurasianjmed.2015.15030. PubMed PMID: 27551171; PubMed Central PMCID: PMC4970562. OBJECTIVE: The aim of this randomized controlled study was to evaluate the efficacy of oral native type II collagen treatment on the symptoms and biological markers of cartilage degradation, when given concomitantly with acetaminophen in patients with knee osteoarthritis. MATERIALS AND METHODS: Thirty-nine patients diagnosed with knee osteoarthritis were included and randomly distributed into two groups: one treated with 1500 mg/day of acetaminophen (group AC; n=19) and the other treated with 1500 mg/day of acetaminophen plus 10 mg/day of native type II collagen (group AC+CII; n=20) for 3 months. Visual Analogue Scale (VAS) at rest and during walking, Western Ontario McMaster (WOMAC) pain, WOMAC function, and Short Form-36 (SF-36) scores, were recorded. Coll2-1, Coll2-1NO2 and Fibulin-3 levels were quantified in urine as biomarkers of disease progression. ClinicalTrials.gov: NCT02237989. RESULTS: After 3 months of treatment, significant improvements compared to baseline were reported in joint pain (VAS walking), function (WOMAC) and quality of life (SF-36) in the AC+CII group, while only improvements in some subscales of the SF-36 survey and VAS walking were detected in the AC group. Comparisons between the groups revealed a significant difference in VAS walking score in favour of the AC+CII group as compared to AC group. Biochemical markers of cartilage degradation in urine did not significantly improve in any of the groups. CONCLUSION: All in all, these results suggest that native type II collagen treatment combined with acetaminophen is superior to only acetaminophen for symptomatic treatment of patients with knee osteoarthritis.

Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study Kanzaki N, Ono Y, Shibata H, Moritani T. Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study. Clin Interv Aging. 2015 Oct 28;10:1743-53. doi: 10.2147/CIA.S93077. eCollection 2015. PubMed PMID: 26604721; PubMed Central PMCID: PMC4631410. BACKGROUND: The aim of this study was to investigate the ability of a glucosamine-containing supplement to improve locomotor functions in subjects with knee pain. METHODS: A randomized, double-blind, placebo-controlled, parallel-group comparative study was conducted for 16 weeks in 100 Japanese subjects (age, 51.8±0.8 years) with knee pain. Subjects were randomly assigned to one of the two supplements containing 1) 1,200 mg of glucosamine hydrochloride, 60 mg of chondroitin sulfate, 45 mg of type II collagen peptides, 90 mg of quercetin glycosides, 10 mg of imidazole peptides, and 5 μg of vitamin D per day (GCQID group, n=50) or 2) a placebo (placebo group, n=50). Japanese Knee Osteoarthritis Measure, visual analog scale score, normal walking speed, and knee-extensor strength were measured to evaluate the effects of the supplement on knee-joint functions and locomotor functions. RESULTS: In subjects eligible for efficacy assessment, there was no significant group × time interaction, and there were improvements in knee-joint functions and locomotor functions in both groups, but there was no significant difference between the groups. In subjects with mild-to-severe knee pain at baseline, knee-extensor strength at week 8 (104.6±5.0% body weight vs 92.3±5.5% body weight, P=0.030) and the change in normal walking speed at week 16 (0.11±0.03 m/s vs 0.05±0.02 m/s, P=0.038) were significantly greater in the GCQID group than in the placebo group. Further subgroup analysis based on Kellgren-Lawrence (K-L) grade showed that normal walking speed at week 16 (1.36±0.05 m/s vs 1.21±0.02 m/s, P<0.05) was significantly greater in the GCQID group than in the placebo group in subjects with K-L grade I. No adverse effect of treatment was identified in the safety assessment. CONCLUSION: In subjects with knee pain, GCQID supplementation was effective for relieving knee pain and improving locomotor functions.

Glucosamine (Glucosamine Sulfate Complex) CLINICAL STUDIES

Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee Zeng C, et al. Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee. Sci Rep. 2015 Nov 18;5:16827. doi: 10.1038/srep16827. PubMed PMID: 26576862; PubMed Central PMCID: PMC4649492. This study aimed to investigate the effectiveness and safety of glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of knee osteoarthritis (OA). PubMed, Embase and Cochrane Library were searched through from inception to February 2015. A total of 54 studies covering 16427 patients were included. Glucosamine plus chondroitin, glucosamine alone, and celecoxib were all more effective than placebo in pain relief and function improvement. Specifically, celecoxib is most likely to be the best treatment option, followed by the combination group. All treatment options showed clinically significant improvement from baseline pain, but only glucosamine plus chondroitin showed clinically significant improvement from baseline function. In terms of the structure-modifying effect, both glucosamine alone and chondroitin alone achieved a statistically significant reduction in joint space narrowing. Although no significant difference was observed among the five options with respect to the three major adverse effects (withdrawal due to adverse events, serious adverse events and the number of patients with adverse events), the additional classical meta-analysis showed that celecoxib exhibited a higher rate of gastrointestinal adverse effect comparing with the placebo group. The present study provided evidence for the symptomatic efficacy of glucosamine plus chondroitin in the treatment of knee OA.

MGlucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study Kanzaki N, Ono Y, Shibata H, Moritani T. Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study. Clin Interv Aging. 2015 Oct 28;10:1743-53. doi: 10.2147/CIA.S93077. eCollection 2015. PubMed PMID: 26604721; PubMed Central PMCID: PMC4631410. BACKGROUND: The aim of this study was to investigate the ability of a glucosamine-containing supplement to improve locomotor functions in subjects with knee pain. METHODS: A randomized, double-blind, placebo-controlled, parallel-group comparative study was conducted for 16 weeks in 100 Japanese subjects (age, 51.8±0.8 years) with knee pain. Subjects were randomly assigned to one of the two supplements containing 1) 1,200 mg of glucosamine hydrochloride, 60 mg of chondroitin sulfate, 45 mg of type II collagen peptides, 90 mg of quercetin glycosides, 10 mg of imidazole peptides, and 5 μg of vitamin D per day (GCQID group, n=50) or 2) a placebo (placebo group, n=50). Japanese Knee Osteoarthritis Measure, visual analog scale score, normal walking speed, and knee-extensor strength were measured to evaluate the effects of the supplement on knee-joint functions and locomotor functions. RESULTS: In subjects eligible for efficacy assessment, there was no significant group × time interaction, and there were improvements in knee-joint functions and locomotor functions in both groups, but there was no significant difference between the groups. In subjects with mild-to-severe knee pain at baseline, knee-extensor strength at week 8 (104.6±5.0% body weight vs 92.3±5.5% body weight, P=0.030) and the change in normal walking speed at week 16 (0.11±0.03 m/s vs 0.05±0.02 m/s, P=0.038) were significantly greater in the GCQID group than in the placebo group. Further subgroup analysis based on Kellgren-Lawrence (K-L) grade showed that normal walking speed at week 16 (1.36±0.05 m/s vs 1.21±0.02 m/s, P<0.05) was significantly greater in the GCQID group than in the placebo group in subjects with K-L grade I. No adverse effect of treatment was identified in the safety assessment. CONCLUSION: In subjects with knee pain, GCQID supplementation was effective for relieving knee pain and improving locomotor functions.

Meriva®+Glucosamine versus Condroitin+Glucosamine in patients with knee osteoarthritis: an observational study Belcaro G, et al. Meriva®+Glucosamine versus Condroitin+Glucosamine in patients with knee osteoarthritis: an observational study. Eur Rev Med Pharmacol Sci. 2014;18(24):3959-63. PubMed PMID: 25555891. OBJECTIVE: Osteoarthritis (OA) is a major cause of physical disability and impaired quality of life. Non-steroidal anti-inflammatory drugs are the most used treatment for OA, but they are frequently associated to adverse events. Alternative therapies are under investigation for the treatment of OA. Meriva® is a lecithin delivery form of curcumin, a powerful promoter of anti-oxidant response studied in a number of conditions related to chronic inflammation and pain. PATIENTS AND METHODS: This 4-month observational study, conducted in a 'real-life' scenario, compares the association of Meriva and glucosamine (n=63) with chondroitin sulphate+glucosamine (n=61) in 124 patients with grade 1-2 OA of the knee. RESULTS: Patients treated with Meriva+glucosamine had significantly higher Karnofsky Index and WOMAC score (both in the physical and emotional domains), compared to those in the chondroitin+glucosamine group. Noteworthy, the walking distance at the treadmill test after 1 month was also significantly higher in the meriva+glucosamine group; this advantage was sustained until the end of the study. Although the need for concomitant drugs and medical attention decreased in both groups, this reduction was more evident for patients treated with Meriva+glucosamine. CONCLUSIONS: Taken together, the results of this study shows that the 4-month administration of the association of Meriva and glucosamine can result in a faster onset of action and improved outcomes than the administration of an association of chondroitin sulphate and glucosamine in patients with OA.

Role of glucosamine in the treatment for osteoarthritis Reginster JY, Neuprez A, Lecart MP, Sarlet N, Bruyere O. Role of glucosamine in the treatment for osteoarthritis. Rheumatol Int. 2012 Oct;32(10):2959-67. Epub 2012 Mar 30. Review. PubMed PMID: 22461188; PubMed Central PMCID: PMC3456914. Over the last 20 years, several studies have investigated the ability of glucosamine sulfate to improve the symptoms (pain and function) and to delay the structural progression of osteoarthritis. There is now a large, convergent body of evidence that glucosamine sulfate, given at a daily oral dose of 1,500 mg, is able to significantly reduce the symptoms of osteoarthritis in the lower limbs. This dose of glucosamine sulfate has also been shown, in two independent studies, to prevent the joint space narrowing observed at the femorotibial compartment in patients with mild-to-moderate knee osteoarthritis. This effect also translated into a 50 % reduction in the incidence of osteoarthritis-related surgery of the lower limbs during a 5-year period following the withdrawal of the treatment. Some discrepancies have been described between the results of studies performed with a patent-protected formulation of glucosamine sulfate distributed as a drug and those having used glucosamine preparations purchased from global suppliers, packaged, and sold over-the-counter as nutritional supplements.

Chondroitin Sulfate CLINICAL STUDIES

Pharmaceutical-grade Chondroitin sulfate is as effective as celecoxib and superior to placebo in symptomatic knee osteoarthritis: the ChONdroitin versus CElecoxib versus Placebo Trial (CONCEPT) Reginster JY, Dudler J, Blicharski T, Pavelka K. Pharmaceutical-grade Chondroitin sulfate is as effective as celecoxib and superior to placebo in symptomatic knee osteoarthritis: the ChONdroitin versus CElecoxib versus Placebo Trial (CONCEPT). Ann Rheum Dis. 2017 Sep;76(9):1537-1543. doi: 10.1136/annrheumdis-2016-210860. Epub 2017 May 22. PubMed PMID: 28533290; PubMed Central PMCID: PMC5561371. OBJECTIVES: Chondroitin sulfate 800 mg/day (CS) pharmaceutical-grade in the management of symptomatic knee osteoarthritis consistent with the European Medicines Agency guideline. METHODS: A prospective, randomised, 6-month, 3-arm, double-blind, double-dummy, placebo and celecoxib (200 mg/day)-controlled trial assessing changes in pain on a Visual Analogue Scale (VAS) and in the Lequesne Index (LI) as coprimary endpoints. Minimal-Clinically Important Improvement (MCII), Patient-Acceptable Symptoms State (PASS) were used as secondary endpoints. RESULTS: 604 patients (knee osteoarthritis) diagnosed according to American College of Rheumalogy (ACR) criteria, recruited in five European countries and followed for 182 days. CS and celecoxib showed a greater significant reduction in pain and LI than placebo. In the intention-to-treat (ITT) population, pain reduction in VAS at day 182 in the CS group (-42.6 mm) and in celecoxib group (-39.5 mm) was significantly greater than the placebo group (-33.3 mm) (p=0.001 for CS and p=0.009 for celecoxib), while no difference observed between CS and celecoxib. Similar trend for the LI, as reduction in this metric in the CS group (-4.7) and celecoxib group (-4.6) was significantly greater than the placebo group (-3.7) (p=0.023 for CS and p=0.015 for celecoxib), no difference was observed between CS and celecoxib. Both secondary endpoints (MCII and PASS) at day 182 improved significantly in the CS and celecoxib groups. All treatments demonstrated excellent safety profiles. CONCLUSION: A 800 mg/day pharmaceutical-grade CS is superior to placebo and similar to celecoxib in reducing pain and improving function over 6 months in symptomatic knee osteoarthritis (OA) patients. This formulation of CS should be considered a first-line treatment in the medical management of knee OA.

Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee Zeng C, et al. Effectiveness and safety of Glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of osteoarthritis of the knee. Sci Rep. 2015 Nov 18;5:16827. doi: 10.1038/srep16827. PubMed PMID: 26576862; PubMed Central PMCID: PMC4649492. This study aimed to investigate the effectiveness and safety of glucosamine, chondroitin, the two in combination, or celecoxib in the treatment of knee osteoarthritis (OA). PubMed, Embase and Cochrane Library were searched through from inception to February 2015. A total of 54 studies covering 16427 patients were included. Glucosamine plus chondroitin, glucosamine alone, and celecoxib were all more effective than placebo in pain relief and function improvement. Specifically, celecoxib is most likely to be the best treatment option, followed by the combination group. All treatment options showed clinically significant improvement from baseline pain, but only glucosamine plus chondroitin showed clinically significant improvement from baseline function. In terms of the structure-modifying effect, both glucosamine alone and chondroitin alone achieved a statistically significant reduction in joint space narrowing. Although no significant difference was observed among the five options with respect to the three major adverse effects (withdrawal due to adverse events, serious adverse events and the number of patients with adverse events), the additional classical meta-analysis showed that celecoxib exhibited a higher rate of gastrointestinal adverse effect comparing with the placebo group. The present study provided evidence for the symptomatic efficacy of glucosamine plus chondroitin in the treatment of knee OA.

Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study Kanzaki N, Ono Y, Shibata H, Moritani T. Glucosamine-containing supplement improves locomotor functions in subjects with knee pain: a randomized, double-blind, placebo-controlled study. Clin Interv Aging. 2015 Oct 28;10:1743-53. doi: 10.2147/CIA.S93077. eCollection 2015. PubMed PMID: 26604721; PubMed Central PMCID: PMC4631410. BACKGROUND: The aim of this study was to investigate the ability of a glucosamine-containing supplement to improve locomotor functions in subjects with knee pain. METHODS: A randomized, double-blind, placebo-controlled, parallel-group comparative study was conducted for 16 weeks in 100 Japanese subjects (age, 51.8±0.8 years) with knee pain. Subjects were randomly assigned to one of the two supplements containing 1) 1,200 mg of glucosamine hydrochloride, 60 mg of chondroitin sulfate, 45 mg of type II collagen peptides, 90 mg of quercetin glycosides, 10 mg of imidazole peptides, and 5 μg of vitamin D per day (GCQID group, n=50) or 2) a placebo (placebo group, n=50). Japanese Knee Osteoarthritis Measure, visual analog scale score, normal walking speed, and knee-extensor strength were measured to evaluate the effects of the supplement on knee-joint functions and locomotor functions. RESULTS: In subjects eligible for efficacy assessment, there was no significant group × time interaction, and there were improvements in knee-joint functions and locomotor functions in both groups, but there was no significant difference between the groups. In subjects with mild-to-severe knee pain at baseline, knee-extensor strength at week 8 (104.6±5.0% body weight vs 92.3±5.5% body weight, P=0.030) and the change in normal walking speed at week 16 (0.11±0.03 m/s vs 0.05±0.02 m/s, P=0.038) were significantly greater in the GCQID group than in the placebo group. Further subgroup analysis based on Kellgren-Lawrence (K-L) grade showed that normal walking speed at week 16 (1.36±0.05 m/s vs 1.21±0.02 m/s, P<0.05) was significantly greater in the GCQID group than in the placebo group in subjects with K-L grade I. No adverse effect of treatment was identified in the safety assessment. CONCLUSION: In subjects with knee pain, GCQID supplementation was effective for relieving knee pain and improving locomotor functions.

L-proline CLINICAL STUDIES

Alterations of amino acid metabolism in osteoarthritis: its implications for nutrition and health. Li Y, Xiao W, Luo W, Zeng C, Deng Z, Ren W, Wu G, Lei G. Alterations of amino acid metabolism in osteoarthritis: its implications for nutrition and health. Amino Acids. 2016 Apr;48(4):907-14. doi: 10.1007/s00726-015-2168-x. Epub 2016 Jan 14. Review. PubMed PMID: 26767374. Osteoarthritis (OA) is a common form of arthritis in humans. It has long been regarded as a non-inflammatory disease, but a degree of inflammation is now recognized as being a vital inducer of subpopulation of OA. Besides inflammation, the establishment and development of OA are associated with alterations in metabolism and profiles of amino acids (AA), including glutamate- and arginine-family AA as well as their related metabolites (e.g., creatinine, hydroxyproline, γ-aminobutyrate, dimethylarginines and homoarginine). Functional AA (e.g., glutamine, arginine, glutamate, glycine, proline, and tryptophan) have various benefits (i.e., anti-inflammation and anti-oxidation) in treatment of inflammation-associated diseases, including OA. Thus, these AA have potential as immunomodulatory nutrients for patients with inflammation-induced OA.

Design and synthesis of proline-derived α2δ ligands Rawson DJ, et al. Part 3: Design and synthesis of proline-derived α2δ ligands. Bioorg Med Chem Lett. 2011 Jun 15;21(12):3771-3. doi: 10.1016/j.bmcl.2011.04.058. Epub 2011 Apr 20. PubMed PMID: 21550802. A potent series of substituted (2S,4S)-benzylproline α(2)δ ligands have been designed from the readily available starting material (2S,4R)-hydroxy-L-proline. The ligands have improved pharmacokinetic profile over the (4S)-phenoxyproline derivatives described previously and have potential for development as oral agents for the treatment of neuropathic pain. Compound 16 has been progressed to clinical development.

L-glutamine CLINICAL STUDIES

Alterations of amino acid metabolism in osteoarthritis: its implications for nutrition and health. Li Y, Xiao W, Luo W, Zeng C, Deng Z, Ren W, Wu G, Lei G. Alterations of amino acid metabolism in osteoarthritis: its implications for nutrition and health. Amino Acids. 2016 Apr;48(4):907-14. doi: 10.1007/s00726-015-2168-x. Epub 2016 Jan 14. Review. PubMed PMID: 26767374. Osteoarthritis (OA) is a common form of arthritis in humans. It has long been regarded as a non-inflammatory disease, but a degree of inflammation is now recognized as being a vital inducer of subpopulation of OA. Besides inflammation, the establishment and development of OA are associated with alterations in metabolism and profiles of amino acids (AA), including glutamate- and arginine-family AA as well as their related metabolites (e.g., creatinine, hydroxyproline, γ-aminobutyrate, dimethylarginines and homoarginine). Functional AA (e.g., glutamine, arginine, glutamate, glycine, proline, and tryptophan) have various benefits (i.e., anti-inflammation and anti-oxidation) in treatment of inflammation-associated diseases, including OA. Thus, these AA have potential as immunomodulatory nutrients for patients with inflammation-induced OA.

Combined glutamate and glutamine levels in pain-processing brain regions are associated with individual pain sensitivity Zunhammer M, et al. Combined glutamate and glutamine levels in pain-processing brain regions are associated with individual pain sensitivity. Journal of Int Assn for Study of Pain. 2016 Oct. 157(10); 2248-56. The relationship between glutamate and γ-aminobutyric acid (GABA) levels in the living human brain and pain sensitivity is unknown. Combined glutamine/glutamate (Glx), as well as GABA levels can be measured in vivo with single-voxel proton magnetic resonance spectroscopy. In this cross-sectional study, we aimed at determining whether Glx and/or GABA levels in pain-related brain regions are associated with individual differences in pain sensitivity. Experimental heat, cold, and mechanical pain thresholds were obtained from 39 healthy, drug-free individuals (25 men) according to the quantitative sensory testing protocol and summarized into 1 composite measure of pain sensitivity. The Glx levels were measured using point-resolved spectroscopy at 3 T, within a network of pain-associated brain regions comprising the insula, the anterior cingulate cortex, the mid-cingulate cortex, the dorsolateral prefrontal cortex, and the thalamus. GABA levels were measured using GABA-edited spectroscopy (Mescher–Garwood point-resolved spectroscopy) within the insula, the anterior cingulate cortex, and the mid-cingulate cortex. Glx and/or GABA levels correlated positively across all brain regions. Gender, weekly alcohol consumption, and depressive symptoms were significantly associated with Glx and/or GABA levels. A linear regression analysis including all these factors indicated that Glx levels pooled across pain-related brain regions were positively associated with pain sensitivity, whereas no appreciable relationship with GABA was found. In sum, we show that the levels of the excitatory neurotransmitter glutamate and its precursor glutamine across pain-related brain regions are positively correlated with individual pain sensitivity. Future studies will have to determine whether our findings also apply to clinical populations.

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Turkey Tail mushroom (Coriolus versicolor)

Phase 1 Clinical Trial of Trametes versicolor in Women with Breast Cancer Torkelson CJ, et al. Phase 1 Clinical Trial of Trametes versicolor in Women with Breast Cancer. ISRN Oncology. 2012;2012:251632. doi:10.5402/2012/251632. Introduction. Orally administered preparations from the Trametes versicolor (Tv) mushroom have been hypothesized to improve immune response in women with breast cancer after standard chemotherapy and radiotherapy. Methods. A phase I, two-center, dose escalation study was done to determine the maximum tolerated dose of a Tv preparation when taken daily in divided doses for 6 weeks after recent completion of radiotherapy. Eleven participants were recruited and nine women completed the study. Each cohort was comprised of three participants given one of three doses of Tv (3, 6, or 9 grams). Immune data was collected pre- and postradiation, at 3 on-treatment time points and after a 3-week washout. Results. Nine adverse events were reported (7 mild, 1 moderate, and 1 severe), suggesting that Tv was well tolerated. Immunological results indicated trends in (1) increased lymphocyte counts at 6 and 9 grams/day; (2) increased natural killer cell functional activity at 6 grams/day; (3) dose-related increases in CD8+ T cells and CD19+ B cells , but not CD4+ T cells or CD16+56+ NK cells. Conclusion. These findings show that up to 9 grams/day of a Tv preparation is safe and tolerable in women with breast cancer in the postprimary treatment setting. This Tv preparation may improve immune status in immunocompromised breast cancer patients following standard primary oncologic treatment.


