Anti-cancer and potential chemopreventive actions of ginseng by activating Nrf2 (NFE2L2) anti-oxidative stress/anti-inflammatory pathways
Tóm tắt
This article reviews recent basic and clinical studies of ginseng, particularly the anti-cancer effects and the potential chemopreventive actions by activating the transcriptional factor, nuclear factor (erythroid-derived 2)-like 2 (Nrf2 or NFE2L2)-mediated anti-oxidative stress or anti-inflammatory pathways. Nrf2 is a novel target for cancer prevention as it regulates the antioxidant responsive element (ARE), a critical regulatory element in the promoter region of genes encoding cellular phase II detoxifying and anti-oxidative stress enzymes. The studies on the chemopreventive effects of ginseng or its components/products showed that Nrf2 could also be a target for ginseng's actions. A number of papers also demonstrated the anti-inflammatory effects of ginseng. Targeting Nrf2 pathway is a novel approach to the investigation of ginseng's cancer chemopreventive actions, including some oxidative stress and inflammatory conditions responsible for the initiation, promotion and progression of carcinogenesis.
Tài liệu tham khảo
Gillis CN: Panax ginseng pharmacology: a nitric oxide link?. Biochem Pharmacol. 1997, 54 (1): 1-8. 10.1016/S0006-2952(97)00193-7.
Yue PY, Mak NK, Cheng YK, Leung KW, Ng TB, Fan DT, Yeung HW, Wong RN: Pharmacogenomics and the Yin/Yang actions of ginseng: anti-tumor, angiomodulating and steroid-like activities of ginsenosides. Chin Med. 2007, 2: 6-10.1186/1749-8546-2-6.
Helms S: Cancer prevention and therapeutics: Panax ginseng. Altern Med Rev. 2004, 9 (3): 259-274.
Saita T, Katano M, Matsunaga H, Kouno I, Fujito H, Mori M: Screening of polyacetylenic alcohols in crude drugs using the ELISA for panaxytriol. Biol Pharm Bull. 1995, 18 (7): 933-937.
Matsunaga H, Saita T, Nagumo F, Mori M, Katano M: A possible mechanism for the cytotoxicity of a polyacetylenic alcohol, panaxytriol: inhibition of mitochondrial respiration. Cancer Chemother Pharmacol. 1995, 35 (4): 291-296. 10.1007/BF00689447.
Yun TK: Panax ginseng--a non-organ-specific cancer preventive?. Lancet Oncol. 2001, 2 (1): 49-55. 10.1016/S1470-2045(00)00196-0.
Li W, Kong AN: Molecular mechanisms of Nrf2-mediated antioxidant response. Mol Carcinog. 2009, 48 (2): 91-104. 10.1002/mc.20465.
Gum SI, Jo SJ, Ahn SH, Kim SG, Kim JT, Shin HM, Cho MK: The potent protective effect of wild ginseng (Panax ginseng C.A. Meyer) against benzo[alpha]pyrene-induced toxicity through metabolic regulation of CYP1A1 and GSTs. J Ethnopharmacol. 2007, 112 (3): 568-576. 10.1016/j.jep.2007.05.014.
Ng F, Yun H, Lei X, Danishefsky SJ, Fahey J, Stephenson K, Flexner C, Lee L: (3R, 9R, 10R)-Panaxytriol: A molecular-based nutraceutical with possible application to cancer prevention and treatment. Tetrahedron Lett. 2008, 49 (50): 7178-7179. 10.1016/j.tetlet.2008.09.169.
Hwang YP, Jeong HG: Ginsenoside Rb1 protects against 6-hydroxydopamine-induced oxidative stress by increasing heme oxygenase-1 expression through an estrogen receptor-related PI3K/Akt/Nrf2-dependent pathway in human dopaminergic cells. Toxicol Appl Pharmacol. 2010, 242 (1): 18-28. 10.1016/j.taap.2009.09.009.
Morris CA, Avorn J: Internet marketing of herbal products. Jama. 2003, 290 (11): 1505-1509. 10.1001/jama.290.11.1505.
DeAngelis CD, Fontanarosa PB: Drugs alias dietary supplements. Jama. 2003, 290 (11): 1519-1520. 10.1001/jama.290.11.1519.
Dietz BM, Liu D, Hagos GK, Yao P, Schinkovitz A, Pro SM, Deng S, Farnsworth NR, Pauli GF, van Breemen RB, Bolton JL: Angelica sinensis and its alkylphthalides induce the detoxification enzyme NAD(P)H: quinone oxidoreductase 1 by alkylating Keap1. Chem Res Toxicol. 2008, 21 (10): 1939-1948. 10.1021/tx8001274.
Yun TK: Experimental and epidemiological evidence on non-organ specific cancer preventive effect of Korean ginseng and identification of active compounds. Mutat Res. 2003, 523-524: 63-74.
Shibata S: Chemistry and cancer preventing activities of ginseng saponins and some related triterpenoid compounds. J Korean Med Sci. 2001, 16 (Suppl): S28-37.
Chang YS, Seo EK, Gyllenhaal C, Block KI: Panax ginseng: a role in cancer therapy?. Integr Cancer Ther. 2003, 2 (1): 13-33. 10.1177/1534735403251167.
Jia L, Zhao Y, Liang XJ: Current evaluation of the millennium phytomedicine- ginseng (II): Collected chemical entities, modern pharmacology, and clinical applications emanated from traditional Chinese medicine. Curr Med Chem. 2009, 16 (22): 2924-2942. 10.2174/092986709788803204.
Xiang YZ, Shang HC, Gao XM, Zhang BL: A comparison of the ancient use of ginseng in traditional Chinese medicine with modern pharmacological experiments and clinical trials. Phytother Res. 2008, 22 (7): 851-858. 10.1002/ptr.2384.
Qi LW, Wang CZ, Yuan CS: American ginseng: potential structure-function relationship in cancer chemoprevention. Biochem Pharmacol. 2010, 80 (7): 947-954. 10.1016/j.bcp.2010.06.023.
Ni W, Zhang X, Wang B, Chen Y, Han H, Fan Y, Zhou Y, Tai G: Antitumor activities and immunomodulatory effects of ginseng neutral polysaccharides in combination with 5-fluorouracil. J Med Food. 2010, 13 (2): 270-277. 10.1089/jmf.2009.1119.
Cheng H, Li S, Fan Y, Gao X, Hao M, Wang J, Zhang X, Tai G, Zhou Y: Comparative studies of the antiproliferative effects of ginseng polysaccharides on HT-29 human colon cancer cells. Med Oncol. 2010,
Zeng Y: Adjunctive therapy of Ginseng Polysaccharide for lung cancer. China Pharmaceuticals. 2001, 10 (6): 31-32.
Fu W, Chen L, Huang S, Zou H: The role of Panax ginseng polysaccharide injection in chemotherapy of patients with ovarian cancer. Pharm Care & Res. 2005, 5 (2): 169-171.
Xie F, Zeng Z, Huang H, Zhao C, Lu T: Clinical observation on nasopharyngeal carcinoma treated with combined therapy of radiotherapy and ginseng polysaccharide injection. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2001, 21 (5): 332-334.
Liu J, Sun L, Zhao Y, Zhou T, Zhang J, Sui G, Wu J, Zhou J, Fu L, Lu Q, Liu G, Hui M: Clinical phase II study on immunoimprovement of patients with breast cancer treated by Shenyi capsule. Chin J Clin Oncol. 2000, 27 (7): 534-536.
Liu S, Sun L, Ban L, Zhou T: Ginsenoside Rg3 capsules combined NP regimen in the treatment of advanced non-small cell lung cancer. Chin Clin Oncol. 2007, 12 (11): 847-849.
Wang H, Li X: The application of shengmai injection in malignant tumor. Mod Chin Med. 2003, 16-17. 3
Berenblum I, Armuth V: Two independent aspects of tumor promotion. Biochim Biophys Acta. 1981, 651 (1): 51-63.
Heidelberger C, Freeman AE, Pienta RJ, Sivak A, Bertram JS, Casto BC, Dunkel VC, Francis MW, Kakunaga T, Little JB, Schechtman LM: Cell transformation by chemical agents--a review and analysis of the literature. A report of the U.S. Environmental Protection Agency Gene-Tox Program. Mutat Res. 1983, 114 (3): 283-385.
Weinberg F, Chandel NS: Reactive oxygen species-dependent signaling regulates cancer. Cell Mol Life Sci. 2009, 66 (23): 3663-3673. 10.1007/s00018-009-0099-y.
Mantovani A, Allavena P, Sica A, Balkwill F: Cancer-related inflammation. Nature. 2008, 454 (7203): 436-444. 10.1038/nature07205.
Aggarwal BB, Shishodia S: Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol. 2006, 71 (10): 1397-1421. 10.1016/j.bcp.2006.02.009.
Juge N, Mithen RF, Traka M: Molecular basis for chemoprevention by sulforaphane: a comprehensive review. Cell Mol Life Sci. 2007, 64 (9): 1105-1127. 10.1007/s00018-007-6484-5.
Wattenberg LW: Chemoprevention of cancer. Cancer Res. 1985, 45 (1): 1-8.
Hsu CH, Cheng AL: Clinical studies with curcumin. Adv Exp Med Biol. 2007, 595: 471-480. full_text.
Hatcher H, Planalp R, Cho J, Torti FM, Torti SV: Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci. 2008, 65 (11): 1631-1652. 10.1007/s00018-008-7452-4.
Xu C, Li CY, Kong AN: Induction of phase I, II and III drug metabolism/transport by xenobiotics. Arch Pharm Res. 2005, 28 (3): 249-268. 10.1007/BF02977789.
Valgimigli L, Iori R: Antioxidant and pro-oxidant capacities of ITCs. Environ Mol Mutagen. 2009, 50 (3): 222-237. 10.1002/em.20468.
Yu S, Kong AN: Targeting carcinogen metabolism by dietary cancer preventive compounds. Curr Cancer Drug Targets. 2007, 7 (5): 416-424. 10.2174/156800907781386669.
Shen G, Kong AN: Nrf2 plays an important role in coordinated regulation of Phase II drug metabolism enzymes and Phase III drug transporters. Biopharm Drug Dispos. 2009, 30 (7): 345-355. 10.1002/bdd.680.
Yuan JH, Li YQ, Yang XY: Inhibition of epigallocatechin gallate on orthotopic colon cancer by upregulating the Nrf2-UGT1A signal pathway in nude mice. Pharmacology. 2007, 80 (4): 269-278. 10.1159/000106447.
Yuan JH, Li YQ, Yang XY: Protective effects of epigallocatechin gallate on colon preneoplastic lesions induced by 2-amino-3-methylimidazo[4,5-f ] quinoline in mice. Mol Med. 2008, 14 (9-10): 590-598. 10.2119/2007-00050.Yuan.
Kwak MK, Kensler TW: Targeting NRF2 signaling for cancer chemoprevention. Toxicol Appl Pharmacol. 2010, 244 (1): 66-76. 10.1016/j.taap.2009.08.028.
Khor TO, Yu S, Kong AN: Dietary cancer chemopreventive agents - targeting inflammation and Nrf2 signaling pathway. Planta Med. 2008, 74 (13): 1540-1547. 10.1055/s-0028-1088303.
Nair S, Li W, Kong AN: Natural dietary anti-cancer chemopreventive compounds: redox-mediated differential signaling mechanisms in cytoprotection of normal cells versus cytotoxicity in tumor cells. Acta Pharmacol Sin. 2007, 28 (4): 459-472. 10.1111/j.1745-7254.2007.00549.x.
Katoh Y, Iida K, Kang MI, Kobayashi A, Mizukami M, Tong KI, McMahon M, Hayes JD, Itoh K, Yamamoto M: Evolutionary conserved N-terminal domain of Nrf2 is essential for the Keap1-mediated degradation of the protein by proteasome. Arch Biochem Biophys. 2005, 433 (2): 342-350. 10.1016/j.abb.2004.10.012.
Nguyen T, Nioi P, Pickett CB: The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009, 284 (20): 13291-13295. 10.1074/jbc.R900010200.
Yuan X, Xu C, Pan Z, Keum YS, Kim JH, Shen G, Yu S, Oo KT, Ma J, Kong AN: Butylated hydroxyanisole regulates ARE-mediated gene expression via Nrf2 coupled with ERK and JNK signaling pathway in HepG2 cells. Mol Carcinog. 2006, 45 (11): 841-850. 10.1002/mc.20234.
Abraham NG, Kappas A: Pharmacological and clinical aspects of heme oxygenase. Pharmacol Rev. 2008, 60 (1): 79-127. 10.1124/pr.107.07104.
Moi P, Chan K, Asunis I, Cao A, Kan YW: Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci USA. 1994, 91 (21): 9926-9930. 10.1073/pnas.91.21.9926.
Kwak MK, Wakabayashi N, Kensler TW: Chemoprevention through the Keap1-Nrf2 signaling pathway by phase 2 enzyme inducers. Mutat Res. 2004, 555 (1-2): 133-148.
Jeong WS, Jun M, Kong AN: Nrf2: a potential molecular target for cancer chemoprevention by natural compounds. Antioxid Redox Signal. 2006, 8 (1-2): 99-106. 10.1089/ars.2006.8.99.
Lee LS, Stephenson KK, Fahey JW, Parsons TL, Lietman PS, Andrade AS, Lei X, Yun H, Soon GH, Shen P, Danlshefsky S, Flexner C: Induction of chemoprotective phase 2 enzymes by ginseng and its components. Planta Med. 2009, 75 (10): 1129-1133. 10.1055/s-0029-1185508.
Halim M, Yee DJ, Sames D: Imaging induction of cytoprotective enzymes in intact human cells: coumberone, a metabolic reporter for human AKR1C enzymes reveals activation by panaxytriol, an active component of red ginseng. J Am Chem Soc. 2008, 130 (43): 14123-14128. 10.1021/ja801245y.
Park SH, Jang JH, Chen CY, Na HK, Surh YJ: A formulated red ginseng extract rescues PC12 cells from PCB-induced oxidative cell death through Nrf2-mediated upregulation of heme oxygenase-1 and glutamate cysteine ligase. Toxicology. 2010, 278 (1): 131-139.
Li J, Ichikawa T, Jin Y, Hofseth LJ, Nagarkatti P, Nagarkatti M, Windust A, Cui T: An essential role of Nrf2 in American ginseng-mediated anti-oxidative actions in cardiomyocytes. J Ethnopharmacol. 2010, 130 (2): 222-230. 10.1016/j.jep.2010.03.040.
Kim SH, Park KS, Chang MJ, Sung JH: Effects of Panax ginseng extract on exercise-induced oxidative stress. J Sports Med Phys Fitness. 2005, 45 (2): 178-182.
Lee LS, Wise SD, Chan C, Parsons TL, Flexner C, Lietman PS: Possible differential induction of phase 2 enzyme and antioxidant pathways by american ginseng, Panax quinquefolius. J Clin Pharmacol. 2008, 48 (5): 599-609. 10.1177/0091270008314252.
Wang Y, Ye X, Ma Z, Liang Q, Lu B, Tan H, Xiao C, Zhang B, Gao Y: Induction of cytochrome P450 1A1 expression by ginsenoside Rg1 and Rb1 in HepG2 cells. Eur J Pharmacol. 2008, 601 (1-3): 73-78. 10.1016/j.ejphar.2008.10.057.
Kim J, Cha YN, Surh YJ: A protective role of nuclear erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat Res. 2010, 690 (1-2): 12-23.
Lin W, Wu RT, Wu T, Khor TO, Wang H, Kong AN: Sulforaphane suppressed LPS-induced inflammation in mouse peritoneal macrophages through Nrf2 dependent pathway. Biochem Pharmacol. 2008, 76 (8): 967-973. 10.1016/j.bcp.2008.07.036.
Liu H, Dinkova-Kostova AT, Talalay P: Coordinate regulation of enzyme markers for inflammation and for protection against oxidants and electrophiles. Proc Natl Acad Sci USA. 2008, 105 (41): 15926-15931. 10.1073/pnas.0808346105.
Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, Suh N, Williams C, Risingsong R, Honda T, Gribble GW, Sporn MB, Talalay P: Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci USA. 2005, 102 (12): 4584-4589. 10.1073/pnas.0500815102.
