Cancer chemoprevention by phytochemicals: potential molecular targets, biomarkers and animal models

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Abstract

Recent studies have strongly indicated that certain daily-consumed dietary phytochemicals could have cancer protective effects against transgenic mice cancer models and cancers mediated by carcinogens, irradiations and carcinogenic metabolites derived from exogenous or endogenous sources. The cancer-protective effects elicited by these dietary compounds are believed to be due at least in part to the induction of cellular defense systems including the detoxifying and antioxidant enzymes system, as well as the inhibition of anti-inflammatory and anti-cell growth signaling pathways culminating in cell cycle arrest and/or cell-death. In this review, we summarize the potential mechanisms including the modulation of nuclear factor kappaB (NF-κB), cyclooxygenases-2 (COX-2), activator protein-1 (AP-1), mitogen-activated protein kinases (MAPKs) and the induction of phase II cellular detoxifying and antioxidant enzymes mediated mainly by the antioxidant response elements (ARE) within the promoter regions of these genes through nuclear factor-erythroid 2-related factor 2 (Nrf2), a member of the Cap ‘n’ collar (CNC) family of the basic region-leucine zipper transcription factor. In addition, we also review several animal models of carcinogenesis and cancer chemopreventive efficacy studies of these animal models using dietary chemopreventive compounds. Finally, we discuss the cellular signaling cascades mediated by Nrf2, NF-κB, AP-1, MAPKs and COX-2, which have been considered to play pivotal roles in tumor initiation, promotion and progression processes, and could be promising molecular targets for the design of drugs targeting cancer prevention and therapy.

References

  1. 1

    Sporn MB, Dunlop NM, Newton DL, Smith JM . Prevention of chemical carcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc 1976; 35: 1332–8.

  2. 2

    Surh YJ . Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 2003; 3: 768–80.

  3. 3

    Chen C, Kong AN . Dietary cancer-chemopreventive compounds: from signaling and gene expression to pharmacological effects. Trends Pharmacol Sci 2005; 26: 318–26.

  4. 4

    Hu R, Kong AN . Activation of MAP kinases, apoptosis and nutrigenomics of gene expression elicited by dietary cancer-prevention compounds. Nutrition 2004; 20: 83–8.

  5. 5

    Hu R, Khor TO, Shen G, Jeong WS, Hebbar V, Chen C, et al. Cancer chemoprevention of intestinal polyposis in ApcMin/+ mice by sulforaphane, a natural product derived from cruciferous vegetable. Carcinogenesis 2006; 27: 2038–46.

  6. 6

    Jeong WS, Keum YS, Chen C, Jain MR, Shen G, Kim JH, et al. Differential expression and stability of endogenous nuclear factor E2-related factor 2 (Nrf2) by natural chemopreventive compounds in HepG2 human hepatoma cells. J Biochem Mol Biol 2005; 38: 167–76.

  7. 7

    Khor TO, Hu R, Shen G, Jeong WS, Hebbar V, Chen C, et al. Pharmacogenomics of cancer chemopreventive isothiocyanate compound sulforaphane in the intestinal polyps of ApcMin/+ mice. Biopharm Drug Dispos 2006; 27: 407–20.

  8. 8

    Singletary K, MacDonald C . Inhibition of benzo[a]pyrene- and 1,6-dinitropyrene-DNA adduct formation in human mammary epithelial cells bydibenzoylmethane and sulforaphane. Cancer Lett 2000; 155: 47–54.

  9. 9

    Huang MT, Wang ZY, Georgiadis CA, Laskin JD, Conney AH . Inhibitory effects of curcumin on tumor initiation by benzo[a] pyrene and 7,12-dimethylbenz[a]anthracene. Carcinogenesis 1992; 13: 2183–6.

  10. 10

    Hu R, Kim BR, Chen C, Hebbar V, Kong AN . The roles of JNK and apoptotic signaling pathways in PEITC-mediated responses in human HT-29 colon adenocarcinoma cells. Carcinogenesis 2003; 24: 1361–7.

  11. 11

    Yu R, Mandlekar S, Harvey KJ, Ucker DS, Kong AN . Chemopreventive isothiocyanates induce apoptosis and caspase-3-like protease activity. Cancer Res 1998; 58: 402–8.

  12. 12

    Xu C, Shen G, Chen C, Gelinas C, Kong AN . Suppression of NF-kappaB and NF-kappaB-regulated gene expression by sulforaphane and PEITC through IkappaBalpha, IKK pathway in human prostate cancer PC-3 cells. Oncogene 2005; 24: 4486–95.

