Ginger and its constituents: role in prevention and treatment of gastrointestinal cancer

Sahdeo Prasad, Amit K Tyagi, Sahdeo Prasad, Amit K Tyagi

Abstract

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.

Figures

Figure 1
Figure 1
Different cancer types which are categorized under gastrointestinal cancer.
Figure 2
Figure 2
Ginger, ginger rhizome, and its major active components: 6-gingerol, 6-shogaol, and 6-paradol.
Figure 3
Figure 3
Molecular targets of ginger and its active constituents against gastrointestinal cancer.

References

    1. Marieb E. N. Essentials of Human Anatomy and Physiology. 8th. New York, NY, USA: Benjamin Cummings; 2005.
    1. Klint Å., Engholm G., Storm H. H., et al. Trends in survival of patients diagnosed with cancer of the digestive organs in the Nordic countries 1964–2003 followed up to the end of 2006. Acta Oncologica. 2010;49(5):578–607. doi: 10.3109/02841861003739330.
    1. Siegel R., Desantis C., Jemal A. Colorectal cancer statistics, 2014. CA Cancer Journal for Clinicians. 2014;64(2):104–117. doi: 10.3322/caac.21220.
    1. Prasad S., Kim J. H., Gupta S. C., Aggarwal B. B. Targeting death receptors for TRAIL by agents designed by mother nature. Trends in Pharmacological Sciences. 2014;35(10):520–536. doi: 10.1016/j.tips.2014.07.004.
    1. Prasad S., Sung B., Aggarwal B. B. Age-associated chronic diseases require age-old medicine: role of chronic inflammation. Preventive Medicine. 2012;54:S29–S37. doi: 10.1016/j.ypmed.2011.11.011.
    1. Sung B., Prasad S., Yadav V. R., Lavasanifar A., Aggarwal B. B. Cancer and diet: how are they related? Free Radical Research. 2011;45(8):864–879. doi: 10.3109/10715762.2011.582869.
    1. Aggarwal B. B., van Kuiken M. E., Iyer L. H., Harikumar K. B., Sung B. Molecular targets of nutraceuticals derived from dietary spices: potential role in suppression of inflammation and tumorigenesis. Experimental Biology and Medicine. 2009;234(8):825–849. doi: 10.3181/0902-mr-78.
    1. Zeegers M. P. A., Goldbohm R. A., Van den Brandt P. A. Consumption of vegetables and fruits and urothelial cancer incidence: a prospective study. Cancer Epidemiology Biomarkers and Prevention. 2001;10(11):1121–1128.
    1. Demin G., Yingying Z. Comparative antibacterial activities of crude polysaccharides and flavonoids from Zingiber officinale and their extraction. American Journal of Tropical Medicine. 2010;5:235–238.
    1. Grzanna R., Lindmark L., Frondoza C. G. Ginger—an herbal medicinal product with broad anti-inflammatory actions. Journal of Medicinal Food. 2005;8(2):125–132. doi: 10.1089/jmf.2005.8.125.
    1. Langner E., Greifenberg S., Gruenwald J. Ginger: history and use. Advances in Therapy. 1998;15(1):25–44.
    1. Shukla Y., Singh M. Cancer preventive properties of ginger: a brief review. Food and Chemical Toxicology. 2007;45(5):683–690. doi: 10.1016/j.fct.2006.11.002.
    1. Nair S. V., Ziaullah, Rupasinghe H. P. Fatty acid esters of phloridzin induce apoptosis of human liver cancer cells through altered gene expression. PLoS ONE. 2014;9(9) doi: 10.1371/journal.pone.0107149.e107149
    1. Chen H., Soroka D., Zhu Y., Sang S. Metabolism of ginger component [6]-shogaol in liver microsomes from mouse, rat, dog, monkey, and human. Molecular Nutrition and Food Research. 2013;57(5):865–876. doi: 10.1002/mnfr.201200708.
    1. Hu R., Zhou P., Peng Y.-B., et al. 6-shogaol induces apoptosis in human hepatocellular carcinoma cells and exhibits anti-tumor activity in vivo through endoplasmic reticulum stress. PLoS ONE. 2012;7(6) doi: 10.1371/journal.pone.0039664.e39664
    1. Yang G., Wang S., Zhong L., et al. 6-gingerol induces apoptosis through lysosomal-mitochondrial axis in human hepatoma G2 cells. Phytotherapy Research. 2012;26(11):1667–1673. doi: 10.1002/ptr.4632.