Ahn YH, Hwang Y, Liu H, Wang XJ, Zhang Y, Stephenson KK, Boronina TN, Cole RN, Dinkova-Kostova AT, Talalay P, Cole PA: Electrophilic tuning of the chemoprotective natural product sulforaphane. Proc Natl Acad Sci USA. 2010, 107 (21): 9590-9595. 10.1073/pnas.1004104107.
Banning A, Florian S, Deubel S, Thalmann S, Muller-Schmehl K, Jacobasch G, Brigelius-Flohe R: GPx2 counteracts PGE2 production by dampening COX-2 and mPGES-1 expression in human colon cancer cells. Antioxid Redox Signal. 2008, 10 (9): 1491-1500. 10.1089/ars.2008.2047.
Park YC, Lee CH, Kang HS, Kim KW, Chung HT, Kim HD: Ginsenoside-Rh1 and Rh2 inhibit the induction of nitric oxide synthesis in murine peritoneal macrophages. Biochem Mol Biol Int. 1996, 40 (4): 751-757.
Surh YJ, Na HK, Lee JY, Keum YS: Molecular mechanisms underlying anti-tumor promoting activities of heat-processed Panax ginseng C.A. Meyer. J Korean Med Sci. 2001, 16 (Suppl): S38-41.
Kim ND, Pokharel YR, Kang KW: Ginsenoside Rd enhances glutathione levels in H4IIE cells via NF-kappaB-dependent gamma-glutamylcysteine ligase induction. Pharmazie. 2007, 62 (12): 933-936.
Oh GS, Pae HO, Choi BM, Seo EA, Kim DH, Shin MK, Kim JD, Kim JB, Chung HT: 20(S)-Protopanaxatriol, one of ginsenoside metabolites, inhibits inducible nitric oxide synthase and cyclooxygenase-2 expressions through inactivation of nuclear factor-kappaB in RAW 264.7 macrophages stimulated with lipopolysaccharide. Cancer Lett. 2004, 205 (1): 23-29. 10.1016/j.canlet.2003.09.037.
Darnell JE: Transcription factors as targets for cancer therapy. Nat Rev Cancer. 2002, 2 (10): 740-749. 10.1038/nrc906.
Richmond A: Nf-kappa B, chemokine gene transcription and tumour growth. Nat Rev Immunol. 2002, 2 (9): 664-674. 10.1038/nri887.
Nair S, Doh ST, Chan JY, Kong AN, Cai L: Regulatory potential for concerted modulation of Nrf2- and Nfkb1-mediated gene expression in inflammation and carcinogenesis. Br J Cancer. 2008, 99 (12): 2070-2082. 10.1038/sj.bjc.6604703.
Wang H, Khor TO, Saw CL, Lin W, Wu T, Huang Y, Kong AN: Role of Nrf2 in suppressing LPS-induced inflammation in mouse peritoneal macrophages by polyunsaturated fatty acids docosahexaenoic acid and eicosapentaenoic acid. Mol Pharm. 2010,
Kuang X, Scofield VL, Yan M, Stoica G, Liu N, Wong PK: Attenuation of oxidative stress, inflammation and apoptosis by minocycline prevents retrovirus-induced neurodegeneration in mice. Brain Res. 2009, 1286: 174-184. 10.1016/j.brainres.2009.06.007.
Cho HY, Gladwell W, Wang X, Chorley B, Bell D, Reddy SP, Kleeberger SR: Nrf2-regulated PPAR{gamma} expression is critical to protection against acute lung injury in mice. Am J Respir Crit Care Med. 2010, 182 (2): 170-182. 10.1164/rccm.200907-1047OC.
Saw CL, Huang Y, Kong AN: Synergistic anti-inflammatory effects of low doses of curcumin in combination with polyunsaturated fatty acids: docosahexaenoic acid or eicosapentaenoic acid. Biochem Pharmacol. 2010, 79 (3): 421-430. 10.1016/j.bcp.2009.08.030.
Cheung KL, Khor TO, Kong AN: Synergistic effect of combination of phenethyl isothiocyanate and sulforaphane or curcumin and sulforaphane in the inhibition of inflammation. Pharm Res. 2009, 26 (1): 224-231. 10.1007/s11095-008-9734-9.