  13. 13

    Kim JH, Xu C, Keum YS, Reddy B, Conney A, Kong AN . Inhibition of EGFR signaling in human prostate cancer PC-3 cells by combination treatment with beta-phenylethyl isothiocyanate and curcumin. Carcinogenesis 2006; 27: 475–82.

  14. 14

    Khor TO, Keum YS, Lin W, Kim JH, Hu R, Shen G, et al. Combined inhibitory effects of curcumin and phenethyl isothiocyanate on the growth of human PC-3 prostate xenografts in immunodeficient mice. Cancer Res 2006; 66: 613–21.

  15. 15

    Chen C, Shen G, Hebbar V, Hu R, Owuor ED, Kong AN . Epigallocatechin-3-gallate-induced stress signals in HT-29 human colon adenocarcinoma cells. Carcinogenesis 2003; 24: 1369–78.

  16. 16

    Qin J, Xie LP, Zheng XY, Wang YB, Bai Y, Shen HF, et al. A component of green tea, (-)-epigallocatechin-3-gallate, promotes apoptosis in T24 human bladder cancer cells via modulation of the PI3K/Akt pathway and Bcl-2 family proteins. Biochem Biophys Res Commun 2007; 354: 852–7.

  17. 17

    Keum YS, Yu S, Chang PP, Yuan X, Kim JH, Xu C, et al. Mechanism of action of sulforaphane: inhibition of p38 mitogen-activated protein kinase isoforms contributing to the induction of antioxidant response element-mediated heme oxygenase-1 in human hepatoma HepG2 cells. Cancer Res 2006; 66: 8804–13.

  18. 18

    Maheo K, Morel F, Langouet S, Kramer H, Le Ferrec E, Ketterer B, et al. Inhibition of cytochromes P-450 and induction of glutathione S-transferases by sulforaphane in primary human and rat hepatocytes. Cancer Res 1997; 57: 3649–52.

  19. 19

    Shen G, Xu C, Hu R, Jain MR, Gopalkrishnan A, Nair S, et al. Modulation of nuclear factor E2-related factor 2-mediated gene expression in mice liver and small intestine by cancer chemopreventive agent curcumin. Mol Cancer Ther 2006; 5: 39–51.

  20. 20

    Hu R, Xu C, Shen G, Jain MR, Khor TO, Gopalkrishnan A, et al. Identification of Nrf2-regulated genes induced by chemopreventive isothiocyanate PEITC by oligonucleotide microarray. Life Sci 2006; 79: 1944–55.

  21. 21

    Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, et al. Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem 2000; 275: 16023–9.

  22. 22

    Aoki Y, Sato H, Nishimura N, Takahashi S, Itoh K, Yamamoto M . Accelerated DNA adduct formation in the lung of the Nrf2 knockout mouse exposed to diesel exhaust. Toxicol Appl Pharmacol 2001; 173: 154–60.

  23. 23

    Enomoto A, Itoh K, Nagayoshi E, Haruta J, Kimura T, O'Connor T, et al. High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol Sci 2001; 59: 169–77.

  24. 24

    Ramos-Gomez M, Kwak MK, Dolan PM, Itoh K, Yamamoto M, Talalay P, et al. Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci USA 2001; 98: 3410–5.

  25. 25

    Hayes JD, Chanas SA, Henderson CJ, McMahon M, Sun C, Moffat GJ, et al. The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin. Biochem Soc Trans 2000; 28: 33–41.

  26. 26

    Morimitsu Y, Nakagawa Y, Hayashi K, Fujii H, Kumagai T, Nakamura Y, et al. A sulforaphane analogue that potently activates the Nrf2-dependent detoxification pathway. J Biol Chem 2002; 277: 3456–63.

  27. 27

    Balogun E, Hoque M, Gong P, Killeen E, Green CJ, Foresti R, et al. Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J 2003; 371: 887–95.

  28. 28

    Li W, Yu SW, Kong AN . Nrf2 possesses a redox-sensitive nuclear exporting signal in the Neh5 transactivation domain. J Biol Chem 2006; 281: 27, 251–63.

  29. 29

    Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 1999; 13: 76–86.

  30. 30

    Kobayashi M, Itoh K, Suzuki T, Osanai H, Nishikawa K, Katoh Y, et al. Identification of the interactive interface and phylogenic conservation of the Nrf2-Keap1 system. Genes Cells 2002; 7: 807–20.