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PDQ Integrative, Alternative, and Complementary Therapies Editorial Board. Medicinal Mushrooms (PDQ®): Patient Version. 2017 Oct 24. In: PDQ Cancer Information Summaries [Internet]. Bethesda (MD): National Cancer Institute (US); 2002-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK424937/ Medicinal mushrooms are mushrooms that are used as medicine. They have been used to treat infection for hundreds of years, mostly in Asia. Today, medicinal mushrooms are also used to treat lung diseases and cancer. For more than 30 years, medicinal mushrooms have been approved as an addition to standard cancer treatments in Japan and China. In these countries, mushrooms have been used safely for a long time, either alone or combined with chemotherapy. In Asia, there are more than 100 types of mushrooms used to treat cancer. Some of the more common ones are Ganoderma lucidum (reishi), Trametes versicolor or Coriolus versicolor (turkey tail), Lentinus edodes (shiitake), and Grifola frondosa (maitake). Mushrooms are being studied to find out how they affect the immune system and if they stop or slow the growth of tumors or kill tumor cells. It is thought that certain chemical compounds, such as polysaccharides in turkey tail mushrooms, strengthen the immune system to fight cancer. This PDQ cancer information summary gives an overview of the use of medicinal mushrooms in treating cancer. The following information is given for Trametes versicolor, also called Coriolus versicolor (turkey tail), and Ganoderma lucidum (reishi)"


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"Immune Modulation From Five Major Mushrooms: Application to Integrative Oncology Guggenheim AG, Wright KM, Zwickey HL. Immune Modulation From Five Major Mushrooms: Application to Integrative Oncology. Integrative Medicine: A Clinician’s Journal. 2014;13(1):32-44. This review discusses the immunological roles of 5 major mushrooms in oncology: Agaricus blazei, Cordyceps sinensis, Grifola frondosa, Ganoderma lucidum, and Trametes versicolor. These mushrooms were selected based on the body of research performed on mushroom immunology in an oncology model. First, this article focuses on how mushrooms modify cytokines within specific cancer models and on how those cytokines affect the disease process. Second, this article examines the direct effect of mushrooms on cancer. Finally, this article presents an analysis of how mushrooms interact with chemotherapeutic agents, including their effects on its efficacy and on the myelosuppression that results from it. For these 5 mushrooms, an abundance of in vitro evidence exists that elucidates the anticancer immunological mechanisms. Preliminary research in humans is also available and is promising for treatment."


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"Polysaccharide K and Coriolus versicolor extracts for lung cancer: a systematic review. Fritz H, et al. Polysaccharide K and Coriolus versicolor extracts for lung cancer: a systematic review. Integr Cancer Ther. 2015 May;14(3):201-11. doi: 10.1177/1534735415572883. Epub 2015 Mar 17. Review. PubMed PMID: 25784670. Polysaccharide K, also known as PSK or Krestin, is derived from the Coriolus versicolor mushroom and is widely used in Japan as an adjuvant immunotherapy for a variety of cancer including lung cancer. Despite reported benefits, there has been no English language synthesis of PSK for lung cancer. To address this knowledge gap, we conducted a systematic review of PSK for the treatment of lung cancer. PSK may improve immune function, reduce tumor-associated symptoms, and extend survival in lung cancer patients. Larger, more rigorous randomized controlled trials for PSK in lung cancer patients are warranted."


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"The use of mushroom glucans and proteoglycans in cancer treatment. Kidd PM. The use of mushroom glucans and proteoglycans in cancer treatment. Altern Med Rev. 2000 Feb;5(1):4-27. Review. PubMed PMID: 10696116. Immunoceuticals can be considered as substances having immunotherapeutic efficacy when taken orally. More than 50 mushroom species have yielded potential immunoceuticals that exhibit anticancer activity in vitro or in animal models and of these, six have been investigated in human cancers. All are non-toxic and very well tolerated. Lentinan and schizophyllan have little oral activity. Active Hexose Correlated Compound (AHCC) is poorly defined but has shown early clinical promise. Maitake D-Fraction has limited proof of clinical efficacy to date, but controlled research is underway. Two proteoglycans from Coriolus versicolor - PSK (Polysaccharide-K) and PSP (Polysaccharide-Peptide - have demonstrated the most promise. In Japanese trials since 1970, PSK significantly extended survival at five years or beyond in cancers of the stomach, colon-rectum, esophagus, nasopharynx, and lung (non-small cell types), and in a HLA B40-positive breast cancer subset. PSP was subjected to Phase II and Phase III trials in China. In double-blind trials, PSP significantly extended five-year survival in esophageal cancer. PSP significantly improved quality of life, provided substantial pain relief, and enhanced immune status in 70-97 percent of patients with cancers of the stomach, esophagus, lung, ovary, and cervix. PSK and PSP boosted immune cell production, ameliorated chemotherapy symptoms, and enhanced tumor infiltration by dendritic and cytotoxic T-cells. Their extremely high tolerability, proven benefits to survival and quality of life, and compatibility with chemotherapy and radiation therapy makes them well suited for cancer management regimens."


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"Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer immunotherapy. Fisher M, Yang LX. Anticancer effects and mechanisms of polysaccharide-K (PSK): implications of cancer immunotherapy. Anticancer Res. 2002 May-Jun;22(3):1737-54. Review. PubMed PMID: 12168863. Polysaccharide-K (polysaccharide-Kureha; PSK), also known as krestin, is a unique protein-bound polysaccharide, which has been used as a chemoimmunotherapy agent in the treatment of cancer in Asia for over 30 years. PSK and Polysaccharopeptide (PSP) are both protein-bound polysaccharides which are derived from the CM-101 and COV-1 strains of the fungus Coriolus versicolor by Japanese and Chinese researchers, respectively. Both polysaccharide preparations have documented anticancer activity in vitro, in vivo and in human clinical trials, though PSK has been researched longer and has therefore undergone more thorough laboratory, animal and clinical testing. Several randomized clinical trials have demonstrated that PSK has great potential as an adjuvant cancer therapy agent, with positive results seen in the adjuvant treatment of gastric, esophageal, colorectal, breast and lung cancers. These studies have suggested the efficacy of PSK as an immunotherapy or biological response modifier (BRM). BRMs potentially have the ability to improve the ""host versus tumor response,"" thereby increasing the ability of the host to defend itself from tumor progression. The mechanisms of biological response modification by PSK have yet to be clearly and completely elucidated. Some studies suggest that PSK may act to increase leukocyte activation and response through up-regulation of key cytokines. Indeed, natural killer (NK) and lymphocyte-activated killer (LAK) cell activation has been demonstrated in vivo and in vitro, and recent genetic studies reveal increased expression of key immune cytokines in response to treatment with PSK. An antimetastatic action of PSK has also been demonstrated and is perhaps attributed to its potential to inhibit metalloproteinases and other enzymes involved in metastatic activity. PSK has also been shown to cause differentiation of leukemic cells in vitro, and this effect has been attributed to induction of differentiation cytokines. PSK has further been shown to have antioxidant capacity which may allow it to play a role as a normal tissue chemo- and radio-protector when used in combination with adjuvant or definitive chemotherapy and/or radiotherapy in the treatment of cancer, while it may also enable it to defend the host from oxidative stress. Interestingly, studies have also shown that PSK may actually inhibit carcinogenesis by inhibiting the action of various carcinogens on vulnerable cell lines. This action of PSK may play a role in preventing second primary tumors when an inducing agent, such as tobacco or asbestos, is suspected and may also prevent second malignancies due to the carcinogenic effects of radiotherapy and cytotoxic chemotherapy. Another very important aspect of chemoimmunotherapy, in general is that it may be used on debilitated patients such as those with AIDS and the elderly who might otherwise be denied potentially helpful adjuvant cytotoxic chemotherapy. Further determination of the mechanisms of these anti-cancer, immunostimulating and biological response modifying effects of PSK as well as of other protein-bound polysaccharides is certainly warranted. Indeed, with modern cellular and molecular biology techniques, a better understanding of the specific molecular effects of PSK on tumor cells as well as leukocytes may be determined. Much of the research that has been done on PSK is outlined in this paper and may serve as a foundation toward determining the mechanisms of action of this and other protein-bound polysaccharides in the treatment of cancer. This information may open new doors in the development of novel strategies for the treatment of malignancies using adjuvant immunotherapy in combination with surgery, chemotherapy and/or radiotherapy."


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"Recent developments in mushrooms as anti-cancer therapeutics: a review Patel S, Goyal A. Recent developments in mushrooms as anti-cancer therapeutics: a review. 3 Biotech. 2012;2(1):1-15. doi:10.1007/s13205-011-0036-2. From time immemorial, mushrooms have been valued by humankind as a culinary wonder and folk medicine in Oriental practice. The last decade has witnessed the overwhelming interest of western research fraternity in pharmaceutical potential of mushrooms. The chief medicinal uses of mushrooms discovered so far are as anti-oxidant, anti-diabetic, hypocholesterolemic, anti-tumor, anti-cancer, immunomodulatory, anti-allergic, nephroprotective, and anti-microbial agents. The mushrooms credited with success against cancer belong to the genus Phellinus, Pleurotus, Agaricus, Ganoderma, Clitocybe, Antrodia, Trametes, Cordyceps, Xerocomus, Calvatia, Schizophyllum, Flammulina, Suillus, Inonotus, Inocybe, Funlia, Lactarius, Albatrellus, Russula, and Fomes. The anti-cancer compounds play crucial role as reactive oxygen species inducer, mitotic kinase inhibitor, anti-mitotic, angiogenesis inhibitor, topoisomerase inhibitor, leading to apoptosis, and eventually checking cancer proliferation. The present review updates the recent findings on the pharmacologically active compounds, their anti-tumor potential, and underlying mechanism of biological action in order to raise awareness for further investigations to develop cancer therapeutics from mushrooms. The mounting evidences from various research groups across the globe, regarding anti-tumor application of mushroom extracts unarguably make it a fast-track research area worth mass attention."


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"Novel medicinal mushroom blend suppresses growth and invasiveness of human breast cancer cells Jiang J, Sliva D. Novel medicinal mushroom blend suppresses growth and invasiveness of human breast cancer cells. Int J Oncol. 2010 Dec;37(6):1529-36. PubMed PMID: 21042722. Mushrooms are an integral part of Traditional Chinese Medicine (TCM), and have been used for millennia to prevent or treat a variety of diseases. Currently mushrooms or their extracts are used globally in the form of dietary supplements. In the present study we have evaluated the anticancer effects of the dietary supplement, MycoPhyto® Complex (MC), a novel medicinal mushroom blend which consists of a blend of mushroom mycelia from the species Agaricus blazei, Cordyceps sinensis, Coriolus versicolor, Ganoderma lucidum, Grifola frondosa and Polyporus umbellatus, and β-1,3-glucan isolated from the yeast, Saccharomyces cerevisiae. Here, we show that MC demonstrates cytostatic effects through the inhibition of cell proliferation and cell cycle arrest at the G2/M phase of highly invasive human breast cancer cells MDA-MB-231. DNA-microarray analysis revealed that MC inhibits expression of cell cycle regulatory genes (ANAPC2, ANAPC2, BIRC5, Cyclin B1, Cyclin H, CDC20, CDK2, CKS1B, Cullin 1, E2F1, KPNA2, PKMYT1 and TFDP1). Moreover, MC also suppresses the metastatic behavior of MDA-MB-231 by the inhibition of cell adhesion, cell migration and cell invasion. The potency of MC to inhibit invasiveness of breast cancer cells is linked to the suppression of secretion of the urokinase plasminogen activator (uPA) from MDA-MB-231 cells. In conclusion, the MC dietary supplement could have potential therapeutic value in the treatment of invasive human breast cancer."


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Tocotrienols (gamma)

"Tocotrienols fight cancer by targeting multiple cell signaling pathways Kannappan R, Gupta SC, Kim JH, Aggarwal BB. Tocotrienols fight cancer by targeting multiple cell signaling pathways. Genes & Nutrition. 2012;7(1):43-52. doi:10.1007/s12263-011-0220-3. Cancer cells are distinguished by several distinct characteristics, such as self-sufficiency in growth signal, resistance to growth inhibition, limitless replicative potential, evasion of apoptosis, sustained angiogenesis, and tissue invasion and metastasis. Tumor cells acquire these properties due to the dysregulation of multiple genes and associated cell signaling pathways, most of which are linked to inflammation. For that reason, rationally designed drugs that target a single gene product are unlikely to be of use in preventing or treating cancer. Moreover, targeted drugs can cause serious and even life-threatening side effects. Therefore, there is an urgent need for safe and effective promiscuous (multitargeted) drugs. “Mother Nature” produces numerous such compounds that regulate multiple cell signaling pathways, are cost effective, exhibit low toxicity, and are readily available. One among these is tocotrienol, a member of the vitamin E family, which has exhibited anticancer properties. This review summarizes data from in vitro and in vivo studies of the effects of tocotrienol on nuclear factor-κB, signal transducer and activator of transcription (STAT) 3, death receptors, apoptosis, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), hypoxia-inducible factor (HIF) 1, growth factor receptor kinases, and angiogenic pathways.


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"Tocotrienols, the Vitamin E of the 21st Century: It’s Potential Against Cancer and Other Chronic Diseases Aggarwal BB, Sundaram C, Prasad S, Kannappan R. Tocotrienols, the Vitamin E of the 21st Century: It’s Potential Against Cancer and Other Chronic Diseases. Biochemical pharmacology. 2010;80(11):1613-1631. doi:10.1016/j.bcp.2010.07.043. Initially discovered in 1938 as a “fertility factor,” vitamin E now refers to eight different isoforms that belong to two categories, four saturated analogues (α, β, γ, and δ) called tocopherols and four unsaturated analogues referred to as tocotrienols. While the tocopherols have been investigated extensively, little is known about the tocotrienols. Very limited studies suggest that both the molecular and therapeutic targets of the tocotrienols are distinct from those of the tocopherols. For instance, suppression of inflammatory transcription factor NF-κB, which is closely linked to tumorigenesis and inhibition of HMG-CoA reductase, mammalian DNA polymerases and certain protein tyrosine kinases, is unique to the tocotrienols. This review examines in detail the molecular targets of the tocotrienols and their roles in cancer, bone resorption, diabetes, and cardiovascular and neurological diseases at both preclinical and clinical levels. As disappointment with the therapeutic value of the tocopherols grows, the potential of these novel vitamin E analogues awaits further investigation."


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"Gamma-tocotrienol as an effective agent in targeting prostate cancer stem cell-like population Luk SU, et al. Gamma-tocotrienol as an effective agent in targeting prostate cancer stem cell-like population. Int J Cancer. 2011 May 1;128(9):2182-91. doi: 10.1002/ijc.25546. PubMed PMID: 20617516. Emerging evidence supports that prostate cancer originates from a rare subpopulation of cells, namely prostate cancer stem cells (CSCs). Conventional therapies for prostate cancer are believed to mainly target the majority of differentiated tumor cells but spare CSCs, which may account for the subsequent disease relapse after treatment. Therefore, successful elimination of CSCs may be an effective strategy to achieve complete remission from this disease. Gamma-tocotrienols (γ-T3) is one of the vitamin-E constituents, which have been shown to have anticancer effects against a wide range of human cancers. Recently, we have reported that γ-T3 treatment not only inhibits prostate cancer cell invasion but also sensitizes the cells to docetaxel-induced apoptosis, suggesting that γ-T3 may be an effective therapeutic agent against advanced stage prostate cancer. Here, we demonstrate for the first time that γ-T3 can downregulate the expression of prostate CSC markers (CD133/CD44) in androgen-independent prostate cancer cell lines (PC-3 and DU145), as evident from Western blotting analysis. Meanwhile, the spheroid formation ability of the prostate cancer cells was significantly hampered by γ-T3 treatment. In addition, pretreatment of PC-3 cells with γ-T3 was found to suppress tumor initiation ability of the cells. More importantly, although CD133-enriched PC-3 cells were highly resistant to docetaxel treatment, these cells were as sensitive to γ-T3 treatment as the CD133-depleted population. Our data suggest that γ-T3 may be an effective agent in targeting prostate CSCs, which may account for its anticancer and chemosensitizing effects reported in previous studies."


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A new formulation of Gamma Delta Tocotrienol has superior bioavailability compared to existing Tocotrienol-Rich Fraction in healthy human subjects Meganathan P, et al. A new formulation of Gamma Delta Tocotrienol has superior bioavailability compared to existing Tocotrienol-Rich Fraction in healthy human subjects. Scientific Reports. 2015;5:13550. doi:10.1038/srep13550. Gamma and delta tocotrienols are isomers of Vitamin E with established potency in pre-clinical anti-cancer research. This single-dose, randomized, crossover study aimed to compare the safety and bioavailability of a new formulation of Gamma Delta Tocotrienol (GDT) in comparison with the existing Tocotrienol-rich Fraction (TRF) in terms of gamma and delta isomers in healthy volunteers. Subjects were given either two 300 mg GDT (450 mg γ-T3 and 150 mg δ-T3) capsules or four 200 mg TRF (451.2 mg γ-T3 & 102.72 mg δ-T3) capsules and blood samples were taken at several time points over 24 hours. Plasma tocotrienol concentrations were determined using HPLC method. The 90% CI for gamma and delta tocotrienols for the ratio of log-transformation of GDT/TRF for Cmax and AUC0–∞ (values were anti-logged and expressed as a percentage) were beyond the bioequivalence limits (106.21–195.46, 154.11–195.93 and 52.35–99.66, 74.82–89.44 respectively). The Wilcoxon Signed Rank Test for Tmax did not show any significant difference between GDT and TRF for both isomers (p > 0.05). No adverse events were reported during the entire period of study. GDT was found not bioequivalent to TRF, in terms of AUC and Cmax. Gamma tocotrienol in GDT showed superior bioavailability whilst delta tocotrienol showed less bioavailability compared to TRF.


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"δ and γ tocotrienols suppress human hepatocellular carcinoma cell proliferation via regulation of Ras-Raf-MEK-ERK pathway-associated upstream signaling Burdeos GC, Ito J, Eitsuka T, Nakagawa K, Kimura F, Miyazawa T. δ and γ tocotrienols suppress human hepatocellular carcinoma cell proliferation via regulation of Ras-Raf-MEK-ERK pathway-associated upstream signaling. Food Funct. 2016 Oct 12;7(10):4170-4174. PubMed PMID: 27713963. Tocotrienol (T3) has recently gained increasing interest due to its anti-cancer effect. Here, we investigated the modulating effect of δ and γ T3 on the Ras-Raf-MEK-ERK oncogenic upstream signaling pathway in human hepatocellular carcinoma HepG2 cells. The results indicated that T3 regulated the upstream signaling cascades of this pathway."


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"Tocotrienol and cancer metastasis De Silva L, Chuah LH, Meganathan P, Fu JY. Tocotrienol and cancer metastasis. Biofactors. 2016 Mar-Apr;42(2):149-62. doi: 10.1002/biof.1259. Epub 2016 Mar 7. Review. PubMed PMID: 26948691. Tumor metastasis involves some of the most complex and dynamic processes in cancer, often leading to poor quality of life and inevitable death. The search for therapeutic compounds and treatment strategies to prevent and/or manage metastasis is the ultimate challenge to fight cancer. In the past two decades, research focus on vitamin E has had a shift from saturated tocopherols to unsaturated tocotrienols (T3). Despite sharing structural similarities with tocopherols, T3 strive to gain scientific prominence due to their anti-cancer effects. Recent studies have shed some light on the anti-metastatic properties of T3. In this review, the roles of T3 in each step of the metastatic process are discussed. During the invasion process, signaling pathways that regulate the extracellular matrix and tumor cell motility have been reported to be modulated by T3. Although studies on T3 and tumor cell migration are fairly limited, they were shown to play a vital role in the suppression of angiogenesis. Furthermore, the anti-inflammatory effect of T3 could be highly promising in the regulation of tumor microenvironment, which is crucial in supporting tumor growth in distant organs."


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Garlic

"Anticancer effects of garlic and garlic-derived compounds for breast cancer control Tsubura A, Lai YC, Kuwata M, Uehara N, Yoshizawa K. Anticancer effects of garlic and garlic-derived compounds for breast cancer control. Anticancer Agents Med Chem. 2011 Mar;11(3):249-53. Review. PubMed PMID: 21269259. Garlic and garlic-derived compounds reduce the development of mammary cancer in animals and suppress the growth of human breast cancer cells in culture. Oil-soluble compounds derived from garlic, such as diallyl disulfide (DADS), are more effective than water-soluble compounds in suppressing breast cancer. Mechanisms of action include the activation of metabolizing enzymes that detoxify carcinogens, the suppression of DNA adduct formation, the inhibition of the production of reactive oxygen species, the regulation of cell-cycle arrest and the induction of apoptosis. Selenium-enriched garlic or organoselenium compounds provide more potent protection against mammary carcinogenesis in rats and greater inhibition of breast cancer cells in culture than natural garlic or the respective organosulfur analogues. DADS synergizes the effect of eicosapentaenoic acid, a breast cancer suppressor, and antagonizes the effect of linoleic acid, a breast cancer enhancer. Moreover, garlic extract reduces the side effects caused by anti-cancer agents. Thus, garlic and garlic-derived compounds are promising candidates for breast cancer control."


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"Can garlic reduce risk of cancer? Rivlin RS. Can garlic reduce risk of cancer? The American Journal of Clinical Nutrition. 2009;89(1):17-18. doi:10.3945/ajcn.2008.27181. In addition to inhibiting primary cancer, allium derivatives from garlic may further inhibit metastatic processes. In an androgen-independent prostate cancer mouse model, the water-soluble allium derivative, S-allyllmercaptocysteine, inhibited metastases to the lung and adrenal gland by 90%."


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"Garlic: a review of potential therapeutic effects Bayan L, Koulivand PH, Gorji A. Garlic: a review of potential therapeutic effects. Avicenna Journal of Phytomedicine. 2014;4(1):1-14. Throughout history, many different cultures have recognized the potential use of garlic for prevention and treatment of different diseases. Recent studies support the effects of garlic and its extracts in a wide range of applications. These studies raised the possibility of revival of garlic therapeutic values in different diseases. Different compounds in garlic are thought to reduce the risk for cardiovascular diseases, have anti-tumor and anti-microbial effects, and show benefit on high blood glucose concentration. However, the exact mechanism of all ingredients and their long-term effects are not fully understood. Further studies are needed to elucidate the pathophysiological mechanisms of action of garlic as well as its efficacy and safety in treatment of various diseases."


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"Garlic and onions: Their cancer prevention properties Nicastro HL, Ross SA, Milner JA. Garlic and onions: Their cancer prevention properties. Cancer prevention research (Philadelphia, Pa). 2015;8(3):181-189. doi:10.1158/1940-6207.CAPR-14-0172. The Allium genus includes garlic, onions, shallots, leeks, and chives. These vegetables are popular in cuisines worldwide and are valued for their potential medicinal properties. Epidemiological studies, while limited in their abilities to assess Allium consumption, indicate some associations of Allium vegetable consumption with decreased risk of cancer, particularly cancers of the gastrointestinal tract. Limited intervention studies have been conducted to support these associations. The majority of supportive evidence on Allium vegetables cancer preventive effects comes from mechanistic studies. These studies highlight potential mechanisms of individual sulfur-containing compounds and of various preparations and extracts of these vegetables, including decreased bioactivation of carcinogens, antimicrobial activities, and redox modification. Allium vegetables and their components have effects at each stage of carcinogenesis and affect many biological processes that modify cancer risk. This review discusses the cancer preventive effects of Allium vegetables, particularly garlic and onions, and their bioactive sulfur compounds and highlights research gaps."


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"Garlic [Allium sativum]: a review of its potential use as an anti-cancer agent Thomson M, Ali M. Garlic [Allium sativum]: a review of its potential use as an anti-cancer agent. Curr Cancer Drug Targets. 2003 Feb;3(1):67-81. Review. PubMed PMID: 12570662. Garlic [Allium sativum] is among the oldest of all cultivated plants. It has been used as a medicinal agent for thousands of years. It is a remarkable plant, which has multiple beneficial effects such as antimicrobial, antithrombotic, hypolipidemic, antiarthritic, hypoglycemic and antitumor activity. In this review, we will discuss particularly the largely preclinical use of this agent in the treatment and prevention of cancer. A number of studies have demonstrated the chemopreventive activity of garlic by using different garlic preparations including fresh garlic extract, aged garlic, garlic oil and a number of organosulfur compounds derived from garlic. The chemopreventive activity has been attributed to the presence of organosulfur compounds in garlic. How this is achieved is not fully understood, but several modes of action have been proposed. These include its effect on drug metabolizing enzymes, antioxidant properties and tumor growth inhibition. Most of these studies were carried out in the animal models. Also, recent research has focused on the antimutagenic activity of garlic. Recently, it has been observed that aged garlic extract, but not the fresh garlic extract, exhibited radical scavenging activity. The two major compounds in aged garlic, S-allylcysteine and S-allylmercapto-L-cysteine, had the highest radical scavenging activity. In addition, some organosulfur compounds derived from garlic, including S-allylcysteine, have been found to retard the growth of chemically induced and transplantable tumors in several animal models. Therefore, the consumption of garlic may provide some kind of protection from cancer development."


