By: Brianna Choyce

GINGER

Ginger is a well-known herb that is prevalent in foods of many cultures and has been used historically for its medicinal benefits in ailments such as nausea, gastrointestinal discomfort, and pain. The herb contains potent compounds called gingerols and its derivatives, most notably the dehydrated shogaols, that are being extracted and studied for their medicinal properties. Several studies have confirmed that gingerols have anti-metastatic properties in cancers of the breast, skin (melanoma), pancreas, prostate, liver, lungs, rectum, stomach, and colon.[1] Simply put, gingerols exhibit their anti-metastatic properties through promotion of apoptosis through activation of a certain gene, down-regulation of cancer-promotion genes, and enhancing the body’s cancer-killing defenses. Studies have highlighted ginger as having promising clinical potential in cancer therapy.

 

Anti-Cancer Mechanisms

The parent generation of cancer cells make up less than 1% of the cells of most tumors but often prove to be the most virulent type of cancer cell. This is due to their superior proliferative capabilities and genetic adaptations for survival. These parent cancer cells are named, cancer stem cells, or CSCs. CSCs are blamed, at least in part, for tumor relapse and poor prognostics in various cancer types. It is notable that current chemotherapeutic agents have not demonstrated effective killing of CSCs. The inhibitory activity of a specific gingerol compound, 6-shogaol was investigated against CSCs in breast cancer. Therapy with 6-shogaol resulted in death of CSCs, as suggested by a reduction in CD44 and CD24 surface markers.[1]


Besides its successful targeting of CSCs, 6-shogaol has also shown potent anticancer activity against other cancer cells. Research shows that 6-shogaol has effectively reduced proliferation of cancer cells by suspending them in G1 and G2 in mitotic arrest via damage of microtubules.  Another ginger derivative, 6-gingerol has shown reduction in viability of gastric cancer cells, subjecting them to apoptosis.[2]

The compound 6-shogaol has demonstrated induction of apoptosis in mutated cells via a complex mechanism, even when they proved resistant to traditional chemotherapies. The first part of this mechanism includes application of oxidative stress by creating excess reactive oxygen species. This was followed by glutathione depletion and subsequent apoptosis resulting from a decline in mitochondrial transmembrane potential.[3]

Other mechanisms in which ginger derivatives have induced apoptosis include the following:

  • Induction of autophagy via inhibition of the AKT/mTOR pathway in non-small cell lung cancer with alveolar basal epithelial cell mutation A-549.[4] Similar results were seen in colon cancer cells with HCT-116, positive for transforming growth factor beta 1 and beta 2.[5]  
  • Ginger derivative activation of Peroxisomal proliferator activated receptor gamma (PPAR-γ) resulted in apoptosis in MCF-7 breast and HT-29 colorectal cancer cells.[6]

 

A protective mechanism called notch signaling is a characteristic pathway of multicellular organisms. This pathway regulates the fate of cells during the cell cycle and becomes active when signaled to renew stem cells. Genetic predispositions for notch receptor over-activation have been implicated in the formation of several types of cancers involving solid tumors.[7] Derivatives of ginger have been found to interfere with the notch signaling pathway by reducing its activity and expression of target proteins.[8]

 

Current Evidence

Research has shown that cancer stem cells are virulent and could be at least partially to blame for tumor relapse. Chemotherapy agents such as paclitaxel, doxorubicin, 5-fluorouracil, and the platinum drugs have not demonstrated efficacy in targeting CSCs.[9][10]

A study conducted in 2015 revealed that ginger derivatives have potential therapeutic benefit in targeting cancer stem cells up to 10,000 times greater than traditional chemotherapy agents. The study demonstrated that 6-shogaol inhibits the cancer stem cell self-renewal pathway. Concentrations of the ginger-derived therapy that were found to be efficacious in reducing the number of CSCs in this study were also non-toxic to non-cancerous cells.[1]

A 2007 study, published in the journal Biochemical and Biophysical Research Communications, used gastric cancer cells to evaluate six herbal ingredients based upon reduction of viability of the cancer cells, suppression of their replication, and induction of apoptosis. Chemical derivatives of ginger were shown to suppress tumor growth and induce caspase activation and apoptosis. The 6-shogaol derivative showed an additional benefit of reduced cancer cell viability, which was measured after 24 hours using 96 samples of the cancer cells.[2] Studies have further implicated microtubule damage through interaction with the sulfhydryl moiety of the amino acid cysteine as a means of suppressing tumor growth. [11]

A 2007 article published in the Journal of Agricultural and Food Chemistry, associated with the American Chemical Society, involved treatment of an aggressive human hepatoma characterized by Mahlavu cells with p53 mutation. [12] The proposed novel treatment resulted in successful ginger-induced apoptosis via a caspase-dependent mechanism when traditional agents have failed to do so adequately.