  31. 31

    Thimmulappa RK, Mai KH, Srisuma S, Kensler TW, Yamamoto M, Biswal S . Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 2002; 62: 5196–203.

  32. 32

    Prestera T, Holtzclaw WD, Zhang Y, Talalay P . Chemical and molecular regulation of enzymes that detoxify carcinogens. Proc Natl Acad Sci USA 1993; 90: 2965–9.

  33. 33

    Huang TT, Kudo N, Yoshida M, Miyamoto S . A nuclear export signal in the N-terminal regulatory domain of IkappaBalpha controls cytoplasmic localization of inactive NF-kappaB/Ikappa-Balpha complexes. Proc Natl Acad Sci USA 2000; 97: 1014–19.

  34. 34

    Johnson C, Van Antwerp D, Hope TJ . An N-terminal nuclear export signal is required for the nucleocytoplasmic shuttling of IkappaBalpha. EMBO J 1999; 18: 6682–93.

  35. 35

    Baichwal VR, Baeuerle PA . Activate NF-kappa B or die?. Curr Biol 1997; 7: R94–6.

  36. 36

    Bours V, Bentires-Alj M, Hellin AC, Viatour P, Robe P, Delhalle S, et al. Nuclear factor-kappa B, cancer, and apoptosis. Biochem Pharmacol 2000; 60: 1085–9.

  37. 37

    Karin M, Ben-Neriah Y . Phosphorylation meets ubiquitination: the control of NF-kappaB activity. Annu Rev Immunol 2000; 18: 621–63.

  38. 38

    Hatta Y, Arima N, Machino T, Itoh T, Hashimoto S, Takeuchi J, et al. Mutational analysis of IkappaBalpha in hematologic malignancies. Int J Mol Med 2003; 11: 239–42.

  39. 39

    Huang S, Pettaway CA, Uehara H, Bucana CD, Fidler IJ . Blockade of NF-kappaB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene 2001; 20: 4188–97.

  40. 40

    Kim DW, Sovak MA, Zanieski G, Nonet G, Romieu-Mourez R, Lau AW, et al. Activation of NF-kappaB/Rel occurs early during neoplastic transformation of mammary cells. Carcinogenesis 2000; 21: 871–9.

  41. 41

    Wang W, Abbruzzese JL, Evans DB, Larry L, Cleary KR, Chiao PJ . The nuclear factor-kappa B RelA transcription factor is constitutively activated in human pancreatic adenocarcinoma cells. Clin Cancer Res 1999; 5: 119–27.

  42. 42

    Bharti AC, Aggarwal BB . Nuclear factor-kappa B and cancer: its role in prevention and therapy. Biochem Pharmacol 2002; 64: 883–8.

  43. 43

    Angel P, Karin M . The role of Jun, Fos and the AP-1 complex in cell-proliferation and transformation. Biochim Biophys Acta 1991; 1072: 129–57.

  44. 44

    Eferl R, Wagner EF . AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer 2003; 3: 859–68.

  45. 45

    Shaulian E, Karin M . AP-1 as a regulator of cell life and death. Nat Cell Biol 2002; 4: E131–6.

  46. 46

    Shaulian E, Karin M . AP-1 in cell proliferation and survival. Oncogene 2001; 20: 2390–400.

  47. 47

    Wang ZQ, Grigoriadis AE, Mohle-Steinlein U, Wagner EF . A novel target cell for c-fos-induced oncogenesis: development of chondrogenic tumours in embryonic stem cell chimeras. EMBO J 1991; 10: 2437–50.

  48. 48

    Eferl R, Ricci R, Kenner L, Zenz R, David JP, Rath M, et al. Liver tumor development. c-Jun antagonizes the proapoptotic activity of p53. Cell 2003; 112: 181–92.

  49. 49

    Young MR, Li JJ, Rincon M, Flavell RA, Sathyanarayana BK, Hunziker R, et al. Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion. Proc Natl Acad Sci USA 1999; 96: 9827–32.

  50. 50

    Chang L, Karin M . Mammalian MAP kinase signalling cascades. Nature 2001; 410: 37–40.

  51. 51

    Funakoshi-Tago M, Tago K, Sonoda Y, Tominaga S, Kasahara T . TRAF6 and C-SRC induce synergistic AP-1 activation via PI3-kinase-AKT-JNK pathway. Eur J Biochem 2003; 270: 1257–68.

  52. 52

    Jeong WS, Kim IW, Hu R, Kong AN . Modulatory properties of various natural chemopreventive agents on the activation of NF-kappaB signaling pathway. Pharm Res 2004; 21: 661–70.

  53. 53

    Zhu M, Zhang Y, Cooper S, Sikorski E, Rohwer J, Bowden GT . Phase II enzyme inducer, sulforaphane, inhibits UVB-induced AP-1 activation in human keratinocytes by a novel mechanism. Mol Carcinog 2004; 41: 179–86.

  54. 54

    Jeong WS, Kim IW, Hu R, Kong AN . Modulation of AP-1 by natural chemopreventive compounds in human colon HT-29 cancer cell line. Pharm Res 2004; 21: 649–60.

  55. 55

    Gonzalez FA, Raden DL, Davis RJ . Identification of substrate recognition determinants for human ERK1 and ERK2 protein kinases. J Biol Chem 1991; 266: 22159–63.

  56. 56

    Alvarez E, Northwood IC, Gonzalez FA, Latour DA, Seth A, Abate C, et al. Pro-Leu-Ser/Thr-Pro is a consensus primary sequence for substrate protein phosphorylation. Characterization of the phosphorylation of c-myc and c-jun proteins by an epidermal growth factor receptor threonine 669 protein kinase. J Biol Chem 1991; 266: 15277–85.

  57. 57

    Cobb MH, Goldsmith EJ . How MAP kinases are regulated. J Biol Chem 1995; 270: 14843–6.

  58. 58

    Cano E, Mahadevan LC . Parallel signal processing among mammalian MAPKs. Trends Biochem Sci 1995; 20: 117–22.

  59. 59

    Kyriakis JM, Avruch J . Protein kinase cascades activated by stress and inflammatory cytokines. Bioessays 1996; 18: 567–77.

  60. 60

    Chen YR, Wang X, Templeton D, Davis RJ, Tan TH . The role of c-Jun N-terminal kinase (JNK) in apoptosis induced by ultraviolet C and gamma radiation. Duration of JNK activation may determine cell death and proliferation. J Biol Chem 1996; 271: 31929–36.

  61. 61

    Osborn MT, Chambers TC . Role of the stress-activated/c-Jun NH2-terminal protein kinase pathway in the cellular response to adriamycin and other chemotherapeutic drugs. J Biol Chem 1996; 271: 30950–5.

  62. 62

    Karin M . The regulation of AP-1 activity by mitogen-activated protein kinases. J Biol Chem 1995; 270: 16483–6.

  63. 63

    Lee KW, Kim JH, Lee HJ, Surh YJ . Curcumin inhibits phorbol ester-induced up-regulation of cyclooxygenase-2 and matrix metalloproteinase-9 by blocking ERK1/2 phosphorylation and NF-kappaB transcriptional activity in MCF10A human breast epithelial cells. Antioxid Redox Signal 2005; 7: 1612–20.

  64. 64

    Chen YR, Tan TH . Inhibition of the c-Jun N-terminal kinase (JNK) signaling pathway by curcumin. Oncogene 1998; 17: 173–8.

  65. 65

    Salh B, Assi K, Templeman V, Parhar K, Owen D, Gomez-Munoz A, et al. Curcumin attenuates DNB-induced murine colitis. Am J Physiol Gastrointest Liver Physiol 2003; 285: G235–43.

  66. 66

    Li Y, Li X, Sarkar FH . Gene expression profiles of I3C- and DIM-treated PC3 human prostate cancer cells determined by cDNA microarray analysis. J Nutr 2003; 133: 1011–9.

  67. 67

    Aggarwal BB . Signalling pathways of the TNF superfamily: a double-edged sword. Nat Rev Immunol 2003; 3: 745–56.

  68. 68

    Sugarman BJ, Aggarwal BB, Hass PE, Figari IS, Palladino MA Jr, Shepard HM . Recombinant human tumor necrosis factor-alpha: effects on proliferation of normal and transformed cells in vitro. Science 1985; 230: 943–5.

  69. 69

    Giri DK, Aggarwal BB . Constitutive activation of NF-kappaB causes resistance to apoptosis in human cutaneous T cell lym-phoma HuT-78 cells. Autocrine role of tumor necrosis factor and reactive oxygen intermediates. J Biol Chem 1998; 273: 14008–14.

  70. 70

    Tucker SJ, Rae C, Littlejohn AF, Paul A, MacEwan DJ . Switching leukemia cell phenotype between life and death. Proc Natl Acad Sci USA 2004; 101: 12940–5.

