Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Review Article

Anti-Cancer Effect of Gingerol in Cancer Prevention and Treatment

Author(s): Sana Nafees, Md. Zafaryab, Syed H. Mehdi, Bushra Zia, Moshahid A. Rizvi and Md. Asad Khan*

Volume 21, Issue 4, 2021

Published on: 18 September, 2020

Page: [428 - 432] Pages: 5

DOI: 10.2174/1871520620666200918100833

Price: $65

Abstract

Cancer is one of the most lethal diseases in the world. Because of the high death rate associated with cancer and the side effects of chemotherapy and radiation therapy, patients require alternative strategies for its treatment. Ginger (Zingiber officinale) has enormous medicinal properties and health benefits. In this review, we discuss the basic mechanism by which gingerol (an active component of ginger) modulates a variety of cell signaling pathways linked to cancer, including Nuclear Factors (NF-κB), Signal Transducer and Activator of Transcription 3 (STAT3), Activator Protein-1 (AP-1), β-catenin, Growth Factors Receptors (EGFR, VEGFR); Mitogen-Activated Protein Kinases (MAPK) and pro-inflammatory mediators (TNF-α and COX-2). Both in vitro and in vivo studies support the role of gingerol in cancer. The efficacy of gingerol by clinical trials has also been reported. Importantly, natural agents are already in clinical trials against various kinds of cancer. An effort has been made through this comprehensive review to highlight the recent developments and milestones achieved in cancer therapies via studies based on different cell lines using gingerol.

Keywords: Cancer, signaling pathways, gingerol, nuclear factors, β-catenin, NF-κB.