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"The potential application of Allium sativum (garlic) for the treatment of bladder cancer Lamm DL, Riggs DR. The potential application of Allium sativum (garlic) for the treatment of bladder cancer. Urol Clin North Am. 2000 Feb;27(1):157-62, xi. Review. PubMed PMID: 10696254. Additional studies are needed to identify the active ingredients in Allium Sativum (garlic) that are responsible for the observed antitumor activity and immune stimulation. Garlic seems to detoxify chemical carcinogens and prevent carcinogenesis and can also directly inhibit the growth of cancer cells. Current data suggest that low molecular weight sulfur compounds and protein F4 have immune-stimulation properties. Garlic is reported to stimulate immunity, including macrophage activity, natural killer and killer cells, and LAK cells, and to increase the production of IL-2, TNF, and interferon-gamma. These cytokines are associated with the beneficial Th1 antitumor response, which is characteristic of effective cancer immunotherapies. As is true of BCG, garlic stimulates the proliferation of macrophages and lymphocytes and protects against the suppression of immunity by chemotherapy and ultraviolet radiation. Garlic is clearly not a panacea for cancer, but its broad range of beneficial effects are worthy of serious consideration in clinical trials for the prevention and treatment of cancer."


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Ginger

"Ginger and Its Constituents: Role in Prevention and Treatment of Gastrointestinal Cancer Prasad S, Tyagi AK. Ginger and Its Constituents: Role in Prevention and Treatment of Gastrointestinal Cancer. Gastroenterology Research and Practice. 2015;2015:142979. doi:10.1155/2015/142979. Gastrointestinal (GI) cancer, a cancer of different organs of the digestive system, is one of the most common cancers around the world. The incidence and death rate of some of these cancers are very high. Although a large variety of chemotherapeutic agents have been introduced since the last few decades to combat GI cancer, most of them are very expensive and have side effects. Therefore, the compounds derived from natural sources, which are considered to be safe and cost effective, are needed. Ginger (Zingiber officinale) is one of the most widely used natural products consumed as a spice and medicine for treating nausea, dysentery, heartburn, flatulence, diarrhea, loss of appetite, infections, cough, and bronchitis. Experimental studies showed that ginger and its active components including 6-gingerol and 6-shogaol exert anticancer activities against GI cancer. The anticancer activity of ginger is attributed to its ability to modulate several signaling molecules like NF-κB, STAT3, MAPK, PI3K, ERK1/2, Akt, TNF-α, COX-2, cyclin D1, cdk, MMP-9, survivin, cIAP-1, XIAP, Bcl-2, caspases, and other cell growth regulatory proteins. In this review, the evidences for the chemopreventive and chemotherapeutic potential of ginger extract and its active components using in vitro, animal models, and patients have been described."


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"Benefits of whole ginger extract in prostate cancer Karna P, et al. Benefits of whole ginger extract in prostate cancer. The British journal of nutrition. 2012;107(4):473-484. doi:10.1017/S0007114511003308. It is appreciated far and wide that increased and regular consumption of fruits and vegetables is linked with noteworthy anticancer benefits. Extensively consumed as a spice in foods and beverages worldwide, ginger (Zingiber officinale Roscoe) is an excellent source of several bioactive phenolics, including non-volatile pungent compounds such as gingerols, paradols, shogaols and gingerones. Ginger has been known to display anti-inflammatory, antioxidant and antiproliferative activities, indicating its promising role as a chemopreventive agent. Here, we show that whole ginger extract (GE) exerts significant growth-inhibitory and death-inductory effects in a spectrum of prostate cancer cells. Comprehensive studies have confirmed that GE perturbed cell-cycle progression, impaired reproductive capacity, modulated cell-cycle and apoptosis regulatory molecules and induced a caspase-driven, mitochondrially mediated apoptosis in human prostate cancer cells. Remarkably, daily oral feeding of 100 mg/kg body weight of GE inhibited growth and progression of PC-3 xenografts by approximately 56 % in nude mice, as shown by measurements of tumour volume. Tumour tissue from GE-treated mice showed reduced proliferation index and widespread apoptosis compared with controls, as determined by immunoblotting and immunohistochemical methods. Most importantly, GE did not exert any detectable toxicity in normal, rapidly dividing tissues such as gut and bone marrow. To the best of our knowledge, this is the first report to demonstrate the in vitro and in vivo anticancer activity of whole GE for the management of prostate cancer."


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"Ginger inhibits cell growth and modulates angiogenic factors in ovarian cancer cells Rhode J, et al. Ginger inhibits cell growth and modulates angiogenic factors in ovarian cancer cells. BMC Complementary and Alternative Medicine. 2007;7:44. doi:10.1186/1472-6882-7-44. Ginger (Zingiber officinale Rosc) is a natural dietary component with antioxidant and anticarcinogenic properties. The ginger component [6]-gingerol has been shown to exert anti-inflammatory effects through mediation of NF-κB. NF-κB can be constitutively activated in epithelial ovarian cancer cells and may contribute towards increased transcription and translation of angiogenic factors. In the present study, we investigated the effect of ginger on tumor cell growth and modulation of angiogenic factors in ovarian cancer cells in vitro."


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"Active ingredients of ginger as potential candidates in the prevention and treatment of diseases via modulation of biological activities Rahmani AH, shabrmi FMA, Aly SM. Active ingredients of ginger as potential candidates in the prevention and treatment of diseases via modulation of biological activities. International Journal of Physiology, Pathophysiology and Pharmacology. 2014;6(2):125-136. The current mode of treatment based on synthetic drugs is expensive and also causes genetic and metabolic alterations. However, safe and sound mode of treatment is needed to control the diseases development and progression. In this regards, medicinal plant and its constituents play an important role in diseases management via modulation of biological activities. Ginger, the rhizome of the Zingiber officinale, has shown therapeutic role in the health management since ancient time and considered as potential chemopreventive agent. Numerous studies based on clinical trials and animal model has shown that ginger and its constituents shows significant role in the prevention of diseases via modulation of genetic and metabolic activities. In this review, we focused on the therapeutics effects of ginger and its constituents in the diseases management, and its impact on genetic and metabolic activities."


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"Ginger-derived phenolic substances with cancer preventive and therapeutic potential Kundu JK, Na HK, Surh YJ. Ginger-derived phenolic substances with cancer preventive and therapeutic potential. Forum Nutr. 2009;61:182-92. doi: 10.1159/000212750. Epub 2009 Apr 7. Review. PubMed PMID: 19367122. Ginger, the rhizomes of Zingiber officinale Roscoe (Zingiberaceae), has widely been used as a spice and condiment in different societies. Besides its food-additive functions, ginger has a long history of medicinal use for the treatment of a variety of human ailments including common colds, fever, rheumatic disorders, gastrointestinal complications, motion sickness, diabetes, cancer, etc. Ginger contains several nonvolatile pungent principles viz. gingerols, shogaols, paradols and zingerone, which account for many of its health beneficial effects. Studies conducted in cultured cells as well as in experimental animals revealed that these pungent phenolics possess anticarcinogenic properties. This chapter summarizes updated information on chemopreventive and chemotherapeutic effects of ginger-derived phenolic substances and their underlying mechanisms."


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Ginseng (Panax spp.)

"Red ginseng and cancer treatment Wang C-Z, Anderson S, DU W, He T-C, Yuan C-S. Red ginseng and cancer treatment. Chinese journal of natural medicines. 2016;14(1):7-16. doi:10.3724/SP.J.1009.2016.00007. The ginseng family, including Panax ginseng (Asian ginseng), Panax quinquefolius (American ginseng), and Panax notoginseng (notoginseng), is commonly used herbal medicine. White ginseng is prepared by air-drying after harvest, while red ginseng is prepared by a steaming or heating process. The anticancer activity of red ginseng is significantly increased, due to the production of active anticancer ginsenosides during the steaming treatment, compared with that of white ginseng. Thus far, anticancer studies have been mostly focused on Asian ginseng. In this article, we review the research progress made in the anticancer activities of red Asian ginseng, red American ginseng and red notoginseng. The major anticancer mechanisms of red ginseng compounds include cell cycle arrest, induction of apoptosis/paraptosis, and inhibition of angiogenesis. The structure-function relationship analysis has revealed that the protopanaxadiol group ginsenosides have more potent effects than the protopanaxatriol group. Sugar molecules in ginsenosides inversely impact the antiproliferative potential of these compounds. In addition, ginsenoside stereoselectivity and double bond position also influence the anticancer activity. Future studies should focus on characterizing active red ginseng derivatives as potential anticancer drugs."


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"Anti-breast cancer activity of Fine Black ginseng (Panax ginseng Meyer) and ginsenoside Rg5 Kim S-J, Kim AK. Anti-breast cancer activity of Fine Black ginseng (Panax ginseng Meyer) and ginsenoside Rg5. Journal of Ginseng Research. 2015;39(2):125-134. doi:10.1016/j.jgr.2014.09.003. Background: Black ginseng (Ginseng Radix nigra, BG) refers to the ginseng steamed for nine times and fine roots (hairy roots) of that is called fine black ginseng (FBG). It is known that the content of saponin of FBG is higher than that of BG. Therefore, in this study, we examined antitumor effects against MCF-7 breast cancer cells to target the FBG extract and its main component, ginsenoside Rg5 (Rg5). Methods: Action mechanism was determined by MTT assay, cell cycle assay and western blot analysis. Results: The results from MTT assay showed that MCF-7 cell proliferation was inhibited by Rg5 treatment for 24, 48 and 72 h in a dose-dependent manner. Rg5 at different concentrations (0, 25, 50 and 100 μM), induced cell cycle arrest in G0/G1 phase through regulation of cell cycle-related proteins in MCF-7 cells. As shown in the results from western blot analysis, Rg5 increased expression of p53, p21WAF1/CIP1 and p15INK4B and decreased expression of Cyclin D1, Cyclin E2 and CDK4. Expression of apoptosis–related proteins including Bax, PARP and Cytochrome c was also regulated by Rg5. These results indicate that Rg5 stimulated cell apoptosis and cell cycle arrest at G0/G1 phase via regulation of cell cycle-associated proteins in MCF-7 cells. Conclusion: Rg5 promotes breast cancer cell apoptosis in a multi-path manner with higher potency compared to 20(S)-ginsenoside Rg3 (Rg3) in MCF-7 (HER2−/ER+) and MDA-MB-453 (HER2+/ER−) human breast cancer cell lines, and this suggests that Rg5 might be an effective natural new material in improving breast cancer."


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"Ginseng and Anticancer Drug Combination to Improve Cancer Chemotherapy: A Critical Review Chen S, et al. Ginseng and Anticancer Drug Combination to Improve Cancer Chemotherapy: A Critical Review. Evidence-based Complementary and Alternative Medicine : eCAM. 2014;2014:168940. doi:10.1155/2014/168940. Ginseng, a well-known herb, is often used in combination with anticancer drugs to enhance chemotherapy. Its wide usage as well as many documentations are often cited to support its clinical benefit of such combination therapy. However the literature based on objective evidence to make such recommendation is still lacking. The present review critically evaluated relevant studies reported in English and Chinese literature on such combination. Based on our review, we found good evidence from in vitro and in vivo animal studies showing enhanced antitumor effect when ginseng is used in combination with some anticancer drugs. However, there is insufficient clinical evidence of such benefit as very few clinical studies are available. Future research should focus on clinically relevant studies of such combination to validate the utility of ginseng in cancer."


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"Panax ginseng: a role in cancer therapy? Chang YS, Seo EK, Gyllenhaal C, Block KI. Panax ginseng: a role in cancer therapy? Integr Cancer Ther. 2003 Mar;2(1):13-33. Review. PubMed PMID: 12941165. Panax ginseng is a plant that has been used in traditional medicine in China for thousands of years. It is used as a general tonic or adaptogen with chronically ill patients and is frequently featured in traditional medicine prescriptions from China, Japan, and Korea used by cancer patients. The putative active compounds are the ginsenosides, of which there are more than two dozen. These compounds are found in both Panax ginseng and in other Panax species that are used in herbal medicine. Analysis of ginsenosides is being used in developing quality control assessments for ginseng, which has frequently been adulterated due to its high cost; many currently available standardized extracts do appear to contain the amounts of ginsenosides listed on package labeling. The toxicity of ginseng appears to be low: some of the reports of toxic episodes of ginseng may actually pertain to other components of multicomponent preparations. Very low incidence of toxicity has been observed in ginseng clinical trials using well-characterized preparations. Numerous pharmacological activities of ginseng and the ginsenosides have been explored: the authors review here the activities relating to cancer. Immune system modulation, antistress activities, and antihyperglycemic activities are among the most notable features of ginseng noted in laboratory and clinical analyses. Much testing has been done in humans to explore ginseng's purported antifatigue properties, but this area remains controversial. A number of investigations point to antitumor properties and other pharmacological activities related to cancer, but no trials have yet confirmed a clinically significant anticancer activity. Cancer patients may empirically find ginseng to be useful when they are fatigued, although clinical trials should be conducted to confirm its benefits."


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"Inflammation, cancer, and targets of ginseng Hofseth LJ, Wargovich MJ. Inflammation, cancer, and targets of ginseng. J Nutr. 2007 Jan;137(1 Suppl):183S-185S. Review. PubMed PMID: 17182823. There is evidence that ginseng has potent effects on key players in the inflammatory cascade. For example, ginsan, a polysaccharide extracted from P. ginseng, showed inhibition of s, the p38 MAP kinase pathway, and NF-κB in vitro and inhibition of proinflammatory cytokines in vivo. The ginsenoside Rg3 was shown to inhibit phorbol ester–induced COX-2 and NF-κB induction. BST204, a fermented ginseng extract, can inhibit inducible NOS (iNOS) expression and subsequent nitric oxide production from lipopolysaccharide-stimulated RAW264.7 murine macrophages. In contrast, others showed that incubation of the same cells with P. ginseng showed a dose-dependent stimulation of iNOS. We are currently examining the effects of P. quinquefolius on nitric oxide production in both ANA-1 mouse macrophages and colon cells as a part of ongoing investigations into the potential for ginseng to inhibit colon cancer. We recently showed that P. ginseng can inhibit chemically induced abberant crypt foci in mice. As mentioned, a cytokine storm is associated with active inflammation. It is therefore interesting to find that ginseng inhibits the lipopolysaccharide-induced production of tumor necrosis factor-α and other proinflammatory cytokines by cultured macrophages. Such an effect, therefore, may have a chemopreventive outcome."


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"Enhanced anticancer effects of a mixture of low-dose mushrooms and Panax ginseng root extracts in human colorectal cancer cells Lee MS, et al. Enhanced anticancer effects of a mixture of low-dose mushrooms and Panax ginseng root extracts in human colorectal cancer cells. Oncol Rep. 2017 Sep;38(3):1597-1604. doi: 10.3892/or.2017.5796. Epub 2017 Jul 7. PubMed PMID: 28714027. Worldwide, colorectal cancer is the third most common cancer in men and the second most common in women. As conventional colorectal cancer therapies result in various side effects, there is a need for adjuvant therapy that can enhance the conventional therapies without complications. In this study, we investigated the anticancer effects of combined mixture of the several medicinal mushrooms and Panax ginseng root extracts (also called Amex7) as an adjuvant compound in the treatment of human colorectal cancer. We observed the in vivo inhibitory effect of Amex7 (1.25, 6.25, and 12.5 ml/kg, oral administration, twice daily) on tumor growth in a mouse model xenografted with HT-29 human colorectal cancer cells. In vitro, at 6, 12, and 24 h after 4% Amex7 treatment, we analyzed cell cycle by flow cytometry and the expression levels of cell cycle progression, apoptosis, and DNA damage repair-related proteins using immunoblotting and immunofluorescence staining in HT-29 cell line. As a result, Amex7 significantly suppressed tumor growth in HT-29 human colorectal cancer cells and xenografts. In vitro, Amex7 induced G2/M arrest through the regulation of cell cycle proteins and cell death by apoptosis and autophagy. Additionally, Amex7 consistently induced DNA damage and delayed the repair of Amex7-induced DNA damage by reducing the level of HR repair proteins. In conclusion, Amex7 enhanced anticancer effects through the induction of G2/M arrest and cell death, including apoptosis and autophagy. Furthermore, Amex7 impaired DNA damage repair. The present study provides a scientific rationale for the clinical use of a combined mixture of medicinal mushrooms and P. ginseng root extracts as an adjuvant treatment in human colorectal cancer."


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"Ginseng and cancer Unlu A, Nayir E, Kirca O, Ay H, Ozdogan M. Ginseng and cancer. J BUON. 2016 Nov-Dec;21(6):1383-1387. Review. PubMed PMID: 28039696. Derived from the Greek word Panacea that means 'cure for all', Ginseng (Panax) has had an important place in Chinese Medicine for many of years. As the name suggests, it is believed to be a miraculous plant effective in the treatment of many health problems. It is claimed to have many effects such as sedative, hypnotic, aphrodisiac, antidepressant, diuretic, and stimulating effects, and to be effective in the treatment of certain health problems such as diabetes, Alzheimer's disease, erectile dysfunction and infections. In addition, its effects on the prevention and treatment of cancer as well as on the reduction of cancer-related symptoms have been prioritized in recent years. However, the studies that have been done so far do not confirm these effects. Although certain favorable results have been obtained in some studies intended for investigating its effects on acute nasopharyngitis, diabetes, Alzheimer's disease, and erectile dysfunction, it is early to say anything conclusive. And in cancer patients, it has been shown to be effective in reducing weakness due to cancer and its treatment. On the other hand, ginseng may cause important drug interactions, although it is described as a relatively safe product. For now, it seems to be reasonable to use ginseng only for cancer-related weakness in cancer patients at this point. But this should definitely be done within the knowledge and under the control of oncologists."


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Green tea extract (standardized to EGCg 50%)

"Cancer and metastasis: prevention and treatment by green tea Khan N, Mukhtar H. Cancer and metastasis: prevention and treatment by green tea. Cancer metastasis reviews. 2010;29(3):435-445. doi:10.1007/s10555-010-9236-1. Metastasis is the most deadly aspect of cancer and results from several interconnected processes including cell proliferation, angiogenesis, cell adhesion, migration, and invasion into the surrounding tissue. The appearance of metastases in organs distant from the primary tumor is the most destructive feature of cancer. Metastasis remains the principal cause of the deaths of cancer patients despite decades of research aimed at restricting tumor growth. Therefore, inhibition of metastasis is one of the most important issues in cancer research. Several in vitro, in vivo, and epidemiological studies have reported that the consumption of green tea may decrease cancer risk. (−)-Epigallocatechin-3-gallate, major component of green tea, has been shown to inhibit tumor invasion and angiogenesis which are essential for tumor growth and metastasis. This article summarizes the effect of green tea and its major polyphenolic compounds on cancer and metastasis against most commonly diagnosed cancer sites."


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"Green tea compounds in breast cancer prevention and treatment Li M-J, Yin Y-C, Wang J, Jiang Y-F. Green tea compounds in breast cancer prevention and treatment. World Journal of Clinical Oncology. 2014;5(3):520-528. doi:10.5306/wjco.v5.i3.520. Breast cancer is the most common cancer among women. In recent years, many in vitro and in vivo studies indicate that green tea possesses anti-cancer effects. The epidemiological studies, however, have produced inconclusive results in humans. Likewise, results from animal models about the preventive or therapeutic effects of green tea components are inconclusive. The mechanisms by which green tea intake may influence the risk of breast cancer in humans remain elusive mechanisms by which green tea intake may influence. Here, we review recent studies of green tea polyphenols and their applications in the prevention and treatment of breast cancer. Furthermore, we discuss the effect of green tea components on breast cancer by reviewing epidemiological studies, animal model studies and clinical trials. At last, we discuss the mechanisms by which green tea components suppress the development and recurrence of breast cancer. A better understanding of the mechanisms will improve the utilization of green tea in breast cancer prevention and therapy and pave the way to novel prevention and treatment strategies for breast cancer."


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"Green tea: Health benefits as cancer preventive for humans Fujiki H. Green tea: Health benefits as cancer preventive for humans. Chem Rec. 2005;5(3):119-32. Review. PubMed PMID: 15889414. Green tea is an acknowledged cancer preventive in Japan. The aim of this review article is to develop the concept of cancer prevention with green tea beverage for humans, which has largely been our exclusive research territory. This paper briefly reviews several topics, beginning with the introduction of our initial work on penta-O-galloyl-beta-D-glucose and (-)-epigallocatechin gallate (EGCG), the main constituent of green tea extract. The mechanisms of EGCG action, particularly the reduction of TNF-alpha are discussed, and we show how use of 3H-EGCG revealed a wide range of target organs for cancer prevention. The results of an epidemiological study in Saitama Prefecture allowed us to determine the cancer preventive amount of green tea-10 Japanese-size cups per day, about 2.5 g green tea extract-which made it possible for us to introduce the two-stage strategy of cancer prevention with green tea. The first stage is the delay of cancer onset for the general population. The second stage is the prevention of recurrence of cancer for patients following cancer treatment. Combination cancer prevention with green tea and cancer preventive drugs is proving especially beneficial for Japanese, who drink green tea every day. And finally, the stimulating comments of Prof. Jim Watson have encouraged green tea scientists."


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"Implications of Green Tea and Its Constituents in the Prevention of Cancer via the Modulation of Cell Signalling Pathway Rahmani AH, Al shabrmi Fahad M., Allemailem KS, Aly SM, Khan MA. Implications of Green Tea and Its Constituents in the Prevention of Cancer via the Modulation of Cell Signalling Pathway. BioMed Research International. 2015;2015:925640. doi:10.1155/2015/925640. Green tea is commonly used as a beverage worldwide, especially in China, Japan, Morocco, and Saudi Arabia. Green tea and its constituents have been considered very effective in the prevention and treatment of various diseases. It contains a variety of catechins, which show a pivotal role in the modulation of biological activities and also act as chemopreventive agents. Earlier studies have confirmed that green tea and its chief constituent epigallocatechin gallate (EGCG) have a potential role in the management of cancer through the modulation of cell signaling pathways. In this review, we focused on the beneficial effects of green tea and its constituents in the cancer prevention and treatment and its impact on modulation of molecular pathways."


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"EGCG, GREEN TEA POLYPHENOLS AND THEIR SYNTHETIC ANALOGS AND PRODRUGS FOR HUMAN CANCER PREVENTION AND TREATMENT Chen D, et al. EGCG, GREEN TEA POLYPHENOLS AND THEIR SYNTHETIC ANALOGS AND PRODRUGS FOR HUMAN CANCER PREVENTION AND TREATMENT. Advances in Clinical Chemistry. 2011;53:155-177. Cancer-preventive effects of tea polyphenols, especially epigallocatechin-3-gallate (EGCG), have been demonstrated by epidemiological, preclinical, and clinical studies. Green tea polyphenols such as EGCG have the potential to affect multiple biological pathways, including gene expression, growth factor-mediated pathways, the mitogen-activated protein kinase-dependent pathway, and the ubiquitin/proteasome degradation pathway. Therefore, identification of the molecular targets of EGCG should greatly facilitate a better understanding of the mechanisms underlying its anticancer and cancer-preventive activities. Performing structure–activity relationship (SAR) studies could also greatly enhance the discovery of novel tea polyphenol analogs as potential anticancer and cancer-preventive agents. In this chapter, we review the relevant literature as it relates to the effects of natural and synthetic green tea polyphenols and EGCG analogs on human cancer cells and their potential molecular targets as well as their antitumor effects. We also discuss the implications of green tea polyphenols in cancer prevention."