 

Additional Health Benefits

Ginger has shown to offer benefits in the following conditions:

  • Inflammation- The bioactive components of ginger have anti-inflammatory and antioxidant effects.[13]
  • Nausea- Ginger has been used as a remedy for morning sickness and many other forms of nausea, including chemotherapy-induced nausea and vomiting.[14]
  • Muscle pain- Ginger has been shown to produce moderate to large reductions in exercise-associated muscle pain.[15]
  • Arthritis- Statistically significant reduction in symptoms of osteoarthritis of the knee has been reported with ginger use.[16]
  • High blood sugar- Daily intake of dried ginger resulted in a 12% reduction in fasting blood sugar and a 10% reduction in HbA1c (hemoglobin A1c).[17]
  • High cholesterol- Ginger powder has shown evidence in reducing triglycerides, LDL and VLDL.[18]

 

Evidence points to ginger and the potential of its potent derivatives in fighting cancer cells. Numerous theories of just how ginger performs anticancer activities have been researched and studied in human populations, as well as in other mammals. The mechanisms listed in this article are just a few among many that support the use of ginger extracts in the prevention and treatment of several types of cancer. Ginger undoubtedly has the ability to target cancer stem cells and other tumor cells with genetic mutations resistant to traditional chemotherapies. Past and current research provides an exciting perspective of how this natural herb can help with many common ailments and even cancer.

 

References

  1. Ray A, Vasudevan S, Sengupta S (2015) 6-Shogaol Inhibits Breast Cancer Cells and  Stem Cell-Like Spheroids by Modulation of Notch Signaling Pathway and Induction of Autophagic Cell Death. PLoS ONE 10(9): e0137614. https://doi.org/10.1371/journal.pone.0137614
  2. Ishiguro K, et al. (2007) Ginger ingredients reduce viability of gastric cancer cells via distinct mechanisms. Biochem Biophys Res Commun 362: 21–223. PMID:17706603
  3. Chen CY, et al. (2007) 6-shogaol (alkanone from ginger) induces apoptotic cell death of human hepatoma p53 mutant Mahlavu subline via an oxidative stress-mediated caspase-dependent mechanism. J Agric Food Chem 55: 948–954. PMID:17263498
  4. Hung JY, et al. (2009) 6-Shogaol, an active constituent of dietary ginger, induces autophagy by inhibiting the AKT/mTOR pathway in human non-small cell lung cancer A549 cells. J Agric Food Chem 57: 9809–9816. PMID:19799425
  5. Gan FF, et al. (2011) Shogaols at proapoptotic concentrations induce G(2)/M arrest and aberrant mitotic cell death associated with tubulin aggregation. Apoptosis 16: 856–867. PMID:21598039
  6. Tan BS, et al. (2013) 6-Shogaol inhibits breast and colon cancer cell proliferation through activation of peroxisomal proliferator activated receptor gamma (PPARgamma). Cancer Lett 336: 127–139. PMID:23612072
  7. Dontu G, et al. (2004) Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res 6: R605–615. PMID:15535842
  8. Artavanis-Tsakonas S, Rand MD, Lake RJ. (1999) Notch signaling: cell fate control and signal integration in development. Science 284: 770–776. PMID:10221902
  9. Alvero AB, et al. (2009) Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance.Cell Cycle 8: 158–166. PMID:19158483
  10. Fillmore CM, Kuperwasser C. (2008) Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res 10: R25. PMID:1366788
  11. Ishiguro K, Ando T, Watanabe O, Goto H. (2008) Specific reaction of alpha, beta-unsaturated carbonyl compounds such as 6-shogaol with sulfhydryl groups in tubulin leading to microtubule damage. FEBS Lett 582: 3531–3536. PMID:1805415
  12. Chen CY, et al. 6-shogaol (alkanone from ginger) induces apoptotic cell death of human hepatoma p53 mutant Mahlavu subline via an oxidative stress-mediated caspase-dependent mechanism. J Agric Food Chem. 2007 Feb 7;55(3):948-54. PubMed PMID: 17263498.
  13. Wang S, Zhang C, Yang G, Yang Y. Biological properties of 6-gingerol: a brief review. Nat Prod Commun. 2014 Jul;9(7):1027-30. Review. PubMed PMID: 25230520.
  14. Pillai AK, Sharma KK, Gupta YK, Bakhshi S. Anti-emetic effect of ginger powder versus placebo as an add-on therapy in children and young adults receiving high emetogenic chemotherapy. Pediatr Blood Cancer. 2011 Feb;56(2):234-8. doi: 10.1002/pbc.22778. Epub 2010 Sep 14. PubMed PMID: 20842754.
  15. Black CD, Herring MP, Hurley DJ, O’Connor PJ. Ginger (Zingiber officinale) reduces muscle pain caused by eccentric exercise. J Pain. 2010 Sep;11(9):894-903. doi: 10.1016/j.jpain.2009.12.013. Epub 2010 Apr 24. PubMed PMID: 204114.
  16. Altman RD, Marcussen KC. Effects of a ginger extract on knee pain in patients with osteoarthritis. Arthritis Rheum. 2001 Nov;44(11):2531-8. PubMed PMID: 11710709.
  17. Khandouzi N,et al. The Effects of Ginger on Fasting Blood Sugar, Hemoglobin A1c, Apolipoprotein B, Apolipoprotein A-I and Malondialdehyde in Type 2 Diabetic Patients. Iranian Journal of Pharmaceutical Research : IJPR. 2015;14(1):131-140.
  18. Alizadeh-Navaei R,et al. Investigation of the effect of ginger on the lipid levels. A double blind controlled clinical trial. Saudi Med J. 2008 Sep;29(9):1280-4. PubMed PMID: 1813412.


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