Graphical Abstract
[1]
Iqbal, J.; Abbasi, B.A.; Mahmood, T.; Kanwal, S.; Ali, B.; Shah, S.A.; Khalil, A.T. Plant-derived anticancer agents: A green anticancer approach.Asian Pac. J. Trop. Biomed, 2017, 7(12), 1129-1150.
[http://dx.doi.org/10.1016/j.apjtb.2017.10.016]
[2]
Vinogradov, S.; Wei, X. Cancer stem cells and drug resistance: The potential of nanomedicine. Nanomedicine (Lond.), 2012, 7(4), 597-615.
[http://dx.doi.org/10.2217/nnm.12.22] [PMID: 22471722]
[3]
Patra, C.R.; Mukherjee, S.; Kotcherlakota, R. Biosynthesized silver nanoparticles: A step forward for cancer theranostics? Nanomedicine (Lond.), 2014, 9(10), 1445-1448.
[http://dx.doi.org/10.2217/nnm.14.89] [PMID: 25253493]
[4]
Mukherjee, S.; Patra, C.R. Therapeutic application of anti-angiogenic nanomaterials in cancers. Nanoscale, 2016, 8(25), 12444-12470.
[http://dx.doi.org/10.1039/C5NR07887C] [PMID: 27067119]
[5]
Eren, D.; Betul, Y.M. Revealing the effect of 6-gingerol, 6-shogaol and curcumin on mPGES-1, GSK-3β and β-catenin pathway in A549 cell line. Chem. Biol. Interact., 2016, 258, 257-265.
[http://dx.doi.org/10.1016/j.cbi.2016.09.012] [PMID: 27645308]
[6]
Sekiwa, Y.; Kubota, K.; Kobayashi, A. Isolation of novel glucosides related to gingerdiol from ginger and their antioxidative activities. J. Agric. Food Chem., 2000, 48(2), 373-377.
[http://dx.doi.org/10.1021/jf990674x] [PMID: 10691642]
[7]
Shukla, Y.; Singh, M. Cancer preventive properties of ginger: A brief review. Food Chem. Toxicol., 2007, 45(5), 683-690.
[http://dx.doi.org/10.1016/j.fct.2006.11.002] [PMID: 17175086]
[8]
Mishra, R.K.; Kumar, A.; Kumar, A. Pharmacological Activity of Zingiber officinale. Int. J. Pharma Chem. Sci., 2012, 1, 1073.
[9]
Rahmani, A.H.; Shabrmi, F.M.A.; Aly, S.M. Active ingredients of ginger as potential candidates in the prevention and treatment of diseases via modulation of biological activities. Int. J. Physiol. Pathophysiol. Pharmacol., 2014, 6(2), 125-136.
[PMID: 25057339]
[10]
Brooks, B.R.; Brooks, C.L., III; Mackerell, A.D., Jr; Nilsson, L.; Petrella, R.J.; Roux, B.; Won, Y.; Archontis, G.; Bartels, C.; Boresch, S.; Caflisch, A.; Caves, L.; Cui, Q.; Dinner, A.R.; Feig, M.; Fischer, S.; Gao, J.; Hodoscek, M. Im, W.; Kuczera, K.; Lazaridis, T.; Ma, J.; Ovchinnikov, V.; Paci, E.; Pastor, R.W.; Post, C.B.; Pu, J.Z.; Schaefer, M.; Tidor, B.; Venable, R.M.; Woodcock, H.L.; Wu, X.; Yang, W.; York, D.M.; Karplus, M. CHARMM: The biomolecular simulation program. J. Comput. Chem., 2009, 30(10), 1545-1614.
[http://dx.doi.org/10.1002/jcc.21287] [PMID: 19444816]
[11]
Ferlay, J.; Steliarova-Foucher, E.; Lortet-Tieulent, J.; Rosso, S.; Coebergh, J.W.; Comber, H.; Forman, D.; Bray, F. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012. Eur. J. Cancer, 2013, 49(6), 1374-1403.
[http://dx.doi.org/10.1016/j.ejca.2012.12.027] [PMID: 23485231]
[12]
Mendelsohn, J.; Baselga, J. Epidermal growth factor receptor targeting in cancer. Semin. Oncol., 2006, 33(4), 369-385.
[http://dx.doi.org/10.1053/j.seminoncol.2006.04.003] [PMID: 16890793]
[13]
Christensen, J.G.; Burrows, J.; Salgia, R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett., 2005, 225(1), 1-26.