    1. Peng F., Tao Q., Wu X., et al. Cytotoxic, cytoprotective and antioxidant effects of isolated phenolic compounds from fresh ginger. Fitoterapia. 2012;83(3):568–585. doi: 10.1016/j.fitote.2011.12.028.
    1. Weng C.-J., Wu C.-F., Huang H.-W., Ho C.-T., Yen G.-C. Anti-invasion effects of 6-shogaol and 6-gingerol, two active components in ginger, on human hepatocarcinoma cells. Molecular Nutrition and Food Research. 2010;54(11):1618–1627. doi: 10.1002/mnfr.201000108.
    1. Vijaya Padma V., Arul Diana Christie S., Ramkuma K. M. Induction of apoptosis by ginger in HEp-2 cell line is mediated by reactive oxygen species. Basic and Clinical Pharmacology and Toxicology. 2007;100(5):302–307. doi: 10.1111/j.1742-7843.2007.00046.x.
    1. Chen C.-Y., Liu T.-Z., Liu Y.-W., 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. Journal of Agricultural and Food Chemistry. 2007;55(3):948–954. doi: 10.1021/jf0624594.
    1. Nakamura Y., Yoshida C., Murakami A., Ohigashi H., Osawa T., Uchida K. Zerumbone, a tropical ginger sesquiterpene, activates phase II drug metabolizing enzymes. FEBS Letters. 2004;572(1–3):245–250. doi: 10.1016/j.febslet.2004.07.042.
    1. Shamoto T., Matsuo Y., Shibata T., et al. Zerumbone inhibits angiogenesis by blocking NF-κB activity in pancreatic cancer. Pancreas. 2014;43(3):396–404. doi: 10.1097/mpa.0000000000000039.
    1. Zhou L., Qi L., Jiang L., et al. Antitumor activity of gemcitabine can be potentiated in pancreatic cancer through modulation of TLR4/NF-κB signaling by 6-shogaol. The AAPS Journal. 2014;16(2):246–257. doi: 10.1208/s12248-013-9558-3.
    1. Rebellato P., Islam M. S. [6]-shogaol induces Ca2+ signals by activating the TRPV1 channels in the rat insulinoma INS-1E cells. Journal of the Pancreas. 2014;15(1):33–37.
    1. Kim S. O., Kim M. R. [6]-gingerol prevents disassembly of cell junctions and activities of MMPs in invasive human pancreas cancer cells through ERK/NF-κB/snail signal transduction pathway. Evidence-based Complementary and Alternative Medicine. 2013;2013:9. doi: 10.1155/2013/761852.761852
    1. Zhang S., Liu Q., Liu Y., Qiao H. Zerumbone, a Southeast Asian ginger sesquiterpene, induced apoptosis of pancreatic carcinoma cells through p53 signaling pathway. Evidence-Based Complementary and Alternative Medicine. 2012;2012:8. doi: 10.1155/2012/936030.936030
    1. Park Y. J., Wen J., Bang S., Park S. W., Song S. Y. [6]-Gingerol induces cell cycle arrest and cell death of mutant p53-expressing pancreatic cancer cells. Yonsei Medical Journal. 2006;47(5):688–697. doi: 10.3349/ymj.2006.47.5.688.
    1. Tsuboi K., Matsuo Y., Shamoto T., et al. Zerumbone inhibits tumor angiogenesis via NF-κB in gastric cancer. Oncology Reports. 2014;31(1):57–64. doi: 10.3892/or.2013.2842.
    1. Gaus K., Huang Y., Israel D. A., Pendland S. L., Adeniyi B. A., Mahady G. B. Standardized ginger (Zingiber officinale) extract reduces bacterial load and suppresses acute and chronic inflammation in Mongolian gerbils infected with cagA+ Helicobacter pylori . Pharmaceutical Biology. 2009;47(1):92–98. doi: 10.1080/13880200802448690.
    1. Ishiguro K., Ando T., Maeda O., et al. Ginger ingredients reduce viability of gastric cancer cells via distinct mechanisms. Biochemical and Biophysical Research Communications. 2007;362(1):218–223. doi: 10.1016/j.bbrc.2007.08.012.
    1. Mahady G. B., Pendland S. L., Yun G. S., Lu Z.-Z., Stoia A. Ginger (Zingiber officinale Roscoe) and the Gingerols Inhibit the Growth of Cag A+ Strains of Helicobacter pylori . Anticancer Research. 2003;23(5):3699–3702.
    1. Mukkavilli R., Gundala S. R., Yang C., et al. Modulation of cytochrome P450 metabolism and transport across intestinal epithelial barrier by ginger biophenolics. PLoS ONE. 2014;9(9) doi: 10.1371/journal.pone.0108386.e108386
    1. Hakim L., Alias E., Makpol S., Ngah W.Z. W., Morad N. A., Yusof Y. A. Gelam honey and ginger potentiate the anti cancer effect of 5-FU against HCT 116 colorectal cancer cells. Asian Pacific Journal of Cancer Prevention. 2014;15(11):4651–4657. doi: 10.7314/apjcp.2014.15.11.4651.
    1. Pan M.-H., Hsieh M.-C., Kuo J.-M., et al. 6-Shogaol induces apoptosis in human colorectal carcinoma cells via ROS production, caspase activation, and GADD 153 expression. Molecular Nutrition and Food Research. 2008;52(5):527–537. doi: 10.1002/mnfr.200700157.
    1. Lee S. H., Cekanova M., Seung J. B. Multiple mechanisms are involved in 6-gingerol-induced cell growth arrest and apoptosis in human colorectal cancer cells. Molecular Carcinogenesis. 2008;47(3):197–208. doi: 10.1002/mc.20374.
    1. Yodkeeree S., Sung B., Limtrakul P., Aggarwal B. B. Zerumbone enhances TRAIL-induced apoptosis through the induction of death receptors in human colon cancer cells: evidence for an essential role of reactive oxygen species. Cancer Research. 2009;69(16):6581–6589. doi: 10.1158/0008-5472.can-09-1161.
    1. Plengsuriyakarn T., Viyanant V., Eursitthichai V., et al. Anticancer activities against cholangiocarcinoma, toxicity and pharmacological activities of Thai medicinal plants in animal models. BMC Complementary and Alternative Medicine. 2012;12, article 23 doi: 10.1186/1472-6882-12-23.
    1. Thatte U., Bagadey S., Dahanukar S. Modulation of programmed cell death by medicinal plants. Cellular and Molecular Biology. 2000;46(1):199–214.
    1. Liu C.-T., Raghu R., Lin S.-H., et al. Metabolomics of ginger essential oil against alcoholic fatty liver in mice. Journal of Agricultural and Food Chemistry. 2013;61(46):11231–11240. doi: 10.1021/jf403523g.
    1. Jeena K., Liju V. B., Kuttan R. Antioxidant, anti-inflammatory and antinociceptive activities of essential oil from ginger. Indian Journal of Physiology and Pharmacology. 2013;57(1):51–62.
    1. Mansour M. A., Bekheet S. A., Al-Rejaie S. S., et al. Ginger ingredients inhibit the development of diethylnitrosoamine induced premalignant phenotype in rat chemical hepatocarcinogenesis model. BioFactors. 2010;36(6):483–490. doi: 10.1002/biof.122.
    1. Taha M. M. E., Abdul A. B., Abdullah R., Ibrahim T. A. T., Abdelwahab S. I., Mohan S. Potential chemoprevention of diethylnitrosamine-initiated and 2-acetylaminofluorene-promoted hepatocarcinogenesis by zerumbone from the rhizomes of the subtropical ginger (Zingiber zerumbet) Chemico-Biological Interactions. 2010;186(3):295–305. doi: 10.1016/j.cbi.2010.04.029.
    1. Habib S. H. M., Makpol S., Hamid N. A. A., Das S., Ngah W. Z. W., Yusof Y. A. M. Ginger extract (Zingiber officinale) has anti-cancer and anti-inflammatory effects on ethionine-induced hepatoma rats. Clinics (Sao Paulo) 2008;63(6):807–813. doi: 10.1590/s1807-59322008000600017.
    1. Yusof Y. A. M., Ahmad N., Das S., Sulaiman S., Murad N. A. Chemopreventive efficacy of ginger (Zingiber officinale) in ethionine induced rat hepatocarcinogenesis. African Journal of Traditional, Complementary and Alternative Medicines. 2009;6(1):87–93.
    1. Deol P. K., Kaur I. P. Improving the therapeutic efficiency of ginger extract for treatment of colon cancer using a suitably designed multiparticulate system. Journal of Drug Targeting. 2013;21(9):855–865. doi: 10.3109/1061186X.2013.829076.
    1. Ko J. K., Leung C. C. Ginger extract and polaprezinc exert gastroprotective actions by anti-oxidant and growth factor modulating effects in rats. Journal of Gastroenterology and Hepatology (Australia) 2010;25(12):1861–1869. doi: 10.1111/j.1440-1746.2010.06347.x.