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"Biological Effects of Green Tea Capsule Supplementation in Pre-Surgery Postmenopausal Breast Cancer Patients Yu SS, et al. Biological Effects of Green Tea Capsule Supplementation in Pre-Surgery Postmenopausal Breast Cancer Patients. Frontiers in Oncology. 2013;3:298. doi:10.3389/fonc.2013.00298. Regular green tea intake has been associated with an inverse risk of breast cancer. There are compelling experimental evidence that green tea, particularly, epigallocatechin gallate, the most potent green tea catechin, possesses a range of anti-cancer properties. We conducted a pre-surgical study of green tea capsules vs. no-green tea in women with primary breast cancer to determine the effects of green tea supplementation on markers of biological response. Postmenopausal women with ductal carcinoma in situ(DCIS) or stage I or II breast cancer took green tea capsules (940 mg per day) for an average of 35 days prior to surgery (n = 13) or received no green tea (n = 18). Paired diagnostic core biopsy and surgical specimen samples were analyzed for cell proliferation (Ki-67), apoptosis (caspase-3), and angiogenesis (CD34) separately in benign and malignant cell components. There were no significant changes in caspase-3 and CD34 in the green tea and no green tea groups and there were no significant differences in the change in these markers between the two groups. However, Ki-67 levels declined in both benign and malignant cell components in the green tea group; the decline in Ki-67 positivity in malignant cells was not statistically significant (P = 0.10) but was statistically significant in benign cells (P = 0.007). Ki-67 levels in benign and malignant cells did not change significantly in the no green tea group. There was a statistically significant difference in the change in Ki-67 in benign cells (P = 0.033) between the green tea and the no green tea groups. The trend of a consistent reduction in Ki-67 in both benign and malignant cells in the green tea group warrants further investigations in a larger study of breast cancer patients or high-risk women."


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"Both Phenolic and Non-phenolic Green Tea Fractions Inhibit Migration of Cancer Cells Seo EJ, et al. Both Phenolic and Non-phenolic Green Tea Fractions Inhibit Migration of Cancer Cells. Front Pharmacol. 2016 Nov 3;7:398. doi: 10.3389/fphar.2016.00398. eCollection 2016. PubMed PMID: 28194107; PubMed Central PMCID: PMC5278262. Green tea consumption is associated with chemoprevention of many cancer types. Fresh tea leaves are rich in polyphenolic catechins, which can constitute up to 30% of the dry leaf weight. While the polyphenols of green tea have been well investigated, it is still largely unknown, whether or not non-phenolic constituents also reveal chemopreventive and anti-metastatic effects. In this study, we investigated the effects of a fraction of green tea rich in phenolic compounds (PF), a non-phenolic fraction (NPF), which contains glyceroglycolipids (GGL), and a pure glyceroglycolipid compound isolated from the non-phenolic fraction in human cancer. Dried green tea leaves were extracted and applied to a Sephadex LH-20 column. The resazurin reduction assay was used to investigate the cytotoxicity of green tea samples toward human HepG2 hepatocellular carcinoma and normal AML12 hepatocytes cells. Gene expression profiling was performed by mRNA microarray hybridization and the microarray results were validated by RT-PCR. The scratch migration assay was used to investigate the effects of green tea samples on cell migration in vitro. The changes of microtubule dynamics were observed using fluorescence microscopy. PF and NPF were prepared from methanol extract of green tea. A GGL was isolated from NPF. All three green tea samples did not show significant cytotoxic activity up to 10 μg/mL in both HepG2 and AML12 cells, whereas cytotoxicity of the control drug doxorubicin was observed with both cell lines (IC50 on AML12: 0.024 μg/mL, IC50 on HepG2: 2.103 μg/mL). We identified three sets of genes differentially expressed upon treatment with the green tea samples. The genes were associated with cytoskeleton formation, cellular movement, and morphology. The correlation coefficients between mRNA expression values determined by microarray and RT-PCR were R = 0.94. HepG2 and U2OS cells treated with green tea extracts showed the delayed closures. Besides, the number of distinct tubulin filaments decreased upon treatment with green tea samples. We identified not only PF, but also glyceroglycolipids in NPF as contributing factors to the chemopreventive effects of green tea. Both PF and NPF of green tea inhibited cancer cell migration by the disassembly of microtubules, even though they were not cytotoxic."


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"Chemoprevention of oral cancer by green tea Hsu SD, et al. Chemoprevention of oral cancer by green tea. Gen Dent. 2002 Mar-Apr;50(2):140-6. PubMed PMID: 12004708. Green tea has been a popular beverage for many centuries. Only recently, however, has the anti-cancer power of green tea constituents been unveiled. Green tea polyphenols are found to induce apoptosis (programmed cell death) in many types of tumor cells, including oral cancer cells. However, mechanisms that enable normal cells to evade the apoptotic effect still are not understood. In this study, cell growth and invasion assays combined with apoptosis assays were used to examine the effects of green tea extracts, green tea polyphenols, and the most potent green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), on normal human keratinocytes and oral carcinoma cells. The results showed that green tea and its constituents selectively induce apoptosis only in oral carcinoma cells, while EGCG was able to inhibit the growth and invasion of oral carcinoma cells. These differential responses to green tea and its constituents between normal and malignant cells were correlated with the induction of p57, a cell cycle regulator. These data suggest that the chemopreventive effects of green tea polyphenols may involve a p57 mediated survival pathway in normal epithelial cells, while oral carcinoma cells undergo an apoptotic pathway. Therefore, regular consumption of green tea could be beneficial in the prevention of oral cancer."


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"Molecular targets for green tea in prostate cancer prevention Adhami VM, Ahmad N, Mukhtar H. Molecular targets for green tea in prostate cancer prevention. J Nutr. 2003 Jul;133(7 Suppl):2417S-2424S. Review. PubMed PMID: 12840218. Prostate cancer (PCa) is the most frequently diagnosed malignancy and the second leading cause of cancer-related deaths in American males. For these reasons, it is necessary to intensify our efforts for better understanding and development of novel treatment and chemopreventive approaches for this disease. In recent years, green tea has gained considerable attention as an agent that could reduce the risk of several cancer types. The cancer-chemopreventive effects of green tea appear to be mediated by the polyphenolic constituents present therein. Based on geographical observations that suggest that the incidence of PCa is lower in Japanese and Chinese populations that consume green tea on a regular basis, we hypothesized that green tea and/or its constituents could be effective for chemoprevention of PCa. To investigate this hypothesis, we initiated a program for the chemoprevention of PCa by green tea. In cell-culture systems that employ human PCa cells DU145 (androgen insensitive) and LNCaP (androgen sensitive), we found that the major polyphenolic constituent (-)-epigallocatechin-3-gallate (EGCG) of green tea induces 1) apoptosis, 2) cell-growth inhibition, and 3) cyclin kinase inhibitor WAF-1/p21-mediated cell-cycle dysregulation. More recently, using a cDNA microarray, we found that EGCG treatment of LNCaP cells results in 1) induction of genes that functionally exhibit growth-inhibitory effects, and 2) repression of genes that belong to the G-protein signaling network. In animal studies that employ a transgenic adenocarcinoma of the mouse prostate (TRAMP), which is a model that mimics progressive forms of human prostatic disease, we observed that oral infusion of a polyphenolic fraction isolated from green tea (GTP) at a human achievable dose (equivalent to 6 cups of green tea/d) significantly inhibits PCa development and metastasis. We extended these studies and more recently observed increased expression of genes related to angiogenesis such as vascular endothelial growth factor (VEGF) and those related to metastasis such as matrix metalloproteinases (MMP)-2 and MMP-9 in prostate cancer of TRAMP mice. Oral feeding of GTP as the sole source of drinking fluid to TRAMP mice results in significant inhibition of VEGF, MMP-2 and MMP-9. These data suggest that there are multiple targets for PCa chemoprevention by green tea and highlight the need for further studies to identify novel pathways that may be modulated by green tea or its polyphenolic constituents that could be further exploited for prevention and/or treatment of PCa."


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Quercetin

"Quercetin in Cancer Treatment, Alone or in Combination with Conventional Therapeutics? Brito AF, et al. Quercetin in Cancer Treatment, Alone or in Combination with Conventional Therapeutics? Curr Med Chem. 2015;22(26):3025-39. Review. PubMed PMID: 26264923. Cancer is a problem of global importance, since the incidence is increasing worldwide and therapeutic options are generally limited. Thus, it becomes imperative to find new therapeutic targets as well as new molecules with therapeutic potential for tumors. Flavonoids are polyphenolic compounds that may be potential therapeutic agents. Several studies have shown that these compounds have a higher anticancer potential. Among the flavonoids in the human diet, quercetin is one of the most important. In the last decades, several anticancer properties of quercetin have been described, such as cell signaling, pro-apoptotic, anti-proliferative and anti-oxidant effects, growth suppression. In fact, it is now well known that quercetin has diverse biological effects, inhibiting multiple enzymes involved in cell proliferation, as well as, in signal transduction pathways. On the other hand, there are also studies reporting potential synergistic effects when combined quercetin with chemotherapeutic agents or radiotherapy. In fact, several studies which aim to explore the anticancer potential of these combined treatments have already been published, the majority with promising results. Actually it is well known that quercetin can act on the chemosensitization and radiosensitization but also as chemoprotective and radioprotective, protecting normal cells of the side effects that results from chemotherapy and radiotherapy, which obviously provides notable advantages in their use in anticancer treatment. Thus, all these data indicate that quercetin may have a key role in anticancer treatment. In this context, this review is focused on the relationship between flavonoids and cancer, with special emphasis on the role of quercetin."


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"Effects of low dose quercetin: Cancer cell-specific inhibition of cell cycle progression Jeong J-H, An JY, Kwon YT, Rhee JG, Lee YJ. Effects of low dose quercetin: Cancer cell-specific inhibition of cell cycle progression. Journal of cellular biochemistry. 2009;106(1):73-82. doi:10.1002/jcb.21977. Quercetin is a flavonoid present in many vegetables, fruits and beverages. Due to its anti-oxidant, anti-tumor and anti-inflammatory activity, quercetin has been studied extensively as a chemoprevention agent in several cancer models. Since most of these studies used higher doses of quercetin than clinically achievable, we focused on the effectiveness of physiologically relevant doses of quercetin. A low dose of quercetin exerted cancer cell-specific inhibition of proliferation and this inhibition resulted from cell cycle arrest at the G1 phase. Quercetin induced p21 CDK inhibitor with a concomitant decrease of phosphorylation of pRb, which inhibits the G1/S cell cycle progression by trapping E2F1. A low dose of quercetin induced mild DNA damage and Chk2 activation, which is the main regulator of p21 expression by quercetin. In addition, quercetin down-regulated the cyclin B1 and CDK1, essential components of G2/M cell cycle progression. Inhibition of the recruitment of key transcription factor NF-Y to cyclin B1 gene promoter by quercetin led to transcriptional inhibition. This study proved that the chemopreventive efficacy of a physiologically relevant dose of quercetin can be achievable through the inhibition of cell cycle progression."


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"Quercetin and Cancer Chemoprevention Gibellini L, Pinti M, Nasi M, et al. Quercetin and Cancer Chemoprevention. Evidence-based Complementary and Alternative Medicine : eCAM. 2011;2011:591356. doi:10.1093/ecam/neq053. Several molecules present in the diet, including flavonoids, can inhibit the growth of cancer cells with an ability to act as “chemopreventers”. Their cancer-preventive effects have been attributed to various mechanisms, including the induction of cell-cycle arrest and/or apoptosis as well as the antioxidant functions. The antioxidant activity of chemopreventers has recently received a great interest, essentially because oxidative stress participates in the initiation and progression of different pathological conditions, including cancer. Since antioxidants are capable of preventing oxidative damage, the wide use of natural food-derived antioxidants is receiving greater attention as potential anti-carcinogens. Among flavonoids, quercetin (Qu) is considered an excellent free-radical scavenging antioxidant, even if such an activity strongly depends on the intracellular availability of reduced glutathione. Apart from antioxidant activity, Qu also exerts a direct, pro-apoptotic effect in tumor cells, and can indeed block the growth of several human cancer cell lines at different phases of the cell cycle. Both these effects have been documented in a wide variety of cellular models as well as in animal models. The high toxicity exerted by Qu on cancer cells perfectly matches with the almost total absence of any damages for normal, non-transformed cells. In this review we discuss the molecular mechanisms that are based on the biological effects of Qu, and their relevance for human health."


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"Quercetin suppresses lung cancer growth by targeting Aurora B kinase Xingyu Z, et al. Quercetin suppresses lung cancer growth by targeting Aurora B kinase. Cancer Medicine. 2016;5(11):3156-3165. doi:10.1002/cam4.891. aurora B kinase is highly expressed in several cancer cells and promotes tumorigenesis and progression, and therefore, it is an important target for drug to treat tumors. Quercetin was identified to be an antitumor agent. Herein, we report for the first time that quercetin inhibited aurora B activities by directly binding with aurora B in vitro and in vivo. Ex vivo studies showed that quercetin inhibited aurora B activities in JB6 Cl41 cells and A549 lung cancer cells. Moreover, knockdown of aurora B in A549 cells decreased their sensitivities to quercetin. In vivo study demonstrated that injection of quercetin in A549 tumor‐bearing mice effectively suppressed cancer growth. The phosphorylation of histone 3 in tumor tissues was also decreased after quercetin treatment. In short, quercetin can suppress growth of lung cancer cells as an aurora B inhibitor both in vitro and in vivo."


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"The flavonoid quercetin inhibits pancreatic cancer growth in vitro and in vivo Angst E, et al. The flavonoid quercetin inhibits pancreatic cancer growth in vitro and in vivo. Pancreas. 2013;42(2):223-229. doi:10.1097/MPA.0b013e318264ccae. The flavonoid quercetin holds promise as an anti-tumor agent in several preclinical animal models. However, the efficacy of oral administration of quercetin in a pancreatic cancer mouse model is unknown. The anti-proliferative effects of quercetin alone or in combination with gemcitabine were tested in two human pancreatic cancer cell lines using cell count and MTT assays. Apoptosis was evaluated by flow cytometry. Tumor growth in vivo was investigated in an orthotopic pancreatic cancer animal model using bioluminescence. Quercetin was administered orally in the diet. Quercetin inhibited the growth of pancreatic cancer cell lines, which was caused by an induction of apoptosis. In addition, dietary supplementation of quercetin attenuated the growth of orthotopically transplanted pancreatic xenografts. The combination of gemcitabine and quercetin had no additional effect compared to quercetin alone. In vivo quercetin caused significant apoptosis and reduced tumor cell proliferation. Our data provide evidence that oral administration of quercetin was capable of inhibiting growth of orthotopic pancreatic tumors in a nude mouse model. These data suggest a possible benefit of quercetin in patients with pancreatic cancer."


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"Quercetin inhibits human breast cancer cell proliferation and induces apoptosis via Bcl-2 and Bax regulation Duo J, Ying GG, Wang GW, Zhang L. Quercetin inhibits human breast cancer cell proliferation and induces apoptosis via Bcl-2 and Bax regulation. Mol Med Rep. 2012 Jun;5(6):1453-6. doi: 10.3892/mmr.2012.845. Epub 2012 Mar 22. PubMed PMID: 22447039. Breast cancer is a disease in which cancer cells form in the tissues of the breast. The present study aimed to explore the effect of the flavonoid compound quercetin on the growth and apoptosis of human breast cancer cells. Varying concentrations (12.5, 25, 50, 100, 200 µM) of quercetin were applied to cultured MCF-7 human breast cancer cells for defined lengths of time. At 50 to 200 µM doses, quercetin significantly inhibited the proliferation of MCF-7 cells assessed by MTT colorimetry, in both dose- and time-dependent manners (P < 0.05). The compound also increased apoptosis after 48 h of exposure (P < 0.05). Furthermore, following quercetin treatment Bcl-2 expression decreased significantly while Bax expression increased significantly (P < 0.05). In brief, quercetin inhibits cell growth and induces apoptosis in MCF-7 human breast cancer cells. The mechanisms behind these effects may stem from the downregulation of Bcl-2 protein expression and upregulation of Bax expression."


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"Molecular mechanisms of action of quercetin in cancer: recent advances Kashyap D, Mittal S, Sak K, Singhal P, Tuli HS. Molecular mechanisms of action of quercetin in cancer: recent advances. Tumour Biol. 2016 Oct;37(10):12927-12939. Epub 2016 Jul 22. Review. PubMed PMID: 27448306. In the last few decades, the scientific community has discovered an immense potential of natural compounds in the treatment of dreadful diseases such as cancer. Besides the availability of a variety of natural bioactive molecules, efficacious cancer therapy still needs to be developed. So, to design an efficacious cancer treatment strategy, it is essential to understand the interactions of natural molecules with their respective cellular targets. Quercetin (Quer) is a naturally occurring flavonol present in many commonly consumed food items. It governs numerous intracellular targets, including the proteins involved in apoptosis, cell cycle, detoxification, antioxidant replication, and angiogenesis. The weight of available synergistic studies vigorously fortifies the utilization of Quer as a chemoprevention drug. This extensive review covers various therapeutic interactions of Quer with their recognized cellular targets involved in cancer treatment."


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Turmeric (Curcumin BCM95 form)

"The multifaceted role of curcumin in cancer prevention and treatment Shanmugam MK, et al. The multifaceted role of curcumin in cancer prevention and treatment. Molecules. 2015 Feb 5;20(2):2728-69. doi: 10.3390/molecules20022728. Review. PubMed PMID: 25665066. Despite significant advances in treatment modalities over the last decade, neither the incidence of the disease nor the mortality due to cancer has altered in the last thirty years. Available anti-cancer drugs exhibit limited efficacy, associated with severe side effects, and are also expensive. Thus identification of pharmacological agents that do not have these disadvantages is required. Curcumin, a polyphenolic compound derived from turmeric (Curcumin longa), is one such agent that has been extensively studied over the last three to four decades for its potential anti-inflammatory and/or anti-cancer effects. Curcumin has been found to suppress initiation, progression, and metastasis of a variety of tumors. These anti-cancer effects are predominantly mediated through its negative regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other oncogenic molecules. It also abrogates proliferation of cancer cells by arresting them at different phases of the cell cycle and/or by inducing their apoptosis. The current review focuses on the diverse molecular targets modulated by curcumin that contribute to its efficacy against various human cancers."


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"Curcumin (Turmeric) and cancer Unlu A, Nayir E, Dogukan Kalenderoglu M, Kirca O, Ozdogan M. Curcumin (Turmeric) and cancer. J BUON. 2016 Sept-Oct;21(5):1050-1060. Review. PubMed PMID: 27837604. Curcumin is a substance obtained from the root of the turmeric plant, which has the feature of being a yellow or orange pigment. It is also the main component of curry powder commonly used in Asian cuisine. Curcumin, a substance that has had an important place in traditional Indian and Chinese medicines for thousands of years, has been the center of interest for scientific studies especially in the field of cancer treatment for several years. Laboratory studies have presented some favorable results in terms of curcumin's antioxidant, antiinflammatory and anticancer properties in particular. However, since such findings have yet to be confirmed in clinical studies, its effect on humans is not clearly known. Therefore, when its advantages in terms of toxicity, cost and availability as well as the favorable results achieved in laboratory studies are considered, it would not be wrong to say that curcumin is a substance worth being studied. However, for now the most correct approach is to abstain from its use for medical purposes due to lack of adequate reliable evidence obtained from clinical studies, and because of its potential to interfere with other drugs."


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"Curcumin in various cancers Shehzad A, Lee J, Lee YS. Curcumin in various cancers. Biofactors. 2013 Jan-Feb;39(1):56-68. doi: 10.1002/biof.1068. Epub 2013 Jan 10. Review. PubMed PMID: 23303705. Curcumin (diferuloylmethane), an active constituent of turmeric, is a well-described phytochemical, which has been used since ancient times for the treatment of various diseases. The dysregulation of cell signaling pathways by the gradual alteration of regulatory proteins is the root cause of cancers. Curcumin modulates regulatory proteins through various molecular mechanisms. Several research studies have provided in-depth analysis of multiple targets through which curcumin induces protective effects against cancers including gastrointestinal, genitourinary, gynecological, hematological, pulmonary, thymic, brain, breast, and bone. The molecular mechanisms of action of curcumin in treating different types of cancers remain under investigation. The multifaceted role of this dietary agent is mediated through its inhibition of several cell signaling pathways at multiple levels. Curcumin has the ability to inhibit carcinogenicity through the modulation of the cell cycle by binding directly and indirectly to molecular targets including transcription factors (NF-kB, STAT3, β-catenin, and AP-1), growth factors (EGF, PDGF, and VEGF), enzymes (COX-2, iNOS, and MMPs), kinases (cyclin D1, CDKs, Akt, PKC, and AMPK), inflammatory cytokines (TNF, MCP, IL-1, and IL-6), upregulation of proapoptotic (Bax, Bad, and Bak) and downregulation of antiapoptotic proteins (Bcl(2) and Bcl-xL). A variety of animal models and human studies have proven that curcumin is safe and well tolerated even at very high doses. This study elaborates the current understanding of the chemopreventive effects of curcumin through its multiple molecular pathways and highlights its therapeutic value in the treatment and prevention of a wide range of cancers."


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"Curcumin and Cancer Cells: How Many Ways Can Curry Kill Tumor Cells Selectively? Ravindran J, Prasad S, Aggarwal BB. Curcumin and Cancer Cells: How Many Ways Can Curry Kill Tumor Cells Selectively? The AAPS Journal. 2009;11(3):495-510. doi:10.1208/s12248-009-9128-x. Cancer is a hyperproliferative disorder that is usually treated by chemotherapeutic agents that are toxic not only to tumor cells but also to normal cells, so these agents produce major side effects. In addition, these agents are highly expensive and thus not affordable for most. Moreover, such agents cannot be used for cancer prevention. Traditional medicines are generally free of the deleterious side effects and usually inexpensive. Curcumin, a component of turmeric (Curcuma longa), is one such agent that is safe, affordable, and efficacious. How curcumin kills tumor cells is the focus of this review. We show that curcumin modulates growth of tumor cells through regulation of multiple cell signaling pathways including cell proliferation pathway (cyclin D1, c-myc), cell survival pathway (Bcl-2, Bcl-xL, cFLIP, XIAP, c-IAP1), caspase activation pathway (caspase-8, 3, 9), tumor suppressor pathway (p53, p21) death receptor pathway (DR4, DR5), mitochondrial pathways, and protein kinase pathway (JNK, Akt, and AMPK). How curcumin selectively kills tumor cells, and not normal cells, is also described in detail."


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"New perspectives of curcumin in cancer prevention Park W, Amin AR. R, Chen ZG, Shin DM. New perspectives of curcumin in cancer prevention. Cancer prevention research (Philadelphia, Pa). 2013;6(5):387-400. doi:10.1158/1940-6207.CAPR-12-0410. Numerous natural compounds have been extensively investigated for their potential for cancer prevention over decades. Curcumin, from Curcuma longa, is a highly promising natural compound that can be potentially used for chemoprevention of multiple cancers. Curcumin modulates multiple molecular pathways involved in the lengthy carcinogenesis process to exert its chemopreventive effects through several mechanisms: promoting apoptosis, inhibiting survival signals, scavenging reactive oxidative species (ROS), and reducing the inflammatory cancer microenvironment. Curcumin fulfills the characteristics for an ideal chemopreventive agent with its low toxicity, affordability, and easy accessibility. Nevertheless, the clinical application of curcumin is currently compromised by its poor bioavailability. Here we review the potential of curcumin in cancer prevention, its molecular targets, and action mechanisms. Finally, we suggest specific recommendations to improve its efficacy and bioavailability for clinical applications."