  71. 71

    Estrov Z, Kurzrock R, Pocsik E, Pathak S, Kantarjian HM, Zipf TF, et al. Lymphotoxin is an autocrine growth factor for Epstein-Barr virus-infected B cell lines. J Exp Med 1993; 177: 763–74.

  72. 72

    Moore RJ, Owens DM, Stamp G, Arnott C, Burke F, East N, et al. Mice deficient in tumor necrosis factor-alpha are resistant to skin carcinogenesis. Nat Med 1999; 5: 828–31.

  73. 73

    Shishodia S, Amin HM, Lai R, Aggarwal BB . Curcumin (diferuloyl-methane) inhibits constitutive NF-kappaB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma. Biochem Pharmacol 2005; 70: 700–13.

  74. 74

    Yang F, de Villiers WJ, McClain CJ, Varilek GW . Green tea polyphenols block endotoxin-induced tumor necrosis factor-production and lethality in a murine model. J Nutr 1998; 128: 2334–40.

  75. 75

    Martin AR, Villegas I, Sanchez-Hidalgo M, de la Lastra CA . The effects of resveratrol, a phytoalexin derived from red wines, on chronic inflammation induced in an experimentally induced colitis model. Br J Pharmacol 2006; 147: 873–85.

  76. 76

    Subbaramaiah K, Dannenberg AJ . Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol Sci 2003; 24: 96–102.

  77. 77

    Plummer SM, Holloway KA, Manson MM, Munks RJ, Kaptein A, Farrow S, et al. Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-kappaB activation via the NIK/IKK signalling complex. Oncogene 1999; 18: 6013–20.

  78. 78

    Mutoh M, Takahashi M, Fukuda K, Matsushima-Hibiya Y, Mutoh H, Sugimura T, et al. Suppression of cyclooxygenase-2 promoter-dependent transcriptional activity in colon cancer cells by chemopreventive agents with a resorcin-type structure. Carcinogenesis 2000; 21: 959–63.

  79. 79

    Gerhauser C, Klimo K, Heiss E, Neumann I, Gamal-Eldeen A, Knauft J, et al. Mechanism-based in vitro screening of potential cancer chemopreventive agents. Mutat Res 2003; 523–4: 163–72.

  80. 80

    Subbaramaiah K, Chung WJ, Michaluart P, Telang N, Tanabe T, Inoue H, et al. Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells. J Biol Chem 1998; 273: 21875–82.

  81. 81

    Plummer SM, Hill KA, Festing MF, Steward WP, Gescher AJ, Sharma RA . Clinical development of leukocyte cyclooxygenase 2 activity as a systemic biomarker for cancer chemopreventive agents. Cancer Epidemiol Biomarkers Prev 2001; 10: 1295–9.

  82. 82

    Garcea G, Berry D P, Jones DJ, Singh R, Dennison AR, Farmer PB, et al. Consumption of the putative chemopreventive agent curcumin by cancer patients: assessment of curcumin levels in the colorectum and their pharmacodynamic consequences. Cancer Epidemiol Biomarkers Prev 2005; 14: 120–5.

  83. 83

    Lee JS, Kim HS, Hahm KB, Sohn MW, Yoo M, Johnson JA, et al. Inhibitory effects of 7-carboxymethyloxy-3′,4′,5-trimethoxy-flavone (DA-6034) on Helicobacter pylori-induced NF-kappa B activation and iNOS expression in AGS cells. Ann N Y Acad Sci 2007; 1095: 527–35.

  84. 84

    Kim OK, Murakami A, Nakamura Y, Ohigashi H . Screening of edible Japanese plants for nitric oxide generation inhibitory activities in RAW 264.7 cells. Cancer Lett 1998; 125: 199–207.

  85. 85

    Greenberg NM, DeMayo FJ, Sheppard PC, Barrios R, Lebovitz R, Finegold M, et al. The rat probasin gene promoter directs hor-monally and developmentally regulated expression of a heter-ologous gene specifically to the prostate in transgenic mice. Mol Endocrinol 1994; 8: 230–9.

  86. 86

    Klein RD . The use of genetically engineered mouse models of prostate cancer for nutrition and cancer chemoprevention research. Mutat Res 2005; 576: 111–9.

  87. 87

    Hernandez I, Maddison LA, Wei Y, DeMayo F, Petras T, Li B, et al. Prostate-specific expression of p53(R172L) differentially regulates p21, Bax, and mdm2 to inhibit prostate cancer progression and prolong survival. Mol Cancer Res 2003; 1: 1036–47.

