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Food Science and Human Wellness 2013, 2(1): 22-28 https://doi.org/10.1016/j.fshw.2013.01.001
Research Article | Open Access | Issue | Published: 25 January 2013

Natural products for cancer prevention associated with Nrf2–ARE pathway

Show Author's Information Xianjuan Koua,1,  Michael Kirbergerb,1,  Yi Yanga,  Ning Chena,c( )
College of Health Science, Wuhan Sports University, Wuhan 430079, China
Department of Natural Sciences, Clayton State University, Morrow, GA 30260, USA
The Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA

1 These authors contributed equally to this work.

Peer review under responsibility of Beijing Academy of Food Sciences.

Keywords:
Natural products, Tumorigenesis, Cancer prevention, Nrf2–ARE pathway, Dietary phytochemicals
Cite this article:
Kou X, Kirberger M, Yang Y, et al. Natural products for cancer prevention associated with Nrf2–ARE pathway. Food Science and Human Wellness, 2013, 2(1): 22-28. https://doi.org/10.1016/j.fshw.2013.01.001
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Abstract Full text About this article

Cancer chemoprevention involves the application of natural or synthetic compounds to reduce the risk of cancer development. One of the most effective strategies for preventing human cancers might involve inducing phase Ⅱ detoxifying enzymes and antioxidant enzymes via natural dietary compounds. The regulatory regions of these inducible genes encode the antioxidant response element (ARE). Nuclear factor-erythroid 2-related factor 2 (Nrf2), as a transcription factor, plays a key role in the expression of ARE-mediated genes. Similarly, Nrf2 performs an essential function in the up-regulation of these genes in response to oxidative stress and treatment with dietary phytochemicals. In this article, we discuss the current state of knowledge regarding the Nrf2/ARE pathway as a potential molecular target for cancer chemoprevention and its molecular regulation mechanisms, and highlight Nrf2/ARE inducers derived from natural products, which may be used as chemopreventive agents for cancer patients.


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About this article

Natural products for cancer prevention associated with Nrf2–ARE pathway

Show Author's information Xianjuan Koua,1, Michael Kirbergerb,1, Yi Yanga, Ning Chena,c( )
College of Health Science, Wuhan Sports University, Wuhan 430079, China
Department of Natural Sciences, Clayton State University, Morrow, GA 30260, USA
The Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA

1 These authors contributed equally to this work.

Peer review under responsibility of Beijing Academy of Food Sciences.

Abstract

Cancer chemoprevention involves the application of natural or synthetic compounds to reduce the risk of cancer development. One of the most effective strategies for preventing human cancers might involve inducing phase Ⅱ detoxifying enzymes and antioxidant enzymes via natural dietary compounds. The regulatory regions of these inducible genes encode the antioxidant response element (ARE). Nuclear factor-erythroid 2-related factor 2 (Nrf2), as a transcription factor, plays a key role in the expression of ARE-mediated genes. Similarly, Nrf2 performs an essential function in the up-regulation of these genes in response to oxidative stress and treatment with dietary phytochemicals. In this article, we discuss the current state of knowledge regarding the Nrf2/ARE pathway as a potential molecular target for cancer chemoprevention and its molecular regulation mechanisms, and highlight Nrf2/ARE inducers derived from natural products, which may be used as chemopreventive agents for cancer patients.

Keywords: Natural products, Tumorigenesis, Cancer prevention, Nrf2–ARE pathway, Dietary phytochemicals

References(77)

[1]

S.H. Moolgavkar, The multistage theory of carcinogenesis and the age distribution of cancer in man, Journal of the National Cancer Institute 61 (1) (1978) 49–52.
DOI Google Scholar
[2]

W.S. Jeong, I.W. Kim, R. Hu, et al., Modulatory properties of various natural chemopreventive agents on the activation of NF-kappaB signaling pathway, Pharmaceutical Research 21 (4) (2004) 661–670.
DOI Google Scholar
[3]