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"Therapeutic Potential of Curcumin for the Treatment of Brain Tumors Klinger NV, Mittal S. Therapeutic Potential of Curcumin for the Treatment of Brain Tumors. Oxid Med Cell Longev. 2016;2016:9324085. Epub 2016 Oct 11. Review. PubMed PMID: 27807473; PubMed Central PMCID: PMC5078657. Brain malignancies currently carry a poor prognosis despite the current multimodal standard of care that includes surgical resection and adjuvant chemotherapy and radiation. As new therapies are desperately needed, naturally occurring chemical compounds have been studied for their potential chemotherapeutic benefits and low toxicity profile. Curcumin, found in the rhizome of turmeric, has extensive therapeutic promise via its antioxidant, anti-inflammatory, and antiproliferative properties. Preclinical in vitro and in vivo data have shown it to be an effective treatment for brain tumors including glioblastoma multiforme. These effects are potentiated by curcumin's ability to induce G2/M cell cycle arrest, activation of apoptotic pathways, induction of autophagy, disruption of molecular signaling, inhibition of invasion, and metastasis and by increasing the efficacy of existing chemotherapeutics. Further, clinical data suggest that it has low toxicity in humans even at large doses. Curcumin is a promising nutraceutical compound that should be evaluated in clinical trials for the treatment of human brain tumors."


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"Molecular Mechanisms of Anti-metastatic Activity of Curcumin Deng YI, Verron E, Rohanizadeh R. Molecular Mechanisms of Anti-metastatic Activity of Curcumin. Anticancer Res. 2016 Nov;36(11):5639-5647. Review. PubMed PMID: 27793885. Cancer is the leading cause of death worldwide. Although cancer occurs as a localized disease, its morbidity and mortality rates remain high due to the ability of cancer cells to break-off from the primary tumor and spread to distant organs. Currently, chemotherapy is the main treatment for cancer; however, the increase in proportion of drug-resistant cancer cells and unpleasant side-effects of chemotherapy are still the major challenges in cancer therapy. Curcumin is a natural polyphenol compound and the main bioactive constituent of Indian spice turmeric, widely used in Indian and Chinese medicines. Curcumin has well-known therapeutic actions, including anti-inflammatory, anti-microbial, anti-oxidant and anti-cancer properties. Curcumin induces cancer cell apoptosis through regulating various signaling pathways and arresting tumor cell cycle. Curcumin's therapeutic/ preventative actions on metastatic cancers have not been yet fully understood and studied. The present review explores the potential anti-metastatic mechanisms of curcumin, including inhibition of transcription factors and their signaling pathways (e.g., NF-κB, ApP-1 and STAT3), inflammatory cytokines (e.g., CXCL1, CXCL2, IL-6, IL-8), multiple proteases (e.g., uPA, MMPs), multiple protein kinases (e.g., MAPKs, FAK), regulation of miRNAs (e.g., miR21, miR181b) and heat shock proteins (HLJ1). In addition, possible synergistic actions of combination therapy of curcumin with current chemotherapies are discussed in this review."


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trans-Resveratrol

"Resveratrol-based combinatorial strategies for cancer management Singh CK, George J, Ahmad N. Resveratrol-based combinatorial strategies for cancer management. Annals of the New York Academy of Sciences. 2013;1290(1):113-121. doi:10.1111/nyas.12160. In recent years, combination chemoprevention is being increasingly appreciated and investigated as a viable and effective strategy for cancer management. A plethora of evidence suggests that a combination of agents may afford synergistic (or additive) advantage for cancer management by multiple means, such as by (1) enhancing the bio-availability of chemopreventive agents, (2) modifying different molecular targets, and (3) lowering the effective dose of agents/drug to be used for cancer management. Resveratrol has been shown to afford chemopreventive as well as therapeutic effects against certain cancers. Recent studies are suggesting that resveratrol may be very useful when given in combination with other agent. The two major advantages of using resveratrol in combination with other agents are: (1) synergistically or additively enhancing the efficacy against cancer, and (2) limiting the toxicity and side effects of existing therapies. However, concerted and multidisciplinary efforts are needed to identify the most optimal combinatorial strategies."


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"Resveratrol in prevention and treatment of common clinical conditions of aging Markus MA, Morris BJ. Resveratrol in prevention and treatment of common clinical conditions of aging. Clinical Interventions in Aging. 2008;3(2):331-339. Resveratrol is a potent member of the class of natural, plant-derived chemicals known as polyphenols. These help explain in part why a diet high in fruit and vegetables confers health benefits and are associated with reduced risk of common complex conditions such as cardiovascular disease, cancer, diabetes, and Alzheimer’s disease. We present the latest molecular findings that account for the beneficial actions of resveratrol. The intracellular pathways activated are crucial for anti-oxidant defence, regulation of the cell cycle, mitochondrial energy production, vascular tone, oncogene suppression, and many other phenomena which if unchecked lead to morbidity and mortality from onset and progression of these various diseases. While a healthy diet and lifestyle is strongly recommended in prevention of such conditions, the future bodes well for the use of resveratrol and analogues of higher potency than the natural form for treatment of diseases that afflict humans, particularly as they age."


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"Curcumin and Resveratrol as Promising Natural Remedies with Nanomedicine Approach for the Effective Treatment of Triple Negative Breast Cancer Shindikar A, Singh A, Nobre M, Kirolikar S. Curcumin and Resveratrol as Promising Natural Remedies with Nanomedicine Approach for the Effective Treatment of Triple Negative Breast Cancer. Journal of Oncology. 2016;2016:9750785. doi:10.1155/2016/9750785. Researchers have made considerable progress in last few decades in understanding mechanisms underlying pathogenesis of breast cancer, its phenotypes, its molecular and genetic changes, its physiology, and its prognosis. This has allowed us to identify specific targets and design appropriate chemical entities for effective treatment of most breast cancer phenotypes, resulting in increased patient survivability. Unfortunately, these strategies have been largely ineffective in the treatment of triple negative breast cancer (TNBC). Hormonal receptors lacking render the conventional breast cancer drugs redundant, forcing scientists to identify novel targets for treatment of TNBC. Two natural compounds, curcumin and resveratrol, have been widely reported to have anticancer properties. In vitro and in vivo studies show promising results, though their effectiveness in clinical settings has been less than satisfactory, owing to their feeble pharmacokinetics. Here we discuss these naturally occurring compounds, their mechanism as anticancer agents, their shortcomings in translational research, and possible methodology to improve their pharmacokinetics/pharmacodynamics with advanced drug delivery systems."


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"Resveratrol Regulates Colorectal Cancer Cell Invasion by Modulation of Focal Adhesion Molecules Buhrmann C, Shayan P, Goel A, Shakibaei M. Resveratrol Regulates Colorectal Cancer Cell Invasion by Modulation of Focal Adhesion Molecules. Nutrients. 2017 Sep 27;9(10). pii: E1073. doi: 10.3390/nu9101073. PubMed PMID: 28953264; PubMed Central PMCID: PMC5691690. Resveratrol, a safe and multi-targeted agent, has been associated with suppression of survival, proliferation and metastasis of cancer, however, the underlying mechanisms for its anti-cancer activity, particularly on cellular signaling during cancer cell migration still remain poorly understood. We investigated the invasion response of two human colorectal cancer (CRC) cells (HCT116 and SW480) to resveratrol and studied the effect of specific pharmacological inhibitors, cytochalasin D (CytD) and focal adhesion kinase-inhibitor (FAK-I) on FAK, cell viability and migration in CRC. We found that resveratrol altered cell phenotype of both CRC cells, reduced cell viability and the results were comparable to FAK-I and CytD. These effects of resveratrol were associated with marked Sirt1 up-regulation, FAK down-regulation, inhibition of focal adhesion and potentiation of effects by combinatorial treatment of resveratrol and inhibitors. Interestingly, inhibition of FAK with FAK-I or treatment with CytD suppressed resveratrol-induced Sirt1 up-regulation and markedly down-regulated FAK expression. Resveratrol or combination treatment with inhibitors significantly activated caspase-3 and potentiated apoptosis. Moreover, resveratrol suppressed invasion and colony forming capacity, cell proliferation, β1-Integrin expression and activation of FAK of cells in alginate tumor microenvironment, similar to FAK-I or CytD. Finally, we demonstrated that resveratrol, FAK-I or CytD inhibited activation of NF-κB, suppressed NF-κB-dependent gene end-products involved in invasion, metastasis, and apoptosis; and these effects of resveratrol were potentiated by combination treatment with FAK-I or CytD. Our data illustrated that the anti-invasion effect of resveratrol by inhibition of FAK activity has a potential beneficial role in disease prevention and therapeutic management of CRC."


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"Resveratrol induces AMPK-dependent MDR1 inhibition in colorectal cancer HCT116/L-OHP cells by preventing activation of NF-κB signaling and suppressing cAMP-responsive element transcriptional activity Wang Z, et al. Resveratrol induces AMPK-dependent MDR1 inhibition in colorectal cancer HCT116/L-OHP cells by preventing activation of NF-κB signaling and suppressing cAMP-responsive element transcriptional activity. Tumour Biol. 2015 Dec;36(12):9499-510. doi: 10.1007/s13277-015-3636-3. Epub 2015 Jul 1. PubMed PMID: 26124005. Resveratrol, a natural polyphenolic compound found in foods and beverages, has attracted increasing attention in recent years because of its potent chemopreventive and anti-tumor effects. In this study, the effects of resveratrol on the expression of P-glycoprotein/multi-drug resistance protein 1 (P-gp/MDR1), and the underlying molecular mechanisms, were investigated in oxaliplatin (L-OHP)-resistant colorectal cancer cells (HCT116/L-OHP). Resveratrol downregulated MDR1 protein and mRNA expression levels and reduced MDR1 promoter activity. It also enhanced the intracellular accumulation of rhodamine 123, suggesting that resveratrol can reverse multi-drug resistance by downregulating MDR1 expression and reducing drug efflux. Resveratrol treatment also reduced nuclear factor-κB (NF-κB) activity, reduced phosphorylation levels of IκBα, and reduced nuclear translocation of the NF-κB subunit p65. Moreover, downregulation of MDR1 expression and promoter activity was mediated by resveratrol-induced AMP-activated protein kinase (AMPK) phosphorylation. The inhibitory effects of resveratrol on MDR1 expression and cAMP-responsive element-binding protein (CREB) phosphorylation were reversed by AMPKα siRNA transfection. We found that the transcriptional activity of cAMP-responsive element (CRE) was inhibited by resveratrol. These results demonstrated that the inhibitory effects of resveratrol on MDR1 expression in HCT116/L-OHP cells were closely associated with the inhibition of NF-κB signaling and CREB activation in an AMPK-dependent manner."


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Triterpenes (10%)

"""Triterpenoids for cancer prevention and treatment: current status and future prospects."" Patlolla JM, Rao CV. Triterpenoids for cancer prevention and treatment: current status and future prospects. Curr Pharm Biotechnol. 2012 Jan;13(1):147-55. Review. PubMed PMID: 21466427. Triterpenoids are ubiquitous in the plant kingdom. Recent evidences support the beneficial effects of naturallyoccurring triterpenoids against several types of human diseases, including various cancers. Here, we have summarized the potential of triterpenoids belonging to the lupane, oleanane, ursane, and cucurbitacin groups, and their beneficial effects based on both laboratory and clinical investigations. Anticancer potential of triterpenoids and their anti-inflammatory, anti-proliferative, and pro-apoptotic effects have been discussed both in in vitro and in vivo models. Importantly, a large number of preclinical efficacy studies using chemically-induced, as well as tumor xenograft models provided evidence that both naturally occurring and synthetic derivatives had chemopreventive and therapeutic effects. In this review, we have highlighted several studies on chemopreventive and anticancer potential of triterpenoids based on various preclinical animal models of colon, breast, prostate, and melanoma cancers. Also, we made an attempt in discussing various mechanisms by which triterpenoids regulate various transcription and growth factors, inflammatory cytokines, and intracellular signaling pathways involved in cancer cell proliferation, apoptosis and tumor angiogenesis."


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"Triterpenoids as potential agents for the chemoprevention and therapy of breast cancer Bishayee A, Ahmed S, Brankov N, Perloff M. Triterpenoids as potential agents for the chemoprevention and therapy of breast cancer. Frontiers in bioscience : a journal and virtual library. 2011;16:980-996. Breast cancer remains a major cause of death in the United States as well as the rest of the world. In view of the limited treatment options for patients with advanced breast cancer, preventive and novel therapeutic approaches play an important role in combating this disease. The plant-derived triterpenoids, commonly used for medicinal purposes in many Asian countries, posses various pharmacological properties. A large number of triterpenoids are known to exhibit cytotoxicity against a variety of tumor cells as well as anticancer efficacy in preclinical animal models. Numerous triterpenoids have been synthesized by structural modification of natural compounds. Some of these analogs are considered to be the most potent antiinflammatory and anticarcinogenic triterpenoids known. This review examines the potential role of natural triterpenoids and their derivatives in the chemoprevention and treatment of mammary tumors. Both in vitro and in vivo effects of these agents and related molecular mechanisms are presented. Potential challenges and future directions involved in the advancement of these promising compounds in the prevention and therapy of human breast cancer are also identified."


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"""Lupeol, A Novel Anti-inflammatory and Anti-cancer Dietary Triterpene"" Saleem M. Lupeol, A Novel Anti-inflammatory and Anti-cancer Dietary Triterpene. Cancer letters. 2009;285(2):109-115. doi:10.1016/j.canlet.2009.04.033. In the Western world, an average of 250 mg per day of triterpenes (member of phytosterol family), largely derived from vegetable oils, cereals, fruits and vegetables is consumed by humans. During the last decade, there has been an unprecedented escalation of interest in triterpenes due to their cholesterol-lowering properties and evidence of this phenomenon include at least 25 clinical studies, 20 patents and at least 10 major commercially triterpene-based products currently being sold all around the world. Lupeol a triterpene [also known as Fagarsterol] found in white cabbage, green pepper, strawberry, olive, mangoes and grapes was reported to possess beneficial effects as a therapeutic and preventive agent for a range of disorders. Last 15 years have seen tremendous efforts by researchers worldwide to develop this wonderful molecule for its clinical use for the treatment of variety of disorders. These studies also provide insight into the mechanism of action of Lupeol and suggest that it is a multi-target agent with immense anti-inflammatory potential targeting key molecular pathways which involve nuclear factor kappa B (NFκB), cFLIP, Fas, Kras, phosphatidylinositol-3-kinase (PI3K)/Akt and Wnt/β-catenin in a variety of cells. It is noteworthy that Lupeol at its effective therapeutic doses exhibit no toxicity to normal cells and tissues. This mini review provides detailed account of preclinical studies conducted to determine the utility of Lupeol as a therapeutic and chemopreventive agent for the treatment of inflammation and cancer."


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"Known triterpenes and their derivatives as scaffolds for the development of new therapeutic agents for cancer. Peron G, Marzaro G, Dall'Acqua S. Known triterpenes and their derivatives as scaffolds for the development of new therapeutic agents for cancer. Curr Med Chem. 2017 Aug 17. doi: 10.2174/0929867324666170818111933. [Epub ahead of print] PubMed PMID: 28820068. Plants produce several bioactive secondary metabolites whose are used as therapeutic agents to treat various diseases, among them cancer. Triterpenes are a category of secondary metabolites that exert inhibitory activity against multiple intracellular and extracellular targets in euchariotic cells. These targets are proteins involved in apoptosis, cell development and differentiation, angiogenesis, metastasis and inflammatory processes. The inhibition of their functions leads to decreased cellular growth, differentiation and migration, resulting in antitumor activity, as shown by the numerous published experimental results. During recent years, synthetic triterpenoids derivatives have also been developed to implement potency and efficacy of starting compounds, allowing the obtainment of new compounds having promising anticancer activity. In this review we report the latest results regarding anticancer activity of some of the most studied triterpenes in the field, as well as of their semi-synthetic derivatives, with the aim to summarize the role of triterpenes as molecular leads for the development of new classes of antitumor agents."


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"Triterpenoids for cancer prevention and treatment: current status and future prospects. Patlolla JM, Rao CV. Triterpenoids for cancer prevention and treatment: current status and future prospects. Curr Pharm Biotechnol. 2012 Jan;13(1):147-55. Review. PubMed PMID: 21466427. Triterpenoids are ubiquitous in the plant kingdom. Recent evidences support the beneficial effects of naturallyoccurring triterpenoids against several types of human diseases, including various cancers. Here, we have summarized the potential of triterpenoids belonging to the lupane, oleanane, ursane, and cucurbitacin groups, and their beneficial effects based on both laboratory and clinical investigations. Anticancer potential of triterpenoids and their anti-inflammatory, anti-proliferative, and pro-apoptotic effects have been discussed both in in vitro and in vivo models. Importantly, a large number of preclinical efficacy studies using chemically-induced, as well as tumor xenograft models provided evidence that both naturally occurring and synthetic derivatives had chemopreventive and therapeutic effects. In this review, we have highlighted several studies on chemopreventive and anticancer potential of triterpenoids based on various preclinical animal models of colon, breast, prostate, and melanoma cancers. Also, we made an attempt in discussing various mechanisms by which triterpenoids regulate various transcription and growth factors, inflammatory cytokines, and intracellular signaling pathways involved in cancer cell proliferation, apoptosis and tumor angiogenesis."


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Vitamin A

"Vitamin A, Cancer Treatment and Prevention: The New Role of Cellular Retinol Binding Proteins Doldo E, Costanza G, Agostinelli S, et al. Vitamin A, Cancer Treatment and Prevention: The New Role of Cellular Retinol Binding Proteins. BioMed Research International. 2015;2015:624627. doi:10.1155/2015/624627. Retinol and vitamin A derivatives influence cell differentiation, proliferation, and apoptosis and play an important physiologic role in a wide range of biological processes. Retinol is obtained from foods of animal origin. Retinol derivatives are fundamental for vision, while retinoic acid is essential for skin and bone growth. Intracellular retinoid bioavailability is regulated by the presence of specific cytoplasmic retinol and retinoic acid binding proteins (CRBPs and CRABPs). CRBP-1, the most diffuse CRBP isoform, is a small 15 KDa cytosolic protein widely expressed and evolutionarily conserved in many tissues. CRBP-1 acts as chaperone and regulates the uptake, subsequent esterification, and bioavailability of retinol. CRBP-1 plays a major role in wound healing and arterial tissue remodelling processes. In the last years, the role of CRBP-1-related retinoid signalling during cancer progression became object of several studies. CRBP-1 downregulation associates with a more malignant phenotype in breast, ovarian, and nasopharyngeal cancers. Reexpression of CRBP-1 increased retinol sensitivity and reduced viability of ovarian cancer cells in vitro. Further studies are needed to explore new therapeutic strategies aimed at restoring CRBP-1-mediated intracellular retinol trafficking and the meaning of CRBP-1 expression in cancer patients' screening for a more personalized and efficacy retinoid therapy."


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"Adjuvant treatment of stage I lung cancer with high-dose vitamin A. Pastorino U, et al. Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J Clin Oncol. 1993 Jul;11(7):1216-22. PubMed PMID: 8391063. PURPOSE: Vitamin A and retinoids are strong inhibitors of epithelial cancer promotion and progression in experimental carcinogenesis. This study examined whether they may prevent the occurrence of upper aerodigestive cancer in subjects heavily exposed to tobacco smoking, such as patients already cured of an early-stage lung cancer. PATIENTS AND METHODS: The adjuvant effect of high-dose vitamin A was tested on 307 patients with stage I non-small-cell lung cancer. After curative surgery, patients were randomly assigned to either a group prescribed retinol palmitate administration (orally 300,000 IU daily for 12 months) or a control group prescribed no treatment. RESULTS: After a median follow-up of 46 months, the number of patients with either recurrence or new primary tumors was 56 (37%) in the treated arm and 75 (48%) in the control arm. Eighteen patients in the treated group developed a second primary tumor, and 29 patients in the control group developed 33 second primary tumors. A statistically significant difference in favor of treatment was observed concerning time to new primary tumors in the field of prevention (P = .045, log-rank test). The treatment difference in terms of disease-free interval was close to statistical significance (P = .054, log-rank test) and just significant when adjusted for primary tumor classification (P = .038, Cox regression model). CONCLUSION: Daily oral administration of high-dose vitamin A is effective in reducing the number of new primary tumors related to tobacco consumption and may improve the disease-free interval in patients curatively resected for stage I lung cancer. The impact of such a treatment on survival needs to be further explored."


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"Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer Niles RM. Recent advances in the use of vitamin A (retinoids) in the prevention and treatment of cancer. Nutrition. 2000 Nov-Dec;16(11-12):1084-9. Review. PubMed PMID: 11118831. Vitamin A, its physiologic metabolites, and synthetic derivatives (retinoids) have been shown to have protective effects against the development of certain types of cancer. In addition, pharmacologic amounts of retinoids have been used with some success in the treatment of a few human tumors. The chemoprevention effect of retinoids is most likely exerted at the tumor-promotion phase of carcinogenesis. Retinoids block tumor promotion by inhibiting proliferation, inducing apoptosis, inducing differentiation, or a combination of these actions. Clinically, isotretinoin (13-cis-retinoic acid) significantly decreases the incidence of second primary tumors in patients with head-and-neck cancer and reduces appearance of non-melanoma skin cancer in patients with xeroderma pigmentosum. Retinoic acid has proved to be an effective treatment for promyelocytic leukemia. However, retinoid resistance limits its use as a single agent. Clinical trials are in progress to determine the efficacy of retinoids in treating other types of cancer such as neuroblastoma and breast carcinoma. The development of receptor-selective retinoids and selective inhibitors of retinoid metabolism may lead to further use of retinoids in both chemoprevention and treatment of cancer."


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"The role of vitamins A, beta-carotene, E and C in cancer cell biology Lupulescu A. The role of vitamins A, beta-carotene, E and C in cancer cell biology. Int J Vitam Nutr Res. 1994;64(1):3-14. Review. PubMed PMID: 8200745. Vitamins A (retinol, retinoids), beta-carotene (provitamin A), E (alpha-tocopherol), and C (ascorbic acid) are used in experimental, clinical and epidemiological studies for cancer chemoprevention and treatment. The cellular and metabolic effects are depending on the dose used, duration of exposure, and cancer cell type. Despite recent advances, the anticarcinogenic mechanisms remain as yet unknown. Studies regarding the role of vitamins A, beta-carotene, E and C in cancer cell biology and metabolism are of critical importance for their use in cancer treatment. Autoradiographic, ultrastructural and cell surface studies demonstrated that vitamins A, E and C are strong regulator factors of cancer cell differentiation, cell regression, membrane biogenesis, DNA, RNA, protein, and collagen synthesis, as well as transformation of precancer cells into cancer cells. These vitamins exert cytotoxic and cytostatic effects, and may reverse the cancer cell to the normal phenotype. Interrelation of vitamins A, E and C with oncogenes and growth factors play an important role in cancer cell biology. The data presented in this review can provide new insights for the understanding of anticarcinogenic mechanisms, and a rationale for the use of vitamins A, E and C in cancer chemo-prevention and treatment."