[http://dx.doi.org/10.1016/j.canlet.2004.09.044] [PMID: 15922853]
[14]
Stone, A.; Harrington, K.; Frakes, M.; Blank, K.; Rajanna, S. EGFR and c-Met inhibitors are effective in reducing tumorigenicity in cancer J. Carcinog. Mutagen, 2014, 5,3
[http://dx.doi.org/10.4172/2157-2518.1000173]
[15]
Howe, L.R.; Subbaramaiah, K.; Brown, A.M.C.; Dannenberg, A.J. Cyclooxygenase-2: A target for the prevention and treatment of breast cancer. Endocr. Relat. Cancer, 2001, 8(2), 97-114.
[http://dx.doi.org/10.1677/erc.0.0080097] [PMID: 11397667]
[16]
Aggarwal, B.B.; Shishodia, S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochem. Pharmacol., 2006, 71(10), 1397-1421.
[http://dx.doi.org/10.1016/j.bcp.2006.02.009] [PMID: 16563357]
[17]
Oda, A.; Okayasu, M.; Kamiyama, Y.; Yoshida, T.; Takahashi, O. Evaluation of docking accuracy and investigations of roles of parameters and each term in scoring functions for protein-ligand docking using Argus lab software.Bull. Chem. Soc. Jpn, 2007, 80, 1920-1925.
[http://dx.doi.org/10.1246/bcsj.80.1920]
[18]
Kumara, M.; Shylajab, M.R.; Nazeem, P.A.; Babu, T. 6-Gingerol is the most potent anticancerous compound in ginger (Zingiber officinale Rosc.). J. Dev. Drugs, 2017, 6, 1.
[19]
Impheng, H.; Richert, L.; Pekthong, D.; Scholfield, C.N.; Pongcharoen, S.; Pungpetchara, I.; Srisawang, P. [6]-Gingerol inhibits de novo fatty acid synthesis and carnitine palmitoyltransferase-1 activity which triggers apoptosis in HepG2. Am. J. Cancer Res., 2015, 5(4), 1319-1336.
[PMID: 26101700]
[20]
Lin, C.B.; Lin, C.C.; Tsay, G.J. 6-Gingerol inhibits growth of colon cancer cell LoVo via induction of G2/M arrest. Evid. Based Complement. Alternat. Med., 2012, 2012326096
[http://dx.doi.org/10.1155/2012/326096] [PMID: 22719783]
[21]
Lee, S.H.; Cekanova, M.; Baek, S.J. Multiple mechanisms are involved in 6-gingerol-induced cell growth arrest and apoptosis in human colorectal cancer cells. Mol. Carcinog., 2008, 47(3), 197-208.
[http://dx.doi.org/10.1002/mc.20374] [PMID: 18058799]
[22]
Zeng, G.F.; Zong, S.H.; Zhang, Z.Y.; Fu, S.W.; Li, K.K.; Fang, Y.; Lu, L.; Xiao, D.Q. The role of 6-gingerol on inhibiting Amyloid beta-protein-induced apoptosis in PC12 cells. Rejuvenation Res., 2015, 18(5), 413-421.
[http://dx.doi.org/10.1089/rej.2014.1657] [PMID: 25811848]
[23]
Tzeng, T.F.; Liu, I.M. 6-gingerol prevents adipogenesis and the accumulation of cytoplasmic lipid droplets in 3T3-L1 cells. Phytomedicine, 2013, 20(6), 481-487.
[http://dx.doi.org/10.1016/j.phymed.2012.12.006] [PMID: 23369342]
[24]
Zamani, N.; Brown, C.W. Emerging roles for the transforming growth factor-beta superfamily in regulating adiposity and energy expenditure. Endocr. Rev., 2011, 32(3), 387-403.
[http://dx.doi.org/10.1210/er.2010-0018] [PMID: 21173384]
[25]
Pan, L.; Shi, X.; Liu, S.; Guo, X.; Zhao, M.; Cai, R.; Sun, G. Fluoride promotes osteoblastic differentiation through canonical Wnt/β-catenin signaling pathway. Toxicol. Lett., 2014, 225(1), 34-42.
[http://dx.doi.org/10.1016/j.toxlet.2013.11.029] [PMID: 24300170]
[26]
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 Med. J., 2006, 47(5), 688-697.