  88. 88

    Kaplan-Lefko PJ, Chen TM, Ittmann MM, Barrios RJ, Ayala GE, Huss WJ, et al. Pathobiology of autochthonous prostate cancer in a pre-clinical transgenic mouse model. Prostate 2003; 55: 219–37.

  89. 89

    Mentor-Marcel R, Lamartiniere CA, Eltoum IE, Greenberg NM, Elgavish A . Genistein in the diet reduces the incidence of poorly differentiated prostatic adenocarcinoma in transgenic mice (TRAMP). Cancer Res 2001; 61: 6777–82.

  90. 90

    Adhami VM, Siddiqui IA, Ahmad N, Gupta S, Mukhtar H . Oral consumption of green tea polyphenols inhibits insulin-like growth factor-I-induced signaling in an autochthonous mouse model of prostate cancer. Cancer Res 2004; 64: 8715–22.

  91. 91

    Bieberich CJ, Fujita K, He WW, Jay G . Prostate-specific and androgen-dependent expression of a novel homeobox gene. J Biol Chem 1996; 271: 31779–82.

  92. 92

    Tanaka T, Kohno H, Suzuki R, Hata K, Sugie S, Niho N, et al. Dextran sodium sulfate strongly promotes colorectal carcinogenesis in Apc(Min/+) mice: inflammatory stimuli by dextran sodium sulfate results in development of multiple colonic neoplasms. Int J Cancer 2006; 118: 25–34.

  93. 93

    Hirono I, Ueno I, Aiso S, Yamaji T, Golberg L . Enhancing effect of dextran sulfate sodium on colorectal carcinogenesis by 1,2-dimethylhydrazine in rats. Gann 1983; 74: 493–6.

  94. 94

    Khor TO, Huang MT, Kwon KH, Chan JY, Reddy BS, Kong AN . Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res 2006; 66: 11580–4.

  95. 95

    Liu LZ, Fang J, Zhou Q, Hu X, Shi X, Jiang BH . Apigenin inhibits expression of vascular endothelial growth factor and angiogenesis in human lung cancer cells: implication of chemo-prevention of lung cancer. Mol Pharmacol 2005; 68: 635–43.

  96. 96

    Singh RP, Agarwal R . Mechanisms of action of novel agents for prostate cancer chemoprevention. Endocr Relat Cancer 2006; 13: 751–78.

  97. 97

    Sarkar FH, Li Y . The role of isoflavones in cancer chemoprevention. Front Biosci 2004; 9: 2714–24.

  98. 98

    Nair S, Xu C, Shen G, Hebbar V, Gopalakrishnan A, Hu R, et al. Toxicogenomics of endoplasmic reticulum stress inducer tunicamycin in the small intestine and liver of Nrf2 knockout and C57BL/6J mice. Toxicol Lett 2007; 168: 21–39.

  99. 99

    Osburn WO, Wakabayashi N, Misra V, Nilles T, Biswal S, Trush MA, et al. Nrf2 regulates an adaptive response protecting against oxidative damage following diquat-mediated formation of su-peroxide anion. Arch Biochem Biophys 2006; 454: 7–15.

  100. 100

    Yu X, Kensler T . Nrf2 as a target for cancer chemoprevention. Mutat Res 2005; 591: 93–102.

  101. 101

    Fahey JW, Haristoy X, Dolan PM, Kensler TW, Scholtus I, Stephenson KK, et al. Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Proc Natl Acad Sci USA 2002; 99: 7610–5.

  102. 102

    Xu C, Huang MT, Shen G, Yuan X, Lin W, Khor TO, et al. Inhibition of 7,12-dimethylbenz(a)anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor 2. Cancer Res 2006; 66: 8293–6.

  103. 103

    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: 459–72.

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Correspondence to Ah-Ng Tony Kong.

Additional information

This study was supported in part by Institutional Funds and by RO1-CA094828, RO1-CA092515, RO1-CA073674 and R01-CA118947 to Dr Ah-Ng Tony KONG from the National Institutes of Health (NIH).

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Kwon, K., Barve, A., Yu, S. et al. Cancer chemoprevention by phytochemicals: potential molecular targets, biomarkers and animal models. Acta Pharmacol Sin 28, 1409–1421 (2007) doi:10.1111/j.1745-7254.2007.00694.x

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Keywords

  • chemoprevention
  • dietary cancer chemopreventive compounds
  • nuclear factor E2-related factor 2
  • nuclear factor-kappaB
  • activator protein-1
  • mitogen-activated protein kinases

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