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Vitamin C

"Intravenously administered vitamin C as cancer therapy: three cases Padayatty SJ, et al. Intravenously administered vitamin C as cancer therapy: three cases. CMAJ : Canadian Medical Association Journal. 2006;174(7):937-942. doi:10.1503/cmaj.050346. Early clinical studies showed that high-dose vitamin C, given by intravenous and oral routes, may improve symptoms and prolong life in patients with terminal cancer. Double-blind placebo-controlled studies of oral vitamin C therapy showed no benefit. Recent evidence shows that oral administration of the maximum tolerated dose of vitamin C (18 g/d) produces peak plasma concentrations of only 220 μmol/L, whereas intravenous administration of the same dose produces plasma concentrations about 25-fold higher. Larger doses (50–100 g) given intravenously may result in plasma concentrations of about 14 000 μmol/L. At concentrations above 1000 μmol/L, vitamin C is toxic to some cancer cells but not to normal cells in vitro. We found 3 well-documented cases of advanced cancers, confirmed by histopathologic review, where patients had unexpectedly long survival times after receiving high-dose intravenous vitamin C therapy. We examined clinical details of each case in accordance with National Cancer Institute (NCI) Best Case Series guidelines. Tumour pathology was verified by pathologists at the NCI who were unaware of diagnosis or treatment. In light of recent clinical pharmacokinetic findings and in vitro evidence of anti-tumour mechanisms, these case reports indicate that the role of high-dose intravenous vitamin C therapy in cancer treatment should be reassessed."


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"Antibiotics and vitamin C could kill cancer cells De Francesco EM, et al. Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs). Oncotarget. Published online June 9 2017 ""Vitamin C and antibiotics could be up to 100 times more effective than drugs at killing cancer cells – without the side effects,"" reports the Mail Online. The news comes from the results of a study that found a new two-pronged approach using the antibiotic doxycycline followed by vitamin C could kill cancer cells. Doxycycline killed many cancer cells, but others became resistant. The resistant cells were then destroyed by vitamin C. While this is encouraging news, it needs to be put into context. The experiments all took place in the laboratory. Researchers used human breast cancer stem cells, but didn't perform any studies on animals or humans. This means we don't know how successful this strategy could be – and the Mail's claim there would be no side effects is unsupported. Though both doxycycline and vitamin C are safe to use in humans, more research is needed to find out how they interact with other cancer treatments and therapies before this can be recommended as a new approach to treating cancer."


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"High-dose vitamin C (ascorbic acid) therapy in the treatment of patients with advanced cancer. Ohno S, Ohno Y, Suzuki N, Soma G, Inoue M. High-dose vitamin C (ascorbic acid) therapy in the treatment of patients with advanced cancer. Anticancer Res. 2009 Mar;29(3):809-15. Review. PubMed PMID: 19414313. Vitamin C (ascorbic acid, ascorbate) has a controversial history in cancer treatment. Emerging evidence indicates that ascorbate in cancer treatment deserves re-examination. As research results concerning ascorbate pharmacokinetics and its mechanisms of action against tumor cells have been published, and as evidence from case studies has continued to mount that ascorbate therapy could be effective if the right protocols were used, interest among physicians and scientists has increased. In this review, high-dose vitamin C therapy in cancer treatment is re-evaluated."


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"The Effects of High Concentrations of Vitamin C on Cancer Cells Park S. The Effects of High Concentrations of Vitamin C on Cancer Cells. Nutrients. 2013;5(9):3496-3505. doi:10.3390/nu5093496. The effect of high doses of vitamin C for the treatment of cancer has been controversial. Our previous studies, and studies by others, have reported that vitamin C at concentrations of 0.25–1.0 mM induced a dose- and time-dependent inhibition of proliferation in acute myeloid leukemia (AML) cell lines and in leukemic cells from peripheral blood specimens obtained from patients with AML. Treatment of cells with high doses of vitamin C resulted in an immediate increase in intracellular total glutathione content and glutathione-S transferase activity that was accompanied by the uptake of cysteine. These results suggest a new role for high concentrations of vitamin C in modulation of intracellular sulfur containing compounds, such as glutathione and cysteine. This review, discussing biochemical pharmacologic studies, including pharmacogenomic and pharmacoproteomic studies, presents the different pharmacological effects of vitamin C currently under investigation."


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"The Effect of Intravenous Vitamin C on Cancer- and Chemotherapy-Related Fatigue and Quality of Life Carr AC, Vissers MCM, Cook JS. The Effect of Intravenous Vitamin C on Cancer- and Chemotherapy-Related Fatigue and Quality of Life. Frontiers in Oncology. 2014;4:283. doi:10.3389/fonc.2014.00283. Cancer patients commonly experience a number of symptoms of disease progression and the side-effects of radiation therapy and adjuvant chemotherapy, which adversely impact on their quality of life (QOL). Fatigue is one of the most common and debilitating symptom reported by cancer patients and can affect QOL more than pain. Several recent studies have indicated that intravenous (IV) vitamin C alleviates a number of cancer- and chemotherapy-related symptoms, such as fatigue, insomnia, loss of appetite, nausea, and pain. Improvements in physical, role, cognitive, emotional, and social functioning, as well as an improvement in overall health, were also observed. In this mini review, we briefly cover the methods commonly used to assess health-related QOL in cancer patients, and describe the few recent studies examining the effects of IV vitamin C on cancer- and chemotherapy-related QOL. We discuss potential mechanisms that might explain an improvement in QOL and also considerations for future studies."


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"High dose concentration administration of ascorbic acid inhibits tumor growth in BALB/C mice implanted with sarcoma 180 cancer cells via the restriction of angiogenesis Yeom C-H, et al. High dose concentration administration of ascorbic acid inhibits tumor growth in BALB/C mice implanted with sarcoma 180 cancer cells via the restriction of angiogenesis. Journal of Translational Medicine. 2009;7:70. doi:10.1186/1479-5876-7-70. To test the carcinostatic effects of ascorbic acid, we challenged the mice of seven experimental groups with 1.7 × 10-4 mol high dose concentration ascorbic acid after intraperitoneal administrating them with sarcoma S-180 cells. The survival rate was increased by 20% in the group that received high dose concentration ascorbic acid, compared to the control. The highest survival rate was observed in the group in which 1.7 × 10-4 mol ascorbic acid had been continuously injected before and after the induction of cancer cells, rather than just after the induction of cancer cells. The expression of three angiogenesis-related genes was inhibited by 0.3 times in bFGF, 7 times in VEGF and 4 times in MMP2 of the groups with higher survival rates. Biopsy Results, gene expression studies, and wound healing analysis in vivo and in vitro suggested that the carcinostatic effect induced by high dose concentration ascorbic acid occurred through inhibition of angiogenesis."


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Vitamin D3

"Vitamin D: potential in the prevention and treatment of lung cancer Norton R, O'Connell MA. Vitamin D: potential in the prevention and treatment of lung cancer. Anticancer Res. 2012 Jan;32(1):211-21. Review. PubMed PMID: 22213310. Vitamin D is a steroid hormone traditionally recognized for maintaining calcium and phosphorous homeostasis in the body. However, it is now widely accepted that it exerts several extraskeletal actions, including anti-tumorigenic and immunomodulatory effects in vitro and in vivo. There is now a huge interest in studying the modes of action of vitamin D in a wide range of infectious and chronic disease settings and its potential in cancer prevention and treatment is currently under detailed investigation. In relation to the lung, evidence from observational studies, animal models and in vitro cell culture suggest that vitamin D may play a beneficial role in pulmonary inflammation. In addition, an adequate vitamin D status may be important for lung cancer prevention. Furthermore, vitamin D or its analogs, alone or in combination with cytotoxics, have potential in the treatment of lung cancer. Vitamin D is converted to its active form locally in the lung, suggesting that it may play an important role in lung health. Here, we review the evidence from observational, clinical and experimental studies in relation to vitamin D and lung cancer. In addition, we discuss vitamin D resistance in lung tumors and the potential molecular mechanisms of vitamin D action in lung cancer cells."


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"Vitamin D in the cancer patient Kennel KA, Drake MT. Vitamin D in the cancer patient. Current opinion in supportive and palliative care. 2013;7(3):272-277. doi:10.1097/SPC.0b013e3283640f74. Recent findings: Vitamin D has now been convincingly shown both in vitro and in preclinical animal models to alter the differentiation, proliferation, and apoptosis of cancer cells. Whether vitamin D prevents cancer in humans or limits cancer progression, however, remain open questions. Epidemiologic and observational data relating circulating 25(OH)D levels and cancer risk suggest an inverse relationship for most cancers including breast, colorectal, leukemia and lymphoma, and prostate, although for each malignancy there also exist studies that have failed to demonstrate such an inverse relationship. Likewise, a more recent report failed to confirm a previously reported association of increased pancreatic cancer risk in patients with higher 25(OH)D levels. A large prospective study in which patients aged at least 50 years receive 2000 IU vitamin D3 daily for 5 years, with cancer as a primary endpoint, has recently been launched. Summary: Although much effort has attempted to delineate a causal relationship between vitamin D and a wide array of human cancers, we await large-scale randomized controlled trial data for definitive answers."


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"Vitamin D for Prevention and Treatment of Colorectal Cancer: What is the Evidence? Ng K. Vitamin D for Prevention and Treatment of Colorectal Cancer: What is the Evidence? Current colorectal cancer reports. 2014;10(3):339-345. doi:10.1007/s11888-014-0238-1. Vitamin D insufficiency is highly prevalent in the U.S., particularly among colorectal cancer (CRC) patients. These low levels of vitamin D are concerning in light of increasing evidence that vitamin D may have health benefits beyond skeletal outcomes. Prospective observational studies suggest that higher vitamin D levels are associated with lower risk of incident CRC as well as improved survival in patients with established CRC, and randomized clinical trials are desperately needed to establish causality. Moreover, there remains a great need to improve prognosis for patients with CRC, and investigating vitamin D as a potential therapeutic modality is an attractive option in regards to safety and cost, particularly in this era of expensive and often toxic anti-neoplastic agents. In this review, the available published evidence on vitamin D’s activity in CRC will be summarized, spanning preclinical, epidemiological, and clinical studies, and future research directions will be discussed."


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"Vitamin D and breast cancer: interpreting current evidence Chlebowski, R.T. Vitamin D and breast cancer: interpreting current evidence. Breast Cancer Res. 2011;13:217–224. Preclinical investigations and selected clinical observational studies support an association between higher vitamin D intake and 25-hydroxyvitamin D levels with lower breast cancer risk. However, the recently updated report from the Institute of Medicine concluded that, for cancer and vitamin D, the evidence was 'inconsistent and insufficient to inform nutritional requirements'. Against this background, reports examining vitamin D intake, 25-hydroxyvitamin D levels and breast cancer incidence and outcome were reviewed. Current evidence supports the pursuit of several research questions but not routine 25-hydroxyvitamin D monitoring and vitamin D supplementation to reduce breast cancer incidence or improve breast cancer outcome."


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"Molecular basis of the potential of vitamin D to prevent cancer Ingraham BA, Bragdon B, Nohe A. Molecular basis of the potential of vitamin D to prevent cancer. Curr Med Res Opin. 2008 Jan;24(1):139-49. Review. PubMed PMID: 18034918. Research strongly supports the view that efforts to improve vitamin D status would have significant protective effects against the development of cancer. The clinical research community is currently revising recommendations for optimal serum levels and for sensible levels of sun exposure, to levels greater than previously thought. Currently, most experts in the field believe that intakes of between 1000 and 4000 IU will lead to a more healthy level of serum 25(OH)D, at approximately 75 nmol/L that will offer significant protection effects against cancers of the breast, colon, prostate, ovary, lungs, and pancreas. The first randomized trial has shown significant protection against breast cancer, and other clinical trials will follow and ultimately lead to improved public health policies and significantly fewer cancers."


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"Vitamin D for cancer prevention: global perspective Garland CF, Gorham ED, Mohr SB, Garland FC. Vitamin D for cancer prevention: global perspective. Ann Epidemiol. 2009 Jul;19(7):468-83. doi: 10.1016/j.annepidem.2009.03.021. Review. PubMed PMID: 19523595. It is projected that raising the minimum year-around serum 25(OH)D level to 40 to 60 ng/mL (100-150 nmol/L) would prevent approximately 58,000 new cases of breast cancer and 49,000 new cases of colorectal cancer each year, and three fourths of deaths from these diseases in the United States and Canada, based on observational studies combined with a randomized trial. Such intakes also are expected to reduce case-fatality rates of patients who have breast, colorectal, or prostate cancer by half. There are no unreasonable risks from intake of 2000 IU per day of vitamin D(3), or from a population serum 25(OH)D level of 40 to 60 ng/mL. The time has arrived for nationally coordinated action to substantially increase intake of vitamin D and calcium."


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Vitamin E

"Vitamin E succinate and cancer treatment: a vitamin E prototype for selective antitumour activity Neuzil J. Vitamin E succinate and cancer treatment: a vitamin E prototype for selective antitumour activity. Br J Cancer. 2003 Nov 17;89(10):1822-6. Review. PubMed PMID: 14612885; PubMed Central PMCID: PMC2394445. Great hope has been given to micronutrients as anticancer agents, since they present natural compounds with beneficial effects for normal cells and tissues. One of these is vitamin E (VE), an antioxidant and an essential component of biological membranes and circulating lipoproteins. In spite of a number of epidemiological and intervention studies, little or no correlation between VE intake and incidence of cancer has been found. Recent reports have identified a redox-silent analogue of VE, alpha-tocopheryl succinate (alpha-TOS), as a potent anticancer agent with a unique structure and pharmacokinetics in vivo. alpha-TOS is highly selective for malignant cells, inducing them into apoptotic death largely via the mitochondrial route. The molecule of alpha-TOS may be modified so that analogues with higher activity are generated. Finally, alpha-TOS and similar agents are metabolised to VE, thereby yielding a compound with a secondary beneficial activity. Thus, alpha-TOS epitomises a group of novel compounds that hold substantial promise as future anticancer drugs. The reasons for this optimistic notion are discussed in the following paragraphs."


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"The role of vitamin E in the prevention of cancer: a meta-analysis of randomized controlled trials Alkhenizan A, Hafez K. The role of vitamin E in the prevention of cancer: a meta-analysis of randomized controlled trials. Ann Saudi Med. 2007 Nov-Dec;27(6):409-14. PubMed PMID: 18059122. BACKGROUND: There are conflicting results in published randomized controlled trials (RCTs) on the role of vitamin E in the prevention of cancer. We conducted a meta-analysis of RCTs to evaluate the role of vitamin E in the prevention of cancer in adults. METHODS: We included RCTs in which the outcomes of the intake of vitamin E supplement alone or with other supplements were compared to a control group. The primary outcomes were total mortality, cancer mortality, total incidence of cancer, and incidence of lung, stomach, esophageal, pancreatic, prostate, breast and thyroid cancers. All identified trials were reviewed independently by the two reviewers to determine whether trials should be included or excluded. The quality of all included studies was scored independently by the two reviewers. RESULTS: Twelve studies, which included 167025 participants, met the inclusion criteria. There were no statistically significant differences in total mortality (relative risk, 0.99; 95% CI, 0.96-1.03) among the different groups of patients included in this meta-analysis. Vitamin E was associated with a significant reduction in the incidence of prostate cancer (relative risk, 0.85; 95% CI, 0.73-0.96, number needed to treat=500), but it did not reduce the incidence of any other types of cancer. CONCLUSIONS: Vitamin E supplementation was not associated with a reduction in total mortality, cancer incidence, or cancer mortality, but it was associated with a statistically significant reduction in the incidence of prostate cancer. Vitamin E can be used in the prevention of prostate cancer in men who are at high risk of prostate cancer."


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"Vitamin E succinate and cancer treatment: a vitamin E prototype for selective antitumour activity Neuzil J. Vitamin E succinate and cancer treatment: a vitamin E prototype for selective antitumour activity. British Journal of Cancer. 2003;89(10):1822-1826. doi:10.1038/sj.bjc.6601360. Numerous epidemiological and intervention studies tested the possibility that VE suppresses cancer. The idea has been attractive, as VE is a micronutrient with high antioxidant activity. To a certain degree, the level of VE can be manipulated by dietary supplementation. As the hepatic system prevents both VE hyper- and hypovitaminosis, maintaining the circulating/tissue levels of VE within a narrow margin, pathologies associated with too much or too little VE, are rare. Therefore, it is apparent that diseases linked to VE deficiency will only occur in association with infrequent syndromes of impairment of VE intake and its maintenance, such as abetalipoproteinaemia or the familial isolated VE deficiency syndrome. On the other hand, given the relatively narrow margin between minimal and maximal VE levels in circulating lipoproteins and in tissues, there is only a limited scope for VE manipulation by intervention therapy. Hence, it is not surprising that little or no association between disease incidence, including neoplasia, and VE intake has been repeatedly observed. Attempts to find a correlation between VE supplementation and pathology may have failed as, following VE ingestion, its level raises only transiently, the ‘excess’ VE being efficiently removed from the body by the hepatic system armed with the saturable α-tocopherol (α-TOH) transfer protein."


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"Vitamin E Transporters in Cancer Therapy Alqahtani S, Kaddoumi A. Vitamin E Transporters in Cancer Therapy. The AAPS Journal. 2015;17(2):313-322. doi:10.1208/s12248-014-9705-5. Besides their potent antioxidant activity, vitamin E isoforms demonstrated multiple therapeutic activities among which is their activity against different cancer types, including breast, prostate, and colon cancers. However, the activity of vitamin E isoforms is limited by their low bioavailability following oral administration. In addition to the low solubility, vitamin E isoforms have been established as substrates for several intestinal and hepatic transport proteins. In this review, we present reported anticancer activity of vitamin E family members and the possible utilization of vitamin E and derivatives as chemosensitizers to reverse multidrug resistance when given as part of a delivery system and/or in combination with anticancer therapeutic drugs. Then, the review discusses disposition of vitamin E members and transport proteins that play a role in determining their systemic bioavailability followed by recent advances in vitamin E formulations and delivery strategies."


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Thiamine

"Linking vitamin B1 with cancer cell metabolism Zastre JA, Sweet RL, Hanberry BS, Ye S. Linking vitamin B1 with cancer cell metabolism. Cancer & Metabolism. 2013;1:16. doi:10.1186/2049-3002-1-16. The resurgence of interest in cancer metabolism has linked alterations in the regulation and exploitation of metabolic pathways with an anabolic phenotype that increases biomass production for the replication of new daughter cells. To support the increase in the metabolic rate of cancer cells, a coordinated increase in the supply of nutrients, such as glucose and micronutrients functioning as enzyme cofactors is required. The majority of co-enzymes are water-soluble vitamins such as niacin, folic acid, pantothenic acid, pyridoxine, biotin, riboflavin and thiamine (Vitamin B1). Continuous dietary intake of these micronutrients is essential for maintaining normal health. How cancer cells adaptively regulate cellular homeostasis of cofactors and how they can regulate expression and function of metabolic enzymes in cancer is underappreciated. Exploitation of cofactor-dependent metabolic pathways with the advent of anti-folates highlights the potential vulnerabilities and importance of vitamins in cancer biology. Vitamin supplementation products are easily accessible and patients often perceive them as safe and beneficial without full knowledge of their effects. Thus, understanding the significance of enzyme cofactors in cancer cell metabolism will provide for important dietary strategies and new molecular targets to reduce disease progression. Recent studies have demonstrated the significance of thiamine-dependent enzymes in cancer cell metabolism. Therefore, this review discusses the current knowledge in the alterations in thiamine availability, homeostasis, and exploitation of thiamine-dependent pathways by cancer cells."


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"High Dose Vitamin B1 Reduces Proliferation in Cancer Cell Lines Analogous to Dichloroacetate Hanberry BS, Berger R, Zastre JA. High Dose Vitamin B1 Reduces Proliferation in Cancer Cell Lines Analogous to Dichloroacetate. Cancer chemotherapy and pharmacology. 2014;73(3):585-594. doi:10.1007/s00280-014-2386-z. Purpose: The dichotomous effect of thiamine supplementation on cancer cell growth is characterized by growth stimulation at low doses and growth suppression at high doses. Unfortunately, how thiamine reduces cancer cell proliferation is currently unknown. Recent focuses on metabolic targets for cancer therapy have exploited the altered regulation of the thiamine-dependent enzyme pyruvate dehydrogenase (PDH). Cancer cells inactivate PDH through phosphorylation by overexpression of pyruvate dehydrogenase kinases (PDKs). Inhibition of PDKs by dichloracetate (DCA) exhibits a growth suppressive effect in many cancers. Recently it has been shown that the thiamine co-enzyme, thiamine pyrophosphate reduces PDK mediated phosphorylation of PDH. Therefore, the objective of this study was to determine if high dose thiamine supplementation reduces cell proliferation through a DCA like mechanism. Methods: Cytotoxicity of thiamine and DCA were assessed in SK-N-BE and Panc-1 cancer cell lines. Comparative effects of high dose thiamine and DCA on PDH phosphorylation were measured by Western blot. The metabolic impact of PDH reactivation was determined by glucose and lactate assays. Changes in the mitochondrial membrane potential, ROS production, and caspase-3 activation were assessed to characterize the mechanism of action. Results: Thiamine exhibited a lower IC50 value in both cell lines compared to DCA. Both thiamine and DCA reduced the extent of PDH phosphorylation, reduced glucose consumption, lactate production, and mitochondrial membrane potential. High dose thiamine and DCA did not increase ROS but increased caspase-3 activity. Conclusion: Our findings suggest that high dose thiamine reduces cancer cell proliferation by a mechanism similar to that described for dichloroacetate."


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"High rate of thiamine deficiency among inpatients with cancer referred for psychiatric consultation: results of a single site prevalence study. Isenberg-Grzeda E, Shen MJ, Alici Y, Wills J, Nelson C, Breitbart W. High rate of thiamine deficiency among inpatients with cancer referred for psychiatric consultation: results of a single site prevalence study. Psychooncology. 2017 Sep;26(9):1384-1389. doi: 10.1002/pon.4155. Epub 2016 May 26. PubMed PMID: 27228202; PubMed Central PMCID: PMC5124411. OBJECTIVE: Thiamine deficiency (TD) is increasingly recognized in medically ill patients. The prevalence of TD among cancer patients is unknown. This study aims to characterize the prevalence of TD among inpatients with cancer. METHODS: Retrospective chart review of patients admitted to a large cancer center who were referred for psychiatric consultation and whose serum thiamine concentration was measured. Patients with alcohol use were excluded. RESULTS: Among 217 patients with various cancer types, TD was found in 55.3%. Risk factors included fluorouracil-based chemotherapy, significant weight loss, and undergoing active cancer treatment. Almost all patients were normal weight, overweight, or obese, and few had concomitant vitamin B12 or folate deficiency. A total of 17.5% were receiving multivitamin supplementation. Nearly half (49.8%) did not receive empiric treatment with thiamine and among those who did, treatment delay occurred in the majority of cases (59.6%). Measurement of serum thiamine concentration preceded psychiatric consultation in only 10.6% of cases. CONCLUSIONS: Our findings suggest that TD is highly prevalent among inpatients with cancer, even among normal and overweight individuals, in the absence of other vitamin deficiencies, and while receiving multivitamin supplements. Several potential risk factors were identified, including active cancer treatment. Evaluation of TD was most commonly not initiated by oncologists. Failure to treat and treatment delay were common. Given these findings, oncologists must be vigilant about detecting TD among inpatients with cancer."