[http://dx.doi.org/10.3349/ymj.2006.47.5.688] [PMID: 17066513]
[27]
Oyagbemi, A.A.; Saba, A.B.; Azeez, O.I. Capsaicin: A novel chemopreventive molecule and its underlying molecular mechanisms of action. Indian J. Cancer, 2010, 47(1), 53-58.
[http://dx.doi.org/10.4103/0019-509X.58860] [PMID: 20071791]
[28]
Alex, R.D.D.; Liz, J.V.; Andreas, S. The role of the apoptotic machinery in tumor suppression. Cold Spring Harb. Perspect. Biol., 2012, 4(11)a008789
[29]
Pandey, M.K.; Gupta, S.C.; Nabavizadeh, A.; Aggarwal, B.B. Regulation of cell signaling pathways by dietary agents for cancer prevention and treatment. Semin. Cancer Biol., 2017, 46, 158-181.
[http://dx.doi.org/10.1016/j.semcancer.2017.07.002] [PMID: 28823533]
[30]
Elkady, A.I.; Abuzinadah, O.A.; Baeshen, N.A.; Rahmy, T.R. Differential control of growth, apoptotic activity, and gene expression in human breast cancer cells by extracts derived from medicinal herbs Zingiber officinale. J. Biomed. Biotechnol., 2012, 2012614356
[http://dx.doi.org/10.1155/2012/614356] [PMID: 22969274]
[31]
Guo, J.; Wu, H.; Du, L.; Zhang, W.; Yang, J. Comparative antioxidant properties of some gingerols and shogaols, and the relationship of their contents with the antioxidant potencies of fresh and dried ginger (Zingiber officinale Roscoe). J. Agric. Sci. Technol., 2014, 16, 1063-1072.
[32]
Kim, S.M.; Kim, C.; Bae, H.; Lee, J.H.; Baek, S.H.; Nam, D.; Chung, W.S.; Shim, B.S.; Lee, S.G.; Kim, S.H.; Sethi, G.; Ahn, K.S. 6-Shogaol exerts anti-proliferative and pro-apoptotic effects through the modulation of STAT3 and MAPKs signaling pathways. Mol. Carcinog., 2015, 54(10), 1132-1146.
[http://dx.doi.org/10.1002/mc.22184] [PMID: 24962868]
[33]
Almada da Silva, J.; Becceneri, A.B.; Sanches Mutti, H.; Moreno Martin, A.C.; Fernandes da Silva, M.F.; Fernandes, J.B.; Vieira, P.C.; Cominetti, M.R. Purification and differential biological effects of ginger-derived substances on normal and tumor cell lines. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci., 2012, 903, 157-162.
[http://dx.doi.org/10.1016/j.jchromb.2012.07.013] [PMID: 22858304]
[34]
Chen, C.Y.; Li, Y.W.; Kuo, S.Y. Effect of [10]-gingerol on [Ca2+]i and cell death in human colorectal cancer cells. Molecules, 2009, 14(3), 959-969.
[http://dx.doi.org/10.3390/molecules14030959] [PMID: 19255554]
[35]
Abdullah, S.; Abidin, S.A.Z.; Murad, N.A.; Makpol, S.; Ngah, W.Z.W.; Yusof, Y.A.M. Ginger extract (Zingiber officinale) triggers apoptosis and G0/G1 cells arrest in HCT 116 and HT 29 colon cancer cell lines. Afr. J. Biochem. Res., 2010, 4(4), 134-142.
[36]
Ryu, M.J.; Chung, H.S. [10]-Gingerol induces mitochondrial apoptosis through activation of MAPK pathway in HCT116 human colon cancer cells. In Vitro Cell. Dev. Biol. Anim., 2015, 51(1), 92-101.
[http://dx.doi.org/10.1007/s11626-014-9806-6] [PMID: 25148824]
[37]
Kiptiyah, K.; Widodo, W.; Ciptadi, G.; Aulanni’am, A.; Widodo, M.A.; Sumitro, S.B. 10-Gingerol as an inducer of apoptosis through HTR1A in cumulus cells: In vitro and in silico studies. J. Taibah Univ. Med. Sci., 2017, 12(5), 397-406.
[http://dx.doi.org/10.1016/j.jtumed.2017.05.012] [PMID: 31435270]