Y.S. Keum, W.S. Jeong, A.N. Kong, Chemoprevention by isothiocyanates and their underlying molecular signaling mechanisms, Mutation Research 555 (1/2) (2004) 191–202.
DOI Google Scholar
[4]

C. Chen, A.N. Kong, Dietary cancer-chemopreventive compounds: from signaling and gene expression to pharmacological effects, Trends in Pharmacological Sciences 26 (6) (2005) 318–326.
DOI Google Scholar
[5]

D.D. Zhang, Mechanistic studies of the Nrf2–Keap1 signaling pathway, Drug Metabolism Reviews 38 (4) (2006) 769–789.
DOI Google Scholar
[6]

J.W. Fahey, X. Haristoy, P.M. Dolan, et al., Sulforaphane inhibits extracellular, intracellular, and antibiotic–resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors, Proceedings of the National Academy of Sciences of the United States of America 99 (11) (2002) 7610–7615.
DOI Google Scholar
[7]

M. Ameyar, M. Wisniewska, J.B. Weitzman, A role for AP-1 in apoptosis: the case for and against, Biochimie 85 (8) (2003) 747–752.
DOI Google Scholar
[8]

E. Shaulian, M. Karin, AP-1 as a regulator of cell life and death, Nature Cell Biology 4 (5) (2002) E131-E136.
DOI Google Scholar
[9]

R. Eferl, E.F. Wagner, AP-1: a double-edged sword in tumorigenesis, Nature Reviews Cancer 3 (11) (2003) 859–868.
DOI Google Scholar
[10]

Y.J. Surh, J.K. Kundu, H.K. Na, Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals, Planta Medica 74 (13) (2008) 1526–1539.
DOI Google Scholar
[11]

A. Lau, N.F. Villeneuve, Z. Sun, et al., Dual roles of Nrf2 in cancer, Pharmacological Research 58 (5/6) (2008) 262–270.
DOI Google Scholar
[12]

Y. Li, J.D. Paonessa, Y. Zhang, Mechanism of chemical activation of Nrf2, PLoS ONE 7 (4) (2012) e35122.
DOI Google Scholar
[13]

X.L. Chen, C. Kunsch, Induction of cytoprotective genes through Nrf2/antioxidant response element pathway: a new therapeutic approach for the treatment of inflammatory diseases, Current Pharmaceutical Design 10 (8) (2004) 879–891.
DOI Google Scholar
[14]

J.S. Lee, Y.J. Surh, Nrf2 as a novel molecular target for chemoprevention, Cancer Letters 224 (2) (2005) 171–184.
DOI Google Scholar
[15]

M. Furukawa, Y. Xiong, BTB protein Keap1 targets antioxidant transcription factor Nrf2 for ubiquitination by the Cullin 3-Roc1 ligase, Molecular and Cellular Biology 25 (1) (2005) 162–171.
DOI Google Scholar
[16]

J.M. Lee, J.A. Johnson, An important role of Nrf2–ARE pathway in the cellular defense mechanism, Journal of Biochemistry and Molecular Biology 37 (2) (2004) 139–143.
DOI Google Scholar
[17]

C.R. Zhao, Z.H. Gao, X.J. Qu, Nrf2–ARE signaling pathway and natural products for cancer chemoprevention, Cancer Epidemiology 34 (5) (2010) 523–533.
DOI Google Scholar
[18]

H.K. Na, Y.J. Surh, Transcriptional regulation via cysteine thiol modification: a novel molecular strategy for chemoprevention and cytoprotection, Molecular Carcinogenesis 45 (6) (2006) 368–380.
DOI Google Scholar
[19]

A.T. Dinkova-Kostova, W.D. Holtzclaw, T.W. Kensler, The role of Keap1 in cellular protective responses, Chemical Research in Toxicology 18 (12) (2005) 1779–1791.
DOI Google Scholar
[20]

D.A. Bloom, A.K. Jaiswal, Phosphorylation of Nrf2 at Ser40 by protein kinase C in response to antioxidants leads to the release of Nrf2 from INrf2, but is not required for Nrf2 stabilization/accumulation in the nucleus and transcriptional activation of antioxidant response element-mediated NAD(P)H:quinone oxidoreductase-1 gene expression, Journal of Biological Chemistry 278 (45) (2003) 44675–44682.
DOI Google Scholar
[21]

R. Yu, C. Chen, Y.Y. Mo, et al., Activation of mitogen-activated protein kinase pathways induces antioxidant response element-mediated gene expression via a Nrf2-dependent mechanism, Journal of Biological Chemistry 275 (51) (2000) 39907–39913.
DOI Google Scholar
[22]

K.W. Kang, S.H. Choi, S.G. Kim, Peroxynitrite activates NF-E2-related factor 2/antioxidant response element through the pathway of phosphatidylinositol 3-kinase: the role of nitric oxide synthase in rat glutathione S-transferase A2 induction, Nitric Oxide 7 (4) (2002) 244–253.
DOI Google Scholar
[23]

S.B. Cullinan, J.A. Diehl, PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress, Journal of Biological Chemistry 279 (19) (2004) 20108–20117.
DOI Google Scholar
[24]

H.C. Huang, T. Nguyen, C.B. Pickett, Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription, Journal of Biological Chemistry 277 (45) (2002) 42769–42774.
DOI Google Scholar
[25]

S. Numazawa, M. Ishikawa, A. Yoshida, et al., Atypical protein kinase C mediates activation of NF-E2-related factor 2 in response to oxidative stress, American Journal of Physiology – Cell Physiology 285 (2) (2003) C334-C342.
DOI Google Scholar
[26]

P. Misra, E.D. Owuor, W. Li, et al., Phosphorylation of transcriptional coactivator peroxisome proliferator-activated receptor (PPAR)-binding protein (PBP), Stimulation of transcriptional regulation by mitogen-activated protein kinase, Journal of Biological Chemistry 277 (50) (2002) 48745–48754.
DOI Google Scholar
[27]

R. Yu, S. Mandlekar, W. Lei, et al., p38 mitogen-activated protein kinase negatively regulates the induction of phase Ⅱ drug-metabolizing enzymes that detoxify carcinogens, Journal of Biological Chemistry 275 (4) (2000) 2322–2327.
DOI Google Scholar
[28]

E. Balogun, M. Hoque, P. Gong, et al., Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element, Biochemical Journal 371 (Pt 3) (2003) 887–895.
DOI Google Scholar
[29]

K.W. Kang, M.K. Cho, C.H. Lee, et al., Activation of phosphatidylinositol 3-kinase and Akt by tert-butylhydroquinone is responsible for antioxidant response element-mediated rGSTA2 induction in H4IIE cells, Molecular Pharmacology 59 (5) (2001) 1147–1156.
DOI Google Scholar
[30]

K. Nakaso, H. Yano, Y. Fukuhara, et al., PI3K is a key molecule in the Nrf2-mediated regulation of antioxidative proteins by hemin in human neuroblastoma cells, FEBS Letters 546 (2/3) (2003) 181–184.
DOI Google Scholar
[31]

J. Pi, Y. Bai, J.M. Reece, et al., Molecular mechanism of human Nrf2 activation and degradation: role of sequential phosphorylation by protein kinase CK2, Free Radical Biology and Medicine 42 (12) (2007) 1797–1806.
DOI Google Scholar
[32]

P. Talalay, J.W. Fahey, Phytochemicals from cruciferous plants protect against cancer by modulating carcinogen metabolism, Journal of Nutrition 131 (11 Suppl.) (2001) 3027S-3033S.
DOI Google Scholar
[33]

C. Chen, A.N. Kong, Dietary chemopreventive compounds and ARE/EpRE signaling, Free Radical Biology and Medicine 36 (12) (2004) 1505–1516.
DOI Google Scholar
[34]

Y.J. Surh, Cancer chemoprevention with dietary phytochemicals, Nature Reviews Cancer 3 (10) (2003) 768–780.
DOI Google Scholar
[35]

C. Chen, R. Yu, E.D. Owuor, et al., Activation of antioxidant-response element (ARE), mitogen-activated protein kinases (MAPKs) and caspases by major green tea polyphenol components during cell survival and death, Archives of Pharmacal Research 23 (6) (2000) 605–612.
DOI Google Scholar
[36]

C.K. Andreadi, L.M. Howells, P.A. Atherfold, et al., Involvement of Nrf2, p38, B-Raf, and nuclear factor-kappaB, but not phosphatidylinositol 3-kinase, in induction of hemeoxygenase-1 by dietary polyphenols, Molecular Pharmacology 69 (3) (2006) 1033–1040.
DOI Google Scholar
[37]

C.C. Wu, M.C. Hsu, C.W. Hsieh, et al., Upregulation of heme oxygenase-1 by Epigallocatechin-3-gallate via the phosphatidylinositol 3-kinase/Akt and ERK pathways, Life Sciences 78 (25) (2006) 2889–2897.
DOI Google Scholar
[38]

N. Sriram, S. Kalayarasan, G. Sudhandiran, Epigallocatechin-3-gallate augments antioxidant activities and inhibits inflammation during bleomycin-induced experimental pulmonary fibrosis through Nrf2–Keap1 signaling, Pulmonary Pharmacology and Therapeutics 22 (3) (2009) 221–236.
DOI Google Scholar
[39]

H.K. Na, E.H. Kim, J.H. Jung, et al., (−)-Epigallocatechin gallate induces Nrf2-mediated antioxidant enzyme expression via activation of PI3K and ERK in human mammary epithelial cells, Archives of Biochemistry and Biophysics 476 (2) (2008) 171–177.
DOI Google Scholar
[40]

H.K. Na, Y.J. Surh, Intracellular signaling network as a prime chemopreventive target of (−)-epigallocatechin gallate, Molecular Nutrition & Food Research 50 (2) (2006) 152–159.
DOI Google Scholar
[41]

C.S. Yang, J.D. Lambert, Z. Hou, et al., Molecular targets for the cancer preventive activity of tea polyphenols, Molecular Carcinogenesis 45 (6) (2006) 431–435.
DOI Google Scholar
[42]

Y. Cao, R. Cao, Angiogenesis inhibited by drinking tea, Nature 398 (6726) (1999) 381.
DOI Google Scholar
[43]

Y.D. Jung, L.M. Ellis, Inhibition of tumour invasion and angiogenesis by epigallocatechin gallate (EGCG), a major component of green tea, International Journal of Experimental Pathology 82 (6) (2001) 309–316.
DOI Google Scholar
[44]

C. Chen, G. Shen, V. Hebbar, et al., Epigallocatechin-3-gallate-induced stress signals in HT-29 human colon adenocarcinoma cells, Carcinogenesis 24 (8) (2003) 1369–1378.
DOI Google Scholar
[45]

V.M. Adhami, I.A. Siddiqui, N. Ahmad, et al., Oral consumption of green tea polyphenols inhibits insulin-like growth factor-I-induced signaling in an autochthonous mouse model of prostate cancer, Cancer Research 64 (23) (2004) 8715–8722.
DOI Google Scholar
[46]

J.H. Yuan, Y.Q. Li, X.Y. Yang, Inhibition of epigallocatechin gallate on orthotopic colon cancer by upregulating the Nrf2–UGT1A signal pathway in nude mice, Pharmacology 80 (4) (2007) 269–278.
DOI Google Scholar
[47]

T.C. Hsieh, J.M. Wu, Differential effects on growth, cell cycle arrest, and induction of apoptosis by resveratrol in human prostate cancer cell lines, Experimental Cell Research 249 (1) (1999) 109–115.
DOI Google Scholar
[48]

Z. Dong, Molecular mechanism of the chemopreventive effect of resveratrol, Mutation Research 523/524 (2003) 145–150.
DOI Google Scholar
[49]

C.Y. Chen, J.H. Jang, M.H. Li, et al., Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells, Biochemical and Biophysical Research Communications 331 (4) (2005) 993–1000.
DOI Google Scholar
[50]

J.H. Jang, Y.J. Surh, Protective effects of resveratrol on hydrogen peroxide-induced apoptosis in rat pheochromocytoma (PC12) cells, Mutation Research 496 (1/2) (2001) 181–190.
DOI Google Scholar
[51]

J.H. Jang, Y.J. Surh, Protective effect of resveratrol on beta-amyloid-induced oxidative PC12 cell death, Free Radical Biology and Medicine 34 (8) (2003) 1100–1110.
DOI Google Scholar
[52]

B.L. Liu, X. Zhang, W. Zhang, et al., New enlightenment of French Paradox: resveratrol’s potential for cancer chemoprevention and anti-cancer therapy, Cancer Biology and Therapy 6 (12) (2007) 1833–1836.
DOI Google Scholar
[53]

A. Kumar, C.K. Singh, H.A. Lavoie, et al., Resveratrol restores Nrf2 level and prevents ethanol-induced toxic effects in the cerebellum of a rodent model of fetal alcohol spectrum disorders, Molecular Pharmacology 80 (3) (2011) 446–457.
DOI Google Scholar
[54]

A. Kode, S. Rajendrasozhan, S. Caito, et al., Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells, American Journal of Physiology – Lung Cellular and Molecular Physiology 294 (3) (2008) L478-L488.
DOI Google Scholar
[55]

H. Hatcher, R. Planalp, J. Cho, et al., Curcumin: from ancient medicine to current clinical trials, Cellular and Molecular Life Sciences 65 (11) (2008) 1631–1652.
DOI Google Scholar
[56]

M.N. Mandal, J.M. Patlolla, L. Zheng, et al., Curcumin protects retinal cells from light-and oxidant stress-induced cell death, Free Radical Biology and Medicine 46 (5) (2009) 672–679.
DOI Google Scholar
[57]

Sreejayan, M.N. Rao, Nitric oxide scavenging by curcuminoids, Journal of Pharmacy and Pharmacology 49 (1) (1997) 105–107.
DOI Google Scholar
[58]

T. Nishinaka, Y. Ichijo, M. Ito, et al., Curcumin activates human glutathione S-transferase P1 expression through antioxidant response element, Toxicology Letters 170 (3) (2007) 238–247.
DOI Google Scholar
[59]

M.C. Myzak, R.H. Dashwood, Chemoprotection by sulforaphane: keep one eye beyond Keap1, Cancer Letters 233 (2) (2006) 208–218.
DOI Google Scholar
[60]

Y. Zhang, P. Talalay, C.G. Cho, et al., A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure, Proceedings of the National Academy of Sciences of the United States of America 89 (6) (1992) 2399–2403.
DOI Google Scholar
[61]

J.R. Bacon, G. Williamson, R.C. Garner, et al., Sulforaphane and quercetin modulate PhIP-DNA adduct formation in human HepG2 cells and hepatocytes, Carcinogenesis 24 (12) (2003) 1903–1911.
DOI Google Scholar
[62]

G.P. Basten, Y. Bao, G. Williamson, Sulforaphane and its glutathione conjugate but not sulforaphane nitrile induce UDP-glucuronosyl transferase (UGT1A1) and glutathione transferase (GSTA1) in cultured cells, Carcinogenesis 23 (8) (2002) 1399–1404.
DOI Google Scholar
[63]

Z.Q. Jiang, C. Chen, B. Yang, et al., Differential responses from seven mammalian cell lines to the treatments of detoxifying enzyme inducers, Life Sciences 72 (20) (2003) 2243–2253.
DOI Google Scholar
[64]

J.D. Brooks, V.G. Paton, G. Vidanes, Potent induction of phase 2 enzymes in human prostate cells by sulforaphane, Cancer Epidemiology, Biomarkers and Prevention 10 (9) (2001) 949–954.
Google Scholar
[65]

R. Munday, C.M. Munday, Induction of phase Ⅱ detoxification enzymes in rats by plant-derived isothiocyanates: comparison of allyl isothiocyanate with sulforaphane and related compounds, Journal of Agricultural and Food Chemistry 52 (7) (2004) 1867–1871.
DOI Google Scholar
[66]

M.A. Riedl, A. Saxon, D. Diaz-Sanchez, Oral sulforaphane increases phase Ⅱ antioxidant enzymes in the human upper airway, Clinical Immunology 130 (3) (2009) 244–251.
DOI Google Scholar
[67]

L. Gamet-Payrastre, S. Lumeau, N. Gasc, et al., Selective cytostatic and cytotoxic effects of glucosinolates hydrolysis products on human colon cancer cells in vitro, Anti-Cancer Drugs 9 (2) (1998) 141–148.
DOI Google Scholar
[68]

L. Gamet-Payrastre, P. Li, S. Lumeau, et al., Sulforaphane, a naturally occurring isothiocyanate, induces cell cycle arrest and apoptosis in HT29 human colon cancer cells, Cancer Research 60 (5) (2000) 1426–1433.
Google Scholar
[69]

R. Yu, W. Lei, S. Mandlekar, et al., Role of a mitogen-activated protein kinase pathway in the induction of phase Ⅱ detoxifying enzymes by chemicals, Journal of Biological Chemistry 274 (39) (1999) 27545–27552.
DOI Google Scholar
[70]

C.S. Yang, S.K. Chhabra, J.Y. Hong, et al., Mechanisms of inhibition of chemical toxicity and carcinogenesis by diallyl sulfide (DAS) and related compounds from garlic, Journal of Nutrition 131 (3s) (2001) 1041S-1045S.
DOI Google Scholar
[71]

Y. Shukla, N. Kalra, Cancer chemoprevention with garlic and its constituents, Cancer Letters 247 (2) (2007) 167–181.
DOI Google Scholar
[72]

A. Herman-Antosiewicz, A.A. Powolny, S.V. Singh, Molecular targets of cancer chemoprevention by garlic-derived organosulfides, Acta Pharmacologica Sinica 28 (9) (2007) 1355–1364.
DOI Google Scholar
[73]

W.S. Jeong, M. Jun, A.N. Kong, Nrf2: a potential molecular target for cancer chemoprevention by natural compounds, Antioxidants and Redox Signalling 8 (1/2) (2006) 99–106.
DOI Google Scholar
[74]

V.L. Sparnins, G. Barany, L.W. Wattenberg, Effects of organosulfur compounds from garlic and onions on benzo[a]pyrene-induced neoplasia and glutathione S-transferase activity in the mouse, Carcinogenesis 9 (1) (1988) 131–134.
DOI Google Scholar
[75]

R.A. Lubet, R. Yao, C.J. Grubbs, et al., Induced expression of drug metabolizing enzymes by preventive agents: role of the antioxidant response element, Chemico-Biological Interactions 182 (1) (2009) 22–28.
DOI Google Scholar
[76]

C.D. Fisher, L.M. Augustine, J.M. Maher, et al., Induction of drug-metabolizing enzymes by garlic and allyl sulfide compounds via activation of constitutive androstane receptor and nuclear factor E2-related factor 2, Drug Metabolism and Disposition: The Biological Fate of Chemicals 35 (6) (2007) 995–1000.
DOI Google Scholar
[77]

T.W. Kensler, P.A. Egner, P.M. Dolan, et al., Mechanism of protection against aflatoxin tumorigenicity in rats fed 5-(2-pyrazinyl)-4-methyl-1, 2-dithiol-3-thione (oltipraz) and related 1,2-dithiol-3-thiones and 1,2-dithiol-3-ones, Cancer Research 47 (16) (1987) 4271–4277.
Google Scholar
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Received: 11 December 2012
Revised: 20 December 2012
Accepted: 06 January 2013
Published: 25 January 2013
Issue date: March 2013

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