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Riboflavin

"Energy-modulating vitamins--a new combinatorial therapy prevents cancer cachexia in rat mammary carcinoma. Perumal SS, Shanthi P, Sachdanandam P. Energy-modulating vitamins--a new combinatorial therapy prevents cancer cachexia in rat mammary carcinoma. Br J Nutr. 2005 Jun;93(6):901-9. PubMed PMID: 16022760. Mitochondria are the major intracellular organelles producing ATP molecules via the electron transport chain. Cancer cells have a deviant energy metabolism, and a high rate of glycolysis is related to a high degree of dedifferentiation and proliferation. The overall net ATP production is diminished with cancer, which ultimately leads to cancer cachexia. The present study was designed to investigate the altered energy metabolism in cancer cells and to enhance ATP production in the normal host cell metabolism by enhancing the activities of mitochondrial enzymes, using energy-modulating vitamins, and thus prevent cancer cachexia. Female Sprague-Dawley rats were selected for the experimental study. Mammary carcinoma was induced by the oral administration of 7,12-dimethylbenz[a]anthracene (25 mg/kg body weight), and treatment was started by the oral administration of the energy-modulating vitamins riboflavin (45 mg/kg body weight per d), niacin (100 mg/kg body weight per d) and coenzyme Q10 (40 mg/kg body weight per d) for 28 d. Mitochondria were isolated from the mammary gland and liver of all four groups, and the Krebs cycle and oxidative phosphorylation enzymes were assayed. In mammary carcinoma-bearing animals, the activities of the Krebs cycle and oxidative phosphorylation enzymes were significantly decreased. These activities were restored to a greater extent in animals treated with energy-modulating vitamins. From these experimental results, one may hypothesize that the combination therapy of energy-modulating vitamins could be of major therapeutic value in breast cancer."


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"Ameliorating effect of coenzyme Q10, riboflavin and niacin in tamoxifen-treated postmenopausal breast cancer patients with special reference to lipids and lipoproteins."" Yuvaraj S, Premkumar VG, Vijayasarathy K, Gangadaran SG, Sachdanandam P. Ameliorating effect of coenzyme Q10, riboflavin and niacin in tamoxifen-treated postmenopausal breast cancer patients with special reference to lipids and lipoproteins. Clin Biochem. 2007 Jun;40(9-10):623-8. Epub 2007 Mar 19. PubMed PMID: 17425952. OBJECTIVES: Tamoxifen (TAM), a non-steroidal anti-estrogen that is widely used in adjuvant therapy for all stages of breast carcinomas and in chemoprevention of high-risk group. The hepatic estrogenic effect of TAM induces hypertriglyceridemia by reduced activity of lipolytic enzymes (LPL) on triglycerides. Coenzyme Q10 (Co Q10), riboflavin and niacin are proved to be potent antioxidant and protective agents against many diseases including cancer and cardiovascular diseases (CVD). In this context, the objective of the study is to find the effect of the combined modality of Co Q10 (100 mg), riboflavin (10 mg) and niacin (50 mg) with TAM (10 mg twice a day) on serum lipids and lipoprotein levels in postmenopausal women with breast cancer. DESIGN AND METHODS: The vitamin supplementation with tamoxifen was given for a period of 90 days. Blood samples were collected at the base line, 45th and 90th day during the course of treatment. Plasma total cholesterol (TC), free cholesterol (FC), ester cholesterol (EC), phospholipids (PL), triglycerides (TGL), free fatty acids (FFA), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and very low density cholesterol (VLDL-C) were estimated in 78 untreated, only TAM-treated and combinatorialy treated group along with 46 age- and sex-matched controls. RESULTS: Serum TGL and VLDL-C (p<0.001) were found to be significantly elevated and LDL-C (p<0.01), significantly reduced among TAM-treated patients as compared to the untreated breast cancer subjects. All the lipids and lipoprotein levels were found to be significantly altered in the untreated breast cancer patients when compared to their normal counterparts. All the lipid and lipoprotein abnormalities were reverted back to near normal levels on 90 days of treatment on combinatorial therapy. CONCLUSION: The study figures the altered lipid and lipoprotein levels in the untreated and TAM-treated breast cancer patients. On combination therapy with Co Q10, riboflavin and niacin, it counteracts the tamoxifen-induced hyperlipidemia to normal levels."


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"Antitumor activity of irradiated riboflavin on human renal carcinoma cell line 786-O."" Chaves Neto AH, Pelizzaro-Rocha KJ, Fernandes MN, Ferreira-Halder CV. Antitumor activity of irradiated riboflavin on human renal carcinoma cell line 786-O. Tumour Biol. 2015 Feb;36(2):595-604. doi: 10.1007/s13277-014-2675-5. Epub 2014 Oct 2. PubMed PMID: 25273173. Riboflavin (vitamin B2) is a precursor for coenzymes involved in energy production, biosynthesis, detoxification, and electron scavenging. Previously, we demonstrated that irradiated riboflavin (IR) has potential antitumoral effects against human leukemia cells (HL60), human prostate cancer cells (PC3), and mouse melanoma cells (B16F10) through a common mechanism that leads to apoptosis. Hence, we here investigated the effect of IR on 786-O cells, a known model cell line for clear cell renal cell carcinoma (CCRCC), which is characterized by high-risk metastasis and chemotherapy resistance. IR also induced cell death in 786-O cells by apoptosis, which was not prevented by antioxidant agents. IR treatment was characterized by downregulation of Fas ligand (TNF superfamily, member 6)/Fas (TNF receptor superfamily member 6) (FasL/Fas) and tumor necrosis factor receptor superfamily, member 1a (TNFR1)/TNFRSF1A-associated via death domain (TRADD)/TNF receptor-associated factor 2 (TRAF) signaling pathways (the extrinsic apoptosis pathway), while the intrinsic apoptotic pathway was upregulated, as observed by an elevated Bcl-2 associated x protein/B-cell CLL/lymphoma 2 (Bax/Bcl-2) ratio, reduced cellular inhibitor of apoptosis 1 (c-IAP1) expression, and increased expression of apoptosis-inducing factor (AIF). The observed cell death was caspase-dependent as proven by caspase 3 activation and poly(ADP-ribose) polymerase-1 (PARP) cleavage. IR-induced cell death was also associated with downregulation of v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homologue (avian)/protein serine/threonine kinase B/extracellular signal-regulated protein kinase 1/2 (Src/AKT/ERK1/2) pathway and activation of p38 MAP kinase (p38) and Jun-amino-terminal kinase (JNK). Interestingly, IR treatment leads to inhibition of matrix metalloproteinase-2 (MMP-2) activity and reduced expression of renal cancer aggressiveness markers caveolin-1, low molecular weight phosphotyrosine protein phosphatase (LMWPTP), and kinase insert domain receptor (a type III receptor tyrosine kinase) (VEGFR-2). Together, these results show the potential of IR for treating cancer."


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"Co-enzyme Q10, riboflavin and niacin supplementation on alteration of DNA repair enzyme and DNA methylation in breast cancer patients undergoing tamoxifen therapy."" Premkumar VG, Yuvaraj S, Shanthi P, Sachdanandam P. Co-enzyme Q10, riboflavin and niacin supplementation on alteration of DNA repair enzyme and DNA methylation in breast cancer patients undergoing tamoxifen therapy. Br J Nutr. 2008 Dec;100(6):1179-82. doi: 10.1017/S0007114508968276. PubMed PMID: 18377693. In the present study, eighty-four breast cancer patients were randomized to receive a daily supplement of 100 mg co-enzyme Q10, 10 mg riboflavin and 50 mg niacin (CoRN), one dosage per d along with 10 mg tamoxifen twice per d. A significant increase in poly(ADP-ribose) polymerase levels and disappearance of RASSF1A DNA methylation patterns were found in patients treated with supplement therapy along with tamoxifen compared to untreated breast cancer patients and tamoxifen alone-treated patients. An increase in DNA repair enzymes and disappearance of DNA methylation patterns attributes to reduction in tumour burden and may suggest good prognosis and efficacy of the treatment."


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Niacin

"Niacin status and treatment-related leukemogenesis."" Kirkland JB. Niacin status and treatment-related leukemogenesis. Mol Cancer Ther. 2009 Apr;8(4):725-32. doi: 10.1158/1535-7163.MCT-09-0042. Review. PubMed PMID: 19372544. Chemotherapy often causes damage to hematopoietic tissues, leading to acute bone marrow suppression and the long term development of leukemias. Niacin deficiency, which is common in cancer patients, causes dramatic genomic instability in bone marrow cells in an in vivo rat model. From a mechanistic perspective, niacin deficiency delays excision repair and causes double strand break accumulation, which in turn favors chromosome breaks and translocations. Niacin deficiency also impairs cell cycle arrest and apoptosis in response to DNA damage, which combine to encourage the survival of cells with leukemogenic potential. Conversely, pharmacological supplementation of rats with niacin increases bone marrow poly(ADP-ribose) formation and apoptosis. Improvement of niacin status in rats significantly decreased nitrosourea-induced leukemia incidence. The data from our rat model suggest that niacin supplementation of cancer patients may decrease the severity of short- and long-term side effects of chemotherapy, and could improve tumor cell killing through activation of poly(ADP-ribose)-dependent apoptosis pathways."


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"Niacin alleviates TRAIL-mediated colon cancer cell death via autophagy flux activation Kim S-W, Lee J-H, Moon J-H, et al. Niacin alleviates TRAIL-mediated colon cancer cell death via autophagy flux activation. Oncotarget. 2016;7(4):4356-4368. doi:10.18632/oncotarget.5374. Niacin, also known as vitamin B3 or nicotinamide is a water-soluble vitamin that is present in black beans and rice among other foods. Niacin is well known as an inhibitor of metastasis in human breast carcinoma cells but the effect of niacin treatment on TRAIL-mediated apoptosis is unknown. Here, we show that niacin plays an important role in the regulation of autophagic flux and protects tumor cells against TRAIL-mediated apoptosis. Our results indicated that niacin activated autophagic flux in human colon cancer cells and the autophagic flux activation protected tumor cells from TRAIL-induced dysfunction of mitochondrial membrane potential and tumor cell death. We also demonstrated that ATG5 siRNA and autophagy inhibitor blocked the niacin-mediated inhibition of TRAIL-induced apoptosis. Taken together, our study is the first report demonstrating that niacin inhibits TRAIL-induced apoptosis through activation of autophagic flux in human colon cancer cells. And our results also suggest that autophagy inhibitors including genetic and pharmacological tools may be a successful therapeutics during anticancer therapy using TRAIL."


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Niacinamide

"Role of Nicotinamide in DNA Damage, Mutagenesis, and DNA Repair Surjana D, Halliday GM, Damian DL. Role of Nicotinamide in DNA Damage, Mutagenesis, and DNA Repair. Journal of Nucleic Acids. 2010;2010:157591. doi:10.4061/2010/157591. Nicotinamide is a water-soluble amide form of niacin (nicotinic acid or vitamin B3). Both niacin and nicotinamide are widely available in plant and animal foods, and niacin can also be endogenously synthesized in the liver from dietary tryptophan. Nicotinamide is also commercially available in vitamin supplements and in a range of cosmetic, hair, and skin preparations. Nicotinamide is the primary precursor of nicotinamide adenine dinucleotide (NAD+), an essential coenzyme in ATP production and the sole substrate of the nuclear enzyme poly-ADP-ribose polymerase-1 (PARP-1). Numerous in vitro and in vivo studies have clearly shown that PARP-1 and NAD+ status influence cellular responses to genotoxicity which can lead to mutagenesis and cancer formation. This paper will examine the role of nicotinamide in the protection from carcinogenesis, DNA repair, and maintenance of genomic stability."


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"Oral Nicotinamide Prevents Common Skin Cancers in High-Risk Patients, Reduces Costs Starr P. Oral Nicotinamide Prevents Common Skin Cancers in High-Risk Patients, Reduces Costs. American Health & Drug Benefits. 2015;8(Spec Issue):13-14. The prevention of common skin cancers and precancers is possible by taking an inexpensive, widely available, oral pill twice daily. The pill—the vitamin B3 supplement called nicotinamide—cut the rate of new squamous-cell and basal-cell skin cancers by 23% compared with placebo after 1 year among patients at high risk for skin cancer. Nicotinamide also reduced the risk for developing actinic keratosis, a common precancer of the skin."


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Pantothenic Acid

"Components of an Anticancer Diet: Dietary Recommendations, Restrictions and Supplements of the Bill Henderson Protocol Mannion C, Page S, Bell LH, Verhoef M. Components of an Anticancer Diet: Dietary Recommendations, Restrictions and Supplements of the Bill Henderson Protocol. Nutrients. 2011;3(1):1-26. doi:10.3390/nu3010001. The use of complementary and alternative medicines including dietary supplements, herbals and special diets to prevent or treat disease continues to be popular. The following paper provides a description of an alternative dietary approach to the self-management and treatment of cancer, the Bill Henderson Protocol (BHP). This diet encourages daily intake of raw foods, a combination of cottage cheese and flaxseed oil and a number of supplements. Some foods and food groups are restricted (e.g., gluten, meat, dairy). Early background theory that contributed to the protocol’s development is presented as is a summary of relevant evidence concerning the anti-cancer fighting properties of the individual components. Supplement intake is considered in relation to daily recommended intakes. Challenges and risks to protocol adherence are discussed. As with many complementary and alternative interventions, clear evidence of this dietary protocol’s safety and efficacy is lacking. Consumers of this protocol may require guidance on the ability of this protocol to meet their individual nutritional needs."


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Vitamin B6

"Vitamin B6 and colorectal cancer: Current evidence and future directions Zhang X-H, Ma J, Smith-Warner SA, Lee JE, Giovannucci E. Vitamin B6 and colorectal cancer: Current evidence and future directions. World Journal of Gastroenterology : WJG. 2013;19(7):1005-1010. doi:10.3748/wjg.v19.i7.1005. Colorectal cancer remains the third most common cancer in both women and men worldwide. Identifying modifiable dietary factors is crucial in developing primary prevention strategies. Vitamin B6 is involved in more than 100 coenzyme reactions, and may influence colorectal cancer risk in multiple ways including through its role in one-carbon metabolism related DNA synthesis and methylation and by reducing inflammation, cell proliferation, and oxidative stress. Observational studies of dietary or dietary plus supplementary intake of vitamin B6 and colorectal cancer risk have been inconsistent with most studies reporting nonsignificant positive or inverse associations. However, published studies of plasma pyridoxal 5’-phosphate (the active form of vitamin B6) levels consistently support an approximately 30%-50% reduction in risk of colorectal cancer comparing high with low concentrations. The reasons for the discrepancy in the results between dietary-based and plasma-based studies remain unresolved. Other unresolved questions include the effects of vitamin B6 intake in early life (i.e., childhood or adolescence) and of suboptimal vitamin B6 status on colorectal cancer risk, whether the associations with vitamin B6 differ across molecular subtypes of colorectal cancer, and whether the vitamin B6-colorectal cancer association is modified by genetic variants of one-carbon metabolism."


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"Vitamins B6 and cancer Choi SW, Friso S. Vitamins B6 and cancer. Subcell Biochem. 2012;56:247-64. doi: 10.1007/978-94-007-2199-9_13. Review. PubMed PMID: 22116703. Epidemiologic and laboratory animal studies have suggested that the availability of vitamin B6 modulates cancer risk. The means by which B6 mediates this effect is not known with any surety but it has been reported that high dietary vitamin B6 attenuates and low dietary vitamin B6 increases the risk of cancer. In fact vitamin B6 is widely distributed in foods and overt deficiency of this vitamin is not common. Nevertheless, marginal or secondary vitamin B6 deficiency, which might have an adverse effect on carcinogenesis, is rather common especially among old adults and alcoholics. This chapter addressed currently available information regarding the relationship between vitamin B6 and cancer."


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"Treatment with B vitamins and incidence of cancer in patients with previous stroke or transient ischemic attack: results of a randomized placebo-controlled trial Hankey GJ, et al; VITAmins TO Prevent Stroke (VITATOPS) Trial Study Group. Treatment with B vitamins and incidence of cancer in patients with previous stroke or transient ischemic attack: results of a randomized placebo-controlled trial. Stroke. 2012 Jun;43(6):1572-7. doi: 10.1161/STROKEAHA.111.641613. Epub 2012 Apr 3. PubMed PMID: 22474057. Daily administration of folic acid, vitamin B(6), and vitamin B(12) to 8164 patients with recent stroke or transient ischemic attack for a median of 3.4 years had no significant effect, compared with placebo, on cancer incidence or mortality. However, a post hoc subgroup analysis raises the hypothesis that folic acid treatment may increase the incidence of cancer among diabetics and reduce the incidence of cancer among nondiabetics with a history of stroke or transient ischemic attack."


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5-tetrahydrofolate

"Hyperproliferation of homocysteine-treated colon cancer cells is reversed by folate and 5-methyltetrahydrofolate Akoglu B, Milovic V, Caspary WF, Faust D. Hyperproliferation of homocysteine-treated colon cancer cells is reversed by folate and 5-methyltetrahydrofolate. Eur J Nutr. 2004 Apr;43(2):93-9. Epub 2004 Jan 6. PubMed PMID: 15083316. Our data suggest that 5-MTHF, being the key metabolite in both the folate and homocysteine metabolic pathway, is the main modulator of growth-promoting actions of homocysteine as well as antiproliferative effects of folate in colon cancer cells."


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"Folate and chemoprevention of colorectal cancer: Is 5-methyl-tetrahydrofolate an active antiproliferative agent in folate-treated colon-cancer cells? Akoglu B, Faust D, Milovic V, Stein J. Folate and chemoprevention of colorectal cancer: Is 5-methyl-tetrahydrofolate an active antiproliferative agent in folate-treated colon-cancer cells? Nutrition. 2001 Jul-Aug;17(7-8):652-3. PubMed PMID: 11448589. There is increasing evidence from epidemiologic studies, human biopsies, and animal and cell culture models suggesting that folate is chemopreventive in colonic carcinogenesis. Recent findings have suggested that folate acts by increasing DNA methylation and repairing and reducing formation of DNA strand breaks of p53 and Apc genes. The underlying mechanisms of antiproliferative and chemopreventive actions of folate are not fully understood. The complexity of the folic-acid metabolic pathway suggests that different metabolites of folate are involved in its multiple effects in normal, preneoplastic, and malignant cells. The folate metabolic pathway has been well elucidated. At one point of its metabolic cascade, folate is essential for the synthesis of S-adenosylmethionine and thereby is involved in DNA methylation. At another, folate is metabolized (via dihydrofolate reductase) to dihydrofolate and tetrahydrofolate and reduced to 5-methyl-tetrahydrofolate via 5,10-methylenetetrahydrofolate through 5,10-methylenetetrahydrofolate reductase. 5,10-Methylenetetrahydrofolate is a product of tetrahydrofolate. A common mutation (677C→T) in 5,10-methylenetetrahydrofolate reductase was found to reduce colon-cancer risk in humans with normal plasma folate levels, likely by increasing 5,10-methylenetetrahydrofolate levels for DNA synthesis. However, in that study, low folate intake and high alcohol consumption negated some of the protective effects."


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Methylcobalamin

"Acupuncture combined with methylcobalamin for the treatment of chemotherapy-induced peripheral neuropathy in patients with multiple myeloma Han X, Wang L, Shi H, et al. Acupuncture combined with methylcobalamin for the treatment of chemotherapy-induced peripheral neuropathy in patients with multiple myeloma. BMC Cancer. 2017;17:40. doi:10.1186/s12885-016-3037-z. After 84 days (three cycles) of therapy, the pain was significantly alleviated in both groups, with a significantly higher decrease in the acupuncture treated group (P < 0.01). The patients’ daily activity evaluated by Fact/GOG-Ntx questionnaires significantly improved in the Met + Acu group (P < 0.001). The NCV in the Met + Acu group improved significantly while amelioration in the control group was not observed."


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"Methylcobalamin ameliorates neuropathic pain induced by vincristine in rats Xu J, et al. Methylcobalamin ameliorates neuropathic pain induced by vincristine in rats: Effect on loss of peripheral nerve fibers and imbalance of cytokines in the spinal dorsal horn. Molecular Pain. 2016;12:1744806916657089. doi:10.1177/1744806916657089. Methylcobalamin attenuated vincrinstine-induced neuropathic pain, which was accompanied by inhibition of intraepidermal nerve fibers loss and mitochondria impairment. Inhibiting the activation of NADPH oxidase and the downstream NF-κB pathway, resulting in the rebalancing of proinflammatory and anti-inflammatory cytokines in the spinal dorsal horn might also be involved. These findings might provide potential target for preventing vincristine-induced neuropathic pain."


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"Induction of apoptosis in an androgen-dependent mouse mammary carcinoma cell line by methylcobalamin Nishizawa Y, Goto HG, Tanigaki Y, Fushiki S, Nishizawa Y. Induction of apoptosis in an androgen-dependent mouse mammary carcinoma cell line by methylcobalamin. Anticancer Res. 2001 Mar-Apr;21(2A):1107-10. PubMed PMID: 11396147. SC-3 is a cloned cell line derived from an androgen-dependent mouse mammary tumor (Shionogi Carcinoma 115). A physiological level of androgen stimulates the growth of SC-3 cells through the production of androgen-induced growth factor. Methylcobalamin (MeCbl), one of the active cobalamins, inhibits the growth of SC-3 cells stimulated by androgen. It is known that apoptosis has an important role in tumor growth. The specific aim of this study is to examine the effects of MeCbl, in the presence of androgen, on apoptosis in SC-3 cells. Morphological analysis revealed budding nuclei and chromatin condensation in cells cultured with MeCbl, but few in cells cultured without MeCbl. Low molecular weight DNA extracted from cells cultured with or without MeCbl was analysed by gel electrophoresis. A characteristic nucleosomal size ladder was detected in the culture with MeCbl. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labelling method was also used to evaluate apoptotic cell death in SC-3 cells. Apoptosis was observed more frequently in SC-3 cells treated with MeCbl than in those without MeCbl. These results demonstrate that androgen-dependent SC-3 cells undergo apoptosis by MeCbl even if in the presence of androgen."


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"Influence of cobalamin on the survival of mice bearing ascites tumor Tsao CS, Myashita K. Influence of cobalamin on the survival of mice bearing ascites tumor. Pathobiology. 1993;61(2):104-8. PubMed PMID: 8216825. The effect of cobalamin (vitamin B12) on the survival time of mice bearing P388 leukemia has been examined. Among the three cobalamins studied, the enzymatically active derivatives, methylcobalamin and 5'-deoxyadenosylcobalamin, were able to significantly increase the survival time of mice implanted intraperitoneally with the tumor cells. The pharmaceutical form, cyanocobalamin, was not active. The antitumor activity of these cobalamins may be associated with their functions in metabolism."


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Zinc

"Zinc: A promising agent in dietary chemoprevention of cancer Dhawan DK, Chadha VD. Zinc: A promising agent in dietary chemoprevention of cancer. The Indian Journal of Medical Research. 2010;132(6):676-682. Proper intake of dietary nutrients is considered crucial for preventing the initiation of events leading to the development of carcinoma. Many dietary compounds have been considered to contribute in cancer prevention including zinc, which plays a pivotal role in host defense against the initiation and promotion of several malignancies. Zinc is an essential element that is integral to many proteins and transcription factors which regulate key cellular functions such as the response to oxidative stress, DNA replication, DNA damage repair, cell cycle progression, and apoptosis. Zinc has been ascribed roles in the metabolism and interaction of malignant cells, particularly in apoptosis. Zinc is involved in structural stabilization and activation of the p53 that appears to be an important component of the apoptotic process and also in activation of certain members of the caspase family of proteases. Zinc exerts a positive beneficial effect against chemically induced preneoplastic progression in rats and provides an effective dietary chemopreventive approach to disease in vulnerable section of population with family history of carcinoma. The present review provides an insight into the research conducted on animals as well as on human subjects for providing the concept that zinc deficiency is an important factor in the development and progression of malignancy and that zinc could be efficacious in the prevention and treatment of several cancers viz., colon, pancreas, oesophageal and head and neck. However, it needs further exploration with regard to other definitive bioassays including protein expression and documentation of specific molecular markers to establish the exact mechanism for zinc-mediated cancer chemoprevention. Preclinical trials need to investigate the genetic and epigenetic pathways of chemoprevention by zinc."


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"Cytotoxic/tumor suppressor role of zinc for the treatment of cancer: an enigma and an opportunity Costello LC, Franklin RB. Cytotoxic/tumor suppressor role of zinc for the treatment of cancer: an enigma and an opportunity. Expert Review of Anticancer Therapy. 2012;12(1):121-128. doi:10.1586/era.11.190. A major issue relating to many cancers is the absence of effective chemotherapeutic agents; so that most often untreatable morbidity and death are prevalent once the cancer has been detected and has advanced. The search for efficacious anticancer agents is imperative. One potential agent is zinc, which is decreased in the development of some cancers in order to avoid its cytotoxic/tumor suppressor effects on the malignant cells. This provides the basis and opportunity to employ a treatment regimen that restores elevated zinc levels in the malignant cells and elicits the cytotoxic/tumor suppressor effects of zinc. The enigma is that this approach and expectation has not reached fruition. The question is “why?”. This article provides a discussion of relevant zinc issues that need to be considered and resolved. Important areas of research are identified as being essential for the successful application of zinc cytotoxicity/tumor suppression actions for the treatment of specific cancers."


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"Role of zinc in the pathogenesis and treatment of prostate cancer: critical issues to resolve Costello L, Feng P, Milon B, Tan M, Franklin R. Role of zinc in the pathogenesis and treatment of prostate cancer: critical issues to resolve. Prostate cancer and prostatic diseases. 2004;7(2):111-117. doi:10.1038/sj.pcan.4500712. The most consistent and persistent biochemical characteristic of prostate cancer (PCa) is the marked decrease in zinc and citrate levels in the malignant cells. This relationship provides compelling evidence that the lost ability of the malignant cells to accumulate zinc is an important factor in the development and progression of prostate malignancy. In addition, this relationship provides a rational basis for the concept that restoration of high zinc levels in malignant cells could be efficacious in the treatment and prevention of PCa. Epidemiological studies regarding dietary zinc effects on PCa have been conflicting and confusing. The purpose of this presentation is to present a current state of information regarding zinc relationships in the pathogenesis and treatment of PCa. We also hope to bring more attention to the medical and research community of the critical need for concerted clinical and basic research regarding zinc and PCa."


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"Zinc and Cancer: Implications for LIV-1 in Breast Cancer Grattan BJ, Freake HC. Zinc and Cancer: Implications for LIV-1 in Breast Cancer. Nutrients. 2012;4(7):648-675. doi:10.3390/nu4070648. Zinc is a trace mineral which is vital for the functioning of numerous cellular processes, is critical for growth, and may play an important role in cancer etiology and outcome. The intracellular levels of this mineral are regulated through the coordinated expression of zinc transporters, which modulate both zinc influx as well as efflux. LIV-1 (ZIP6) was first described in 1988 as an estrogen regulated gene with later work suggesting a role for this transporter in cancer growth and metastasis. Despite evidence of its potential utility as a target gene for cancer prognosis and treatment, LIV-1 has received relatively little attention, with only three prior reviews being published on this topic. Herein, the physiological effects of zinc are reviewed in light of this mineral’s role in cancer growth with specific attention being given to LIV-1 and the potential importance of this transporter to breast cancer etiology."


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"Zinc deficiency, DNA damage and cancer risk Ho E. Zinc deficiency, DNA damage and cancer risk. J Nutr Biochem. 2004 Oct;15(10):572-8. Review. PubMed PMID: 15542347. A large body of evidence suggests that a significant percentage of deaths resulting from cancer in the United States could be avoided through greater attention to proper and adequate nutrition. Although many dietary compounds have been suggested to contribute to the prevention of cancer, there is strong evidence to support the fact that zinc, a key constituent or cofactor of over 300 mammalian proteins, may be of particular importance in host defense against the initiation and progression of cancer. Remarkably, 10% of the U.S. population consumes less than half the recommended dietary allowance for zinc and are at increased risk for zinc deficiency. Zinc is known to be an essential component of DNA-binding proteins with zinc fingers, as well as copper/zinc superoxide dismutase and several proteins involved in DNA repair. Thus, zinc plays an important role in transcription factor function, antioxidant defense and DNA repair. Dietary deficiencies in zinc can contribute to single- and double-strand DNA breaks and oxidative modifications to DNA that increase risk for cancer development. This review will focus on potential mechanisms by which zinc deficiency impairs host protective mechanisms designed to protect against DNA damage, enhances susceptibility to DNA-damaging agents and ultimately increases risk for cancer."


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Selenium

"Is Selenium a Potential Treatment for Cancer Metastasis? Chen Y-C, Prabhu KS, Mastro AM. Is Selenium a Potential Treatment for Cancer Metastasis? Nutrients. 2013;5(4):1149-1168. doi:10.3390/nu5041149. Selenium (Se) is an essential micronutrient that functions as a redox gatekeeper through its incorporation into proteins to alleviate oxidative stress in cells. Although the epidemiological data are somewhat controversial, the results of many studies suggest that inorganic and organic forms of Se negatively affect cancer progression, and that several selenoproteins, such as GPXs, also play important roles in tumor development. Recently, a few scientists have examined the relationship between Se and metastasis, a late event in cancer progression, and have evaluated the potential of Se as an anti-angiogenesis or anti-metastasis agent. In this review, we present the current knowledge about Se compounds and selenoproteins, and their effects on the development of metastasis, with an emphasis on cell migration, invasion, and angiogenesis. In the cancers of breast, prostate, colorectal, fibrosarcoma, melanoma, liver, lung, oral squamous cell carcinoma, and brain glioma, there is either clinical evidence linking selenoproteins, such as thioredoxin reductase-1 to lymph node metastasis; in vitro studies indicating that Se compounds and selenoproteins inhibited cell motility, migration, and invasion, and reduced angiogenic factors in some of these cancer cells; or animal studies showing that Se supplementation resulted in reduced microvessel density and metastasis. Together, these data support the notion that Se may be an anti-metastastatic element in addition to being a cancer preventative agent."


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"Selenium and cancer: from prevention to treatment Brozmanová J. [Selenium and cancer: from prevention to treatment]. Klin Onkol. 2011;24(3):171-9. Review. Slovak. PubMed PMID: 21717786. Selenium (Se) is an essential dietary component for all animals, including human beings, that is regarded as a protective agent against cancer. Although the mode of its anticancer action is not yet fully understood, several mechanisms, such as antioxidant protection through selenoenzymes, stimulation of DNA repair, and apoptosis in tumor prestages have all been proposed. Despite the unsupported results of the last ""SELECT"" trial, the cancer-preventing activity of Se has been demonstrated in a majority of epidemiological studies. Moreover, recent studies suggest that Se has a potential to be used not only in cancer prevention but also in cancer treatment, where in combination with other anticancer drugs or radiation it may increase the efficacy of cancer therapy. In combating cancer cells, Se acts as a prooxidant rather than an antioxidant, inducing apoptosis through the generation of oxidative stress. Thus, inorganic Se compounds, having high redox potency, represent a promising option in cancer therapy."


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"Selenium and Lung Cancer: A Systematic Review and Meta Analysis Fritz H, et al. Selenium and Lung Cancer: A Systematic Review and Meta Analysis. Zhivotovsky B, ed. PLoS ONE. 2011;6(11):e26259. doi:10.1371/journal.pone.0026259. Background: Selenium is a natural health product widely used in the treatment and prevention of lung cancers, but large chemoprevention trials have yielded conflicting results. We conducted a systematic review of selenium for lung cancers, and assessed potential interactions with conventional therapies. Methods and Findings: Two independent reviewers searched six databases from inception to March 2009 for evidence pertaining to the safety and efficacy of selenium for lung cancers. Pubmed and EMBASE were searched to October 2009 for evidence on interactions with chemo- or radiation-therapy. In the efficacy analysis there were nine reports of five RCTs and two biomarker-based studies, 29 reports of 26 observational studies, and 41 preclinical studies. Fifteen human studies, one case report, and 36 preclinical studies were included in the interactions analysis. Based on available evidence, there appears to be a different chemopreventive effect dependent on baseline selenium status, such that selenium supplementation may reduce risk of lung cancers in populations with lower baseline selenium status (serum < 106 ng/mL), but increase risk of lung cancers in those with higher selenium (≥121.6 ng/mL). Pooling data from two trials yielded no impact to odds of lung cancer, OR 0.93 (95% confidence interval 0.61–1.43); other cancers that were the primary endpoints of these trials, OR 1.51 (95%CI 0.70–3.24); and all-cause-death, OR 0.93 (95%CI 0.79–1.10). In the treatment of lung cancers, selenium may reduce cisplatin-induced nephrotoxicity and side effects associated with radiation therapy. Conclusions: Selenium may be effective for lung cancer prevention among individuals with lower selenium status, but at present should not be used as a general strategy for lung cancer prevention. Although promising, more evidence on the ability of selenium to reduce cisplatin and radiation therapy toxicity is required to ensure that therapeutic efficacy is maintained before any broad clinical recommendations can be made in this context."


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"Selenium in the prevention and treatment of hepatocellular carcinoma Darvesh AS, Bishayee A. Selenium in the prevention and treatment of hepatocellular carcinoma. Anticancer Agents Med Chem. 2010 May;10(4):338-45. Review. PubMed PMID: 20380634. Hepatocellular carcinoma (HCC) happens to be one of the most lethal cancers in the world. Even though most cases occur in the developing world, reported cases in Western Europe as well as North America are on a steep rise. Human HCC etiology includes chronic liver disease, viral hepatitis, alcoholism, iron overload as well as dietary carcinogens such as aflatoxins and nitrosoamines. Surgical resection as well as liver transplants, which are currently used to treat HCC, is mostly ineffective. Consequently, there exists a decisive requirement to explore possible alternative chemopreventive and therapeutic strategies for HCC. Both oxidative stress and inflammatory mechanisms have been implicated in the pathophysiology of HCC. The use of dietary antioxidants and micronutrients has been proposed as an effective means for successful management of human HCC. Trace elements such as vanadium and selenium are involved in several major metabolic pathways as well as antioxidant defense systems. Selenium has been shown to be involved in the prevention of numerous chronic illnesses such as several specific cancers and neurodegenerative diseases. This review examines the potential role of selenium in the prevention and treatment of HCC. The in vivo and in vitro effects of selenium and the mechanisms involved in preclinical models of liver cancer are critically reviewed in this article. The chemopreventive and therapeutic effects of selenium are reviewed especially in relation to its antioxidant property. Future directions and potential challenges involved in the advance of selenium use in the prevention and treatment of liver cancer are also discussed."


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"Selenium for preventing cancer Vinceti M, et al. Selenium for preventing cancer. The Cochrane database of systematic reviews. 2014;3:CD005195. doi:10.1002/14651858.CD005195.pub3. Although an inverse association between selenium exposure and the risk of some types of cancer was found in some observational studies, this cannot be taken as evidence of a causal relation, and these results should be interpreted with caution. These studies have many limitations, including issues with assessment of exposure to selenium and to its various chemical forms, heterogeneity, confounding and other biases. Conflicting results including inverse, null and direct associations have been reported for some cancer types. RCTs assessing the effects of selenium supplementation on cancer risk have yielded inconsistent results, although the most recent studies, characterised by a low risk of bias, found no beneficial effect on cancer risk, more specifically on risk of prostate cancer, as well as little evidence of any influence of baseline selenium status. Rather, some trials suggest harmful effects of selenium exposure. To date, no convincing evidence suggests that selenium supplements can prevent cancer in humans."


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Manganese

"Manganese Superoxide Dismutase in Cancer Prevention Robbins D, Zhao Y. Manganese Superoxide Dismutase in Cancer Prevention. Antioxidants & Redox Signaling. 2014;20(10):1628-1645. doi:10.1089/ars.2013.5297. Significance: Cancer is the second leading cause of death in the United States. Considering the quality of life and treatment cost, the best way to fight against cancer is to prevent or suppress cancer development. Cancer is preventable as indicated by human papilloma virus (HPV) vaccination and tamoxifen/raloxifen treatment in breast cancer prevention. The activities of superoxide dismutases (SODs) are often lowered during early cancer development, making it a rational candidate for cancer prevention. Recent Advances:SOD liposome and mimetics have been shown to be effective in cancer prevention animal models. They've also passed safety tests during early phase clinical trials. Dietary supplement-based SOD cancer prevention provides another opportunity for antioxidant-based cancer prevention. New mechanistic studies have revealed that SOD inhibits not only oncogenic activity, but also subsequent metabolic shifts during early tumorigenesis. Critical Issues: Lack of sufficient animal model studies targeting specific cancers; and lack of clinical trials and support from pharmaceutical industries also hamper efforts in further advancing SOD-based cancer prevention. Future Directions: To educate and obtain support from our society that cancer is preventable. To combine SOD-based therapeutics with other cancer preventive agents to obtain synergistic effects. To formulate a dietary supplementation-based antioxidant approach for cancer prevention. Lastly, targeting specific populations who are prone to carcinogens, which can trigger oxidative stress as the mechanism of carcinogenesis."


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"The association between deficient manganese levels and breast cancer: a meta-analysis Shen F, et al. The association between deficient manganese levels and breast cancer: a meta-analysis. International Journal of Clinical and Experimental Medicine. 2015;8(3):3671-3680. There are conflicting reports on the correlation between manganese (Mn) levels and breast cancer. The purpose of the present study is to clarify the association between Mn levels and breast cancer using a meta-analysis approach. We searched articles indexed in Pubmed and the Chinese Journal Full-text Database (CJFD) published as of August 2014 that met our predefined criteria. Eleven eligible studies involving 1302 subjects were identified. Overall, pooled analysis indicated that subjects with breast cancer had lower Mn levels than the healthy controls (SMD = -1.51, 95% CI = [-2.47, -0.56]). Further subgroup analysis found a similar pattern in China (SMD = -1.32, 95% CI = [-2.33, -0.32]) and Korea (SMD = -4.08, 95% CI = [-4.63, -3.54]), but not in Turkey (SMD = -0.96, 95% CI = [-3.19, 1.27]). Further subgroup analysis also found a similar pattern in different sample specimens (serum: SMD = -1.24, 95% CI = [-2.31, -0.16]; hair: SMD = -1.99, 95% CI = [-3.91, -0.06]) and different types of Mn measurement (inductively coupled plasma-atomic absorption spectrometry (ICP-AAS): SMD = -1.14, 95% CI = [-2.24, -0.04]; graphite furnace atomic absorption spectroscopy (GFAAS): SMD = -1.94, 95% CI = [-2.38, -1.49]; inductively coupled plasma-atomic emission spectrometry (ICP-AES): SMD = -3.77, 95% CI = [-4.70, -2.85]). No evidence of publication bias was observed. In conclusion, this meta-analysis supports a significant association between deficient Mn levels and breast cancer. However, the subgroup analysis found that there was contradiction regarding races and geography, like China and Turkey. Thus this finding needs further confirmation by trans-regional multicenter, long-term observation in a cohort design to obtain better understanding of causal relationships between Mn levels and breast cancer, through measuring Mn at baseline to investigate whether the highest Mn category versus lowest was associated with breast cancer risk."


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"Manganese superoxide dismutase (Sod2) and redox-control of signaling events that drive metastasis Hempel N, Carrico PM, Melendez JA. Manganese superoxide dismutase (Sod2) and redox-control of signaling events that drive metastasis. Anti-cancer agents in medicinal chemistry. 2011;11(2):191-201. Manganese superoxide dismutase (Sod2) has emerged as a key enzyme with a dual role in tumorigenic progression. Early studies were primarily directed at defining the tumor suppressive function of Sod2 based on its low level expression in many tumor types. It is now commonly held that loss of Sod2 expression is likely an early event in tumor progression allowing for further propagation of the tumorigenic phenotype resulting from steady state increases in free radical production. Increases in free radical load have also been linked to defects in mitochondrial function and metastatic disease progression. It was initially believed that Sod2 loss may propagate metastatic disease progression, in reality both epidemiologic and experimental evidence indicate that Sod2 levels increase in many tumor types as they progress from early stage non-invasive disease to late stage metastatic disease. Sod2 overexpression in many instances enhances the metastatic phenotype that is reversed by efficient H2O2 scavenging. This review evaluates the many sequelae associated with increases in Sod2 that impinge on the metastatic phenotype. The ability to use Sod2 to modulate the cellular redox-environment has allowed for the identification of redox-responsive signaling events that drive malignancy, such as invasion, migration and prolonged tumor cell survival. Further studies of these redox-driven events will help in the development of targeted therapeutic strategies to efficiently restrict redox-signaling essential for malignant progression."


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"Manganese superoxide dismutase (Sod2) and redox-control of signaling events that drive metastasis Hempel N, Carrico PM, Melendez JA. Manganese superoxide dismutase (Sod2) and redox-control of signaling events that drive metastasis. Anti-cancer agents in medicinal chemistry. 2011;11(2):191-201. Manganese superoxide dismutase (Sod2) has emerged as a key enzyme with a dual role in tumorigenic progression. Early studies were primarily directed at defining the tumor suppressive function of Sod2 based on its low level expression in many tumor types. It is now commonly held that loss of Sod2 expression is likely an early event in tumor progression allowing for further propagation of the tumorigenic phenotype resulting from steady state increases in free radical production. Increases in free radical load have also been linked to defects in mitochondrial function and metastatic disease progression. It was initially believed that Sod2 loss may propagate metastatic disease progression, in reality both epidemiologic and experimental evidence indicate that Sod2 levels increase in many tumor types as they progress from early stage non-invasive disease to late stage metastatic disease. Sod2 overexpression in many instances enhances the metastatic phenotype that is reversed by efficient H2O2 scavenging. This review evaluates the many sequelae associated with increases in Sod2 that impinge on the metastatic phenotype. The ability to use Sod2 to modulate the cellular redox-environment has allowed for the identification of redox-responsive signaling events that drive malignancy, such as invasion, migration and prolonged tumor cell survival. Further studies of these redox-driven events will help in the development of targeted therapeutic strategies to efficiently restrict redox-signaling essential for malignant progression."


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"A novel manganese complex selectively induces malignant glioma cell death by targeting mitochondria Geng J, et al. A novel manganese complex selectively induces malignant glioma cell death by targeting mitochondria. Molecular Medicine Reports. 2016;14(3):1970-1978. doi:10.3892/mmr.2016.5509. Despite advances in treatment, malignant glioma commonly exhibits recurrence, subsequently leading to a poor prognosis. As manganese (Mn) compounds can be transported by the transferrin-transferrin receptor system, the present study synthesized and examined the potential use of Adpa-Mn as a novel antitumor agent. Adpa-Mn time and dose-dependently inhibited U251 and C6 cell proliferation; however, it had little effect on normal astrocytes. Apoptosis was significantly elevated following treatment with Adpa-Mn, as detected by chromatin condensation, Annexin V/propidium iodide staining, cytochrome c release from mitochondria to the cytoplasm, and the activation of caspases-9, -7 and -3 and poly (ADP-ribose) polymerase. In addition, Adpa-Mn enhanced fluorescence intensity of monodansylcadaverine and elevated the expression levels of the autophagy-related protein microtubule-associated protein 1 light chain 3. Pretreatment with the autophagy inhibitors 3-methyladenine and chloroquine enhanced Adpa-Mn-induced cell inhibition, thus indicating that autophagy has an essential role in this process. Furthermore, evidence of mitochondrial dysfunction was detected in the Adpa-Mn-treated group, including disrupted membrane potential, elevated levels of reactive oxygen species (ROS) and depleted adenosine triphosphate. Conversely, treatment with the mitochondrial permeability transition inhibitor cyclosporin A reversed Adpa-Mn-induced ROS production, mitochondrial damage and cell apoptosis, thus suggesting that Adpa-Mn may target the mitochondria. Taken together, these data suggested that Adpa-Mn may be considered for use as a novel anti-glioma therapeutic option."


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Molybdenum

"Distribution of selenium and molybdenum and cancer mortality in Niigata, Japan Nakadaira H, Endoh K, Yamamoto M, Katoh K. Distribution of selenium and molybdenum and cancer mortality in Niigata, Japan. Arch Environ Health. 1995 Sep-Oct;50(5):374-80. PubMed PMID: 7574892. Selenium and molybdenum have inhibitory effects on gastrointestinal carcinogenesis. We investigated the levels of selenium and molybdenum in sediments and mortality from cancers at specific sites in 19 areas of Niigata Prefecture, Japan, and compared these factors. The average concentrations of selenium and molybdenum were 0.44 +/- 0.19 ppm (micrograms/g dry weight; mean +/- standard deviation) and 3.82 +/- 1.03 ppm, respectively. Selenium was not associated significantly with cancer mortality. There were inverse correlations between molybdenum levels and female mortality from cancers of the esophagus (r = -.446, .05 < p < .1) and rectum (r = -.529, p < .05). Molybdenum was correlated positively with female mortality from cancer of the pancreas (r = .603, p < .01). Further investigations are needed for causal interpretation of these results."


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"Effect of Dietary Molybdenum on Esophageal Carcinogenesis in Rats Induced by N-Methyl-N-benzylnitrosamine Komada H, et al. (1990). Effect of Dietary Molybdenum on Esophageal Carcinogenesis in Rats Induced by N-Methyl-N-benzylnitrosamine. American Association for Cancer Research, 50, 2418-22. The influence of dietary molybdenum on esophageal carcinogenesis induced by /V-methyl-/V-benzylnitrosamine (2.5 mg per kg of body weight once a week for 20 wk s.c.) was studied in male F344 rats. The tumor incidence and tumor development in the esophagus were significantly lower in the rats in the high-molybdenum (2 ppm) diet group than in the rats in the low-molybdenum (0.032 ppm) diet group; i.e., 44.4% (0.6 ± 0.8) and 73.2% (2.2 ±2.0), respectively. The molybdenum levels in the esophagus-forestomach, liver, and serum were significantly higher in the high-molybdenum diet group than in the low-molybdenum diet group. Xanthine oxidase activity in the esophagus and forestomach in the highmolybdenum diet group was significantly higher than that in the lowmolybdenum diet group, whereas liver and serum vanilline oxidase activ ities were not significantly different between these two groups. These results suggest that xanthine oxidase in the esophagus plays a significant role in the inhibitory effect of molybdenum on esophageal carcinogenesis."


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"Toxicity of Nano Molybdenum Trioxide toward Invasive Breast Cancer Cells Tran TA, Krishnamoorthy K, Song YW, Cho SK, Kim SJ. Toxicity of Nano Molybdenum Trioxide toward Invasive Breast Cancer Cells. ACS Applied Materials & Interfaces 2014 6 (4), 2980-6. DOI: 10.1021/am405586d Current chemotherapy is limited by the nature of invasive cancer cells, which are similar to cancer stem cells. Nanomaterials provide a potential alternate mode of cancer therapy. This study investigated the cytotoxicity of molybdenum trioxide (MoO3) nanoplates toward invasive breast cancer iMCF-7 cells by analyzing morphological changes and performing Western blot and flow cytometry analyses. The findings suggested that MoO3 exposure induces apoptosis and generates reactive oxygen species (ROS) in iMCF-7 cells. This study revealed the potential utility of MoO3 for treating metastatic cancer cells, which might enable advancements in cancer therapy."


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Independent ingredient review