[38]
Nievergelt, A.; Huonker, P.; Schoop, R.; Altmann, K.H.; Gertsch, J. Identification of serotonin 5-HT1A receptor partial agonists in ginger. Bioorg. Med. Chem., 2010, 18(9), 3345-3351.
[http://dx.doi.org/10.1016/j.bmc.2010.02.062] [PMID: 20363635]
[39]
Turner, J.H.; Garnovskaya, M.N.; Raymond, J.R. Serotonin 5-HT1A receptor stimulates c-Jun N-terminal kinase and induces apoptosis in Chinese hamster ovary fibroblasts. Biochim. Biophys. Acta, 2007, 1773(3), 391-399.
[http://dx.doi.org/10.1016/j.bbamcr.2006.12.003] [PMID: 17208318]
[40]
Hsiung, S.C.; Adlersberg, M.; Arango, V.; Mann, J.J.; Tamir, H.; Liu, K.P. Attenuated 5-HT1A receptor signaling in brains of suicide victims: Involvement of adenylyl cyclase, phosphatidylinositol 3-kinase, Akt and mitogen-activated protein kinase. J. Neurochem., 2003, 87(1), 182-194.
[http://dx.doi.org/10.1046/j.1471-4159.2003.01987.x] [PMID: 12969265]
[41]
Henriksen, R.; Dizeyi, N.; Abrahamsson, P.A. Expression of serotonin receptors 5-HT1A, 5-HT1B, 5-HT2B and 5-HT4 in ovary and in ovarian tumours. Anticancer Res., 2012, 32(4), 1361-1366.
[PMID: 22493371]
[42]
Katayama, K.; Fujita, N.; Tsuruo, T. Akt/protein kinase B-dependent phosphorylation and inactivation of WEE1Hu promote cell cycle progression at G2/M transition. Mol. Cell. Biol., 2005, 25(13), 5725-5737.
[http://dx.doi.org/10.1128/MCB.25.13.5725-5737.2005] [PMID: 15964826]
[43]
Cai, G.; Wang, J.; Xin, X.; Ke, Z.; Luo, J. Phosphorylation of glycogen synthase kinase-3 beta at serine 9 confers cisplatin resistance in ovarian cancer cells. Int. J. Oncol., 2007, 31(3), 657-662.
[PMID: 17671694]
[44]
Phukan, S.; Babu, V.S.; Kannoji, A.; Hariharan, R.; Balaji, V.N. GSK3beta: Role in therapeutic landscape and development of modulators. Br. J. Pharmacol., 2010, 160(1), 1-19.
[http://dx.doi.org/10.1111/j.1476-5381.2010.00661.x] [PMID: 20331603]
[45]
Joo, J.H.; Hong, S.S.; Cho, Y.R.; Seo, D.W. 10-Gingerol inhibits proliferation and invasion of MDA-MB-231 breast cancer cells through suppression of Akt and p38MAPK activity. Oncol. Rep., 2016, 35(2), 779-784.
[http://dx.doi.org/10.3892/or.2015.4405] [PMID: 26554741]
[46]
Wang, S.; Sun, X.; Jiang, L.; Liu, X.; Chen, M.; Yao, X.; Sun, Q.; Yang, G. 6-Gingerol induces autophagy to protect HUVECs survival from apoptosis. Chem. Biol. Interact., 2016, 256, 249-256.
[http://dx.doi.org/10.1016/j.cbi.2016.07.020] [PMID: 27451028]
[47]
Bernard, M.M.; McConnery, J.R.; Hoskin, D.W. [10]-Gingerol, a major phenolic constituent of ginger root, induces cell cycle arrest and apoptosis in triple-negative breast cancer cells. Exp. Mol. Pathol., 2017, 102(2), 370-376.
[http://dx.doi.org/10.1016/j.yexmp.2017.03.006] [PMID: 28315687]
[48]
Poltronieri, J.; Becceneri, A.B.; Fuzer, A.M.; Filho, J.C.; Martin, A.C.; Vieira, P.C.; Pouliot, N.; Cominetti, M.R. [6]-gingerol as a cancer chemopreventive agent: A review of its activity on different steps of the metastatic process. Mini Rev. Med. Chem., 2014, 14(4), 313-321.
[http://dx.doi.org/10.2174/1389557514666140219095510] [PMID: 24552266]
[49]