    1. Sharma S. S., Gupta Y. K. Reversal of cisplatin-induced delay in gastric emptying in rats by ginger (Zingiber officinale) Journal of Ethnopharmacology. 1998;62(1):49–55. doi: 10.1016/s0378-8741(98)00053-1.
    1. Manju V., Viswanathan P., Nalini N. Hypolipidemic effect of ginger in 1,2-dimethyl hydrazine-induced experimental colon carcinogenesis. Toxicology Mechanisms and Methods. 2006;16(8):461–472. doi: 10.1080/15376520600728811.
    1. Manju V., Nalini N. Effect of ginger on bacterial enzymes in 1,2-dimethylhydrazine induced experimental colon carcinogenesis. European Journal of Cancer Prevention. 2006;15(5):377–383. doi: 10.1097/00008469-200610000-00001.
    1. Yoshimi N., Wang A., Morishita Y., et al. Modifying effects of fungal and herb metabolites on azoxymethane-induced intestinal carcinogenesis in rats. Japanese Journal of Cancer Research. 1992;83(12):1273–1278. doi: 10.1111/j.1349-7006.1992.tb02758.x.
    1. Levine M. E., Gillis M. G., Koch S. Y., Voss A. C., Stern R. M., Koch K. L. Protein and ginger for the treatment of chemotherapy-induced delayed nausea. Journal of Alternative and Complementary Medicine. 2008;14(5):545–551. doi: 10.1089/acm.2007.0817.
    1. Zick S. M., Turgeon D. K., Ren J., et al. Pilot clinical study of the effects of ginger root extract on eicosanoids in colonic mucosa of subjects at increased risk for colorectal cancer. Molecular Carcinogenesis. 2014 doi: 10.1002/mc.22163.
    1. Khiewkhern S., Promthet S., Sukprasert A., Eunhpinitpong W., Bradshaw P. Effectiveness of aromatherapy with light thai massage for cellular immunity improvement in colorectal cancer patients receiving chemotherapy. Asian Pacific Journal of Cancer Prevention. 2013;14(6):3903–3907. doi: 10.7314/APJCP.2013.14.6.3903.
    1. Stoner G. D. Ginger: is it ready for prime time? Cancer Prevention Research. 2013;6(4):257–262. doi: 10.1158/1940-6207.capr-13-0055.
    1. Citronberg J., Bostick R., Ahearn T., et al. Effects of ginger supplementation on cell-cycle biomarkers in the normal-appearing colonic mucosa of patients at increased risk for colorectal cancer: results from a pilot, randomized, and controlled trial. Cancer Prevention Research. 2013;6(4):271–281. doi: 10.1158/1940-6207.capr-12-0327.
    1. Jiang Y., Turgeon D. K., Wright B. D., et al. Effect of ginger root on cyclooxygenase-1 and 15-hydroxyprostaglandin dehydrogenase expression in colonic mucosa of humans at normal and increased risk for colorectal cancer. European Journal of Cancer Prevention. 2013;22(5):455–460. doi: 10.1097/CEJ.0b013e32835c829b.
    1. Zick S. M., Turgeon D. K., Vareed S. K., et al. Phase II study of the effects of ginger root extract on eicosanoids in colon mucosa in people at normal risk for colorectal cancer. Cancer Prevention Research. 2011;4(11):1929–1937. doi: 10.1158/1940-6207.CAPR-11-0224.
    1. Tyler V. E. The Therapeutic Use of Phytomedicinals. New York, NY, USA: Pharmaceutical Products Press; 1994.
    1. Ali B. H., Blunden G., Tanira M. O., Nemmar A. Some phytochemical, pharmacological and toxicological properties of ginger (Zingiber officinale Roscoe): a review of recent research. Food and Chemical Toxicology. 2008;46(2):409–420. doi: 10.1016/j.fct.2007.09.085.
    1. Govindarajan V. S. Ginger—chemistry, technology, and quality evaluation. Part 1. Critical reviews in food science and nutrition. 1982;17(1):1–96.
    1. Harold M. On Food and Cooking: The Science and Lore of the Kitchen. 2nd. New York, NY, USA: Scribner; 2004.
    1. Sasidharan I., Nirmala Menon A. Comparative chemical composition and antimicrobial activity fresh & dry ginger oils (zigiber officinale roscoe) International Journal of Current Pharmaceutical Research. 2010;2:40–43.
    1. Holtmann S., Clarke A. H., Scherer H., Hohn M. The anti-motion sickness mechanism of ginger. A comparative study with placebo and dimenhydrinate. Acta Oto-Laryngologica. 1989;108(3-4):168–174. doi: 10.3109/00016488909125515.
    1. Qidwai W., Alim S. R., Dhanani R. H., Jehangir S., Nasrullah A., Raza A. Use of folk remedies among patients in Karachi Pakistan. Journal of Ayub Medical College, Abbottabad. 2003;15(2):31–33.
    1. Alam P. Densitometric HPTLC analysis of 8-gingerol in Zingiber officinale extract and ginger-containing dietary supplements, teas and commercial creams. Asian Pacific Journal of Tropical Biomedicine. 2013;3(8):634–638. doi: 10.1016/S2221-1691(13)60128-8.
    1. Srinivasan K. Antioxidant potential of spices and their active constituents. Critical Reviews in Food Science and Nutrition. 2014;54(3):352–372. doi: 10.1080/10408398.2011.585525.
    1. Pereira M. M., Haniadka R., Chacko P. P., Palatty P. L., Baliga M. S. Zingiber officinale Roscoe (ginger) as an adjuvant in cancer treatment: a review. Journal of B.U.ON. 2011;16(3):414–424.
    1. Sung B., Jhurani S., Kwang S. A., et al. Zerumbone down-regulates chemokine receptor CXCR4 expression leading to inhibition of CXCL12-induced invasion of breast and pancreatic tumor cells. Cancer Research. 2008;68(21):8938–8944. doi: 10.1158/0008-5472.CAN-08-2155.
    1. Ajith T. A. Ameliorating reactive oxygen species-induced in vitro lipid peroxidation in brain, liver, mitochondria and DNA damage by Zingiber officinale Roscoe. Indian Journal of Clinical Biochemistry. 2010;25(1):67–73. doi: 10.1007/s12291-010-0014-1.
    1. Weng C.-J., Chou C.-P., Ho C.-T., Yen G.-C. Molecular mechanism inhibiting human hepatocarcinoma cell invasion by 6-shogaol and 6-gingerol. Molecular Nutrition and Food Research. 2012;56(8):1304–1314. doi: 10.1002/mnfr.201200173.
    1. Jeong C.-H., Bode A. M., Pugliese A., et al. [6]-Gingerol suppresses colon cancer growth by targeting leukotriene A4 hydrolase. Cancer Research. 2009;69(13):5584–5591. doi: 10.1158/0008-5472.can-09-0491.
    1. Radhakrishnan E. K., Bava S. V., Narayanan S. S., et al. [6]-Gingerol induces caspase-dependent apoptosis and prevents PMA-induced proliferation in colon cancer cells by inhibiting MAPK/AP-1 signaling. PLoS ONE. 2014;9(8) doi: 10.1371/journal.pone.0104401.e104401
    1. Fu J., Chen H., Soroka D. N., Warin R. F., Sang S. Cysteine-conjugated metabolites of ginger components, shogaols, induce apoptosis through oxidative stress-mediated p53 pathway in human colon cancer cells. Journal of Agricultural and Food Chemistry. 2014;62(20):4632–4642. doi: 10.1021/jf501351r.
    1. Chen C.-Y., Yang W.-L., Kuo S.-Y. Cytotoxic activity and cell cycle analysis of hexahydrocurcumin on SW 480 human colorectal cancer cells. Natural Product Communications. 2011;6(11):1671–1672.
    1. Park G., Park J., Song H., et al. Anti-cancer activity of Ginger (Zingiber officinale) leaf through the expression of activating transcription factor 3 in human colorectal cancer cells. BMC Complementary and Alternative Medicine. 2014;14(1, article 408) doi: 10.1186/1472-6882-14-408.
    1. Deorukhkar A., Ahuja N., Mercado A. L., et al. Zerumbone increases oxidative stress in a thiol-dependent ROS-independent manner to increase DNA damage and sensitize colorectal cancer cells to radiation. Cancer Medicine. 2015;4(2):278–292. doi: 10.1002/cam4.367.
    1. Plengsuriyakarn T., Viyanant V., Eursitthichai V., et al. Cytotoxicity, toxicity, and anticancer activity of Zingiber officinale roscoe against cholangiocarcinoma. Asian Pacific Journal of Cancer Prevention. 2012;13(9):4597–4606. doi: 10.7314/apjcp.2012.13.9.4597.

Source: PubMed

3
Subscribe