Behroozeh, A.; Mazloumi Tabrizi, M.; Kazemi, S.M.; Choupani, E.; Kabiri, N.; Ilbeigi, D.; Heidari Nasab, A.; Akbarzadeh Khiyavi, A.; Seif Kurdi, A. Evaluation the anti-cancer effect of PEGylated nano-niosomal gingerol, on breast cancer cell lines (T47D), in vitro. Asian Pac. J. Cancer Prev., 2018, 19(3), 645-648.
[PMID: 29580033]
[50]
Meng, B.; Ii, H.; Qu, W.; Yuan, H. Anticancer effects of gingerol in retinoblastoma cancer cells (RB355 cell line) are mediated via apoptosis induction, cell cycle arrest and upregulation of PI3K/Akt signaling pathway. Med. Sci. Monit., 2018, 24, 1980-1987.
[http://dx.doi.org/10.12659/MSM.905450] [PMID: 29615601]
[51]
Gao, X.; Ikuta, K.; Tajima, M.; Sairenji, T. 12-O-tetradecanoylphorbol-13-acetate induces Epstein-Barr virus reactivation via NF-kappaB and AP-1 as regulated by protein kinase C and mitogen-activated protein kinase. Virology, 2001, 286(1), 91-99.
[http://dx.doi.org/10.1006/viro.2001.0965] [PMID: 11448162]
[52]
Simon, P.S.; Sharman, S.K.; Lu, C.; Yang, D.; Paschall, A.V.; Tulachan, S.S.; Liu, K. The NF-κB p65 and p50 homodimer cooperate with IRF8 to activate iNOS transcription. BMC Cancer, 2015, 15, 770.
[http://dx.doi.org/10.1186/s12885-015-1808-6] [PMID: 26497740]
[53]
Ann, M.B.; Dong, Z. The Amazing and Mighty Ginger. In: Herbal Medicine: Biomolecular and Clinical Aspects, 2nd Edition; Benzie, I.F.F.; Wachtel-Galor, S., Eds.; Taylor & Francis: UK, 2011, Chapter 7.
[54]
Wang, S.; Zhang, C.; Yang, G.; Yang, Y. Biological properties of 6-gingerol: A brief review. Nat. Prod. Commun., 2014, 9(7), 1027-1030.
[http://dx.doi.org/10.1177/1934578X1400900736] [PMID: 25230520]
[55]
Lee, T.Y.; Lee, K.C.; Chen, S.Y.; Chang, H.H. 6-Gingerol inhibits ROS and iNOS through the suppression of PKC-alpha and NF-kappaB pathways in lipopolysaccharide-stimulated mouse macrophages. Biochem. Biophys. Res. Commun., 2009, 382(1), 134-139.
[http://dx.doi.org/10.1016/j.bbrc.2009.02.160] [PMID: 19268427]
[56]
Ippoushi, K.; Azuma, K.; Ito, H.; Horie, H.; Higashio, H. [6]-Gingerol inhibits nitric oxide synthesis in activated J774.1 mouse macrophages and prevents peroxynitrite-induced oxidation and nitration reactions. Life Sci., 2003, 73(26), 3427-3437.
[http://dx.doi.org/10.1016/j.lfs.2003.06.022] [PMID: 14572883]
[57]
Tripathi, S.; Maier, K.G.; Bruch, D.; Kittur, D.S. Effect of 6-gingerol on pro-inflammatory cytokine production and costimulatory molecule expression in murine peritoneal macrophages. J. Surg. Res., 2007, 138(2), 209-213.
[http://dx.doi.org/10.1016/j.jss.2006.07.051] [PMID: 17291534]
[58]
Su-Chen, H.; Chang, Y-H. Comparison of inhibitory capacities of 6-, 8- and 10-gingerols/shogaols on the canonical NLRP3 inflammasome- mediated IL-1β secretion. Molecules, 2018, 23(2), 466.
[http://dx.doi.org/10.3390/molecules23020466]
[59]
Dugasani, S.; Pichika, M.R.; Nadarajah, V.D.; Balijepalli, M.K.; Tandra, S.; Korlakunta, J.N. Comparative antioxidant and anti-inflammatory effects of [6]-gingerol, [8]-gingerol, [10]-gingerol and [6]-shogaol. J. Ethnopharmacol., 2010, 127(2), 515-520.
[http://dx.doi.org/10.1016/j.jep.2009.10.004] [PMID: 19833188]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy