European Journal of Nutrition

, Volume 47, Supplement 2, pp 73–88 | Cite as

The cancer chemopreventive actions of phytochemicals derived from glucosinolates

  • John D. HayesEmail author
  • Michael O. Kelleher
  • Ian M. Eggleston


This article reviews the mechanisms by which glucosinolate breakdown products are thought to inhibit carcinogenesis. It describes how isothiocyanates, thiocyanates, nitriles, cyano-epithioalkanes and indoles are produced from glucosinolates through the actions of myrosinase, epithiospecifier protein and epithiospecifier modifier protein released from cruciferous vegetables during injury to the plant. The various biological activities displayed by these phytochemicals are described. In particular, their abilities to induce cytoprotective genes, mediated by the Nrf2 (NF-E2 related factor 2) and AhR (arylhydrocarbon receptor) transcription factors, and their abilities to repress NF-κB (nuclear factor-κB) activity, inhibit histone deacetylase, and inhibit cytochrome P450 are outlined. Isothiocyanates appear to alter gene expression through modification of critical thiols in regulatory proteins such as Keap1 (Kelch-like ECH-associated protein 1) or IKK (IκB kinase), causing activation of Nrf2 and inactivation of NF-κB, respectively. Certain indoles act as ligands for AhR. Isothiocyanates and indoles are also capable of affecting cell cycle arrest and stimulating apoptosis. The mechanisms responsible for these anti-proliferative responses are discussed.

Key words

antioxidant response element apoptosis arylhydrocarbon receptor cytochrome P450 epithionitriles gene induction glucosinolates glutathione S-transferase isothiocyanates NF-κB Nrf2 quinone reductase xenobiotic response element 



We thank Prof Björn Åkesson for critically reading this paper. This article was written as a part of the research integration in the work-package “Mechanisms of modulation of cancer by dietary factors” in the NoE Environmental Cancer risk, Nutrition and Individual Susceptibility (ECNIS, no. 513943; <>). We are grateful to the World Cancer Research Fund (2002/55) and the Association for International Cancer Research (04-088) for supporting some of our work described in this article. Conflict of interest: None of the authors has any financial conflict of interest. We have no commercial arrangement with companies that market glucosinolates nor do we act as consultants for companies working in the phytochemical area.


  1. 1.
    Auborn KJ, Fan S, Rosen EM, Goodwin L, Chandraskaren A, Williams DE, Chen D, Carter TH (2003) Indole-3-carbinol is a negative regulator of estrogen. J Nutr 133:2470S–2475SGoogle Scholar
  2. 2.
    Bacon JR, Plumb GW, Howie AF, Beckett GJ, Wang W, Bao Y (2007) Dual action of sulforaphane in the regulation of thioredoxin reductase and thioredoxin in human HepG2 and Caco-2 cells. J Agric Food Chem 55:1170–1176Google Scholar
  3. 3.
    Bak S, Olsen CE, Petersen BL, Moller BL, Halkier BA (1999) Metabolic engineering of p-hydroxybenzylglucosinolate in Arabidopsis by expression of the cyanogenic CYP79A1 from Sorghum bicolor. Plant J 20:663–671Google Scholar
  4. 4.
    Bjeldanes LF, Kim J-Y, Grose KR, Bartholomew JC, Bradfield CA (1991) Aromatic hydrocarbon responsiveness-receptor agonists generated from indole-3-carbinol in vitro and in vivo: comparisons with 2,3,7,8-tetrachlorodibenzo-p-dioxin. Proc Natl Acad Sci USA 88:9543–9547Google Scholar
  5. 5.
    Bones AM, Rossiter JT (1996) The myrosinase-glucosinolate system, its organisation and biochemistry. Phys Plant 97:194–208Google Scholar
  6. 6.
    Bones AM, Rossiter JT (2006) The enzymic and chemically induced decomposition of glucosinolates. Phytochemistry 67:1053–1067Google Scholar
  7. 7.
    Bonnesen C, Eggleston IM, Hayes JD (2001) Dietary indoles and isothiocyanates that are generated from cruciferous vegetables can both stimulate apoptosis and confer protection against DNA damage in human colon cell lines. Cancer Res 61:6120–6130Google Scholar
  8. 8.
    Brew CT, Aronchik I, Hsu JC, Sheen J-H, Dickson RB, Bjeldanes LF, Firestone GL (2006) Indole-3-carbinol activates the ATM signalling pathway independent of DNA damage to stabilize p53 and induce G1 arrest of human mammary epithelial cells. Int J Cancer 118:857–868Google Scholar
  9. 9.
    Burow M, Zhang ZY, Ober JA, Lambrix VM, Wittstock U, Gershenzon J, Kliebenstein DJ (2008) ESP and ESM1 mediate indol-3-acetonitrile production from indol-3-ylmethyl glucosinolate in Arabidopsis. Phytochemistry 69:663–671Google Scholar
  10. 10.
    Callaway EC, Zhang Y, Chew W, Chow HH (2004) Cellular accumulation of dietary anticarcinogenic isothiocyanates is followed by transporter-mediated export as dithiocarbamates. Cancer Lett 204:23–31Google Scholar
  11. 11.
    Carter TH, Liu K, Ralph W Jr, Chen D, Qi M, Fan S, Yuan F, Rosen EM, Auborn KJ (2002) Diindolylmethane alters gene expression in human keratinocytes in vitro. J Nutr 132:3314–3324Google Scholar
  12. 12.
    Chanas SA, Jiang Q, McMahon M, McWalter GK, McLellan LI, Elcombe CR, Henderson CJ, Wolf CR, Moffat GJ, Itoh K, Yamamoto M, Hayes JD (2002) Loss of the Nrf2 transcription factor causes a marked reduction in constitutive and inducible expression of the glutathione S-transferase Gsta1, Gsta2, Gstm1, Gstm2, Gstm3 and Gstm4 genes in the livers of male and female mice. Biochem J 365:405–416Google Scholar
  13. 13.
    Chen YR, Wang W, Kong AN, Tan TH (1998) Molecular mechanisms of c-Jun N-terminal kinase-mediated apoptosis induced by anticarcinogenic isothiocyanates. J Biol Chem 273:1769–1775Google Scholar
  14. 14.
    Chinni SR, Sarkar FH (2002) Akt inactivation is a key event in indole-3-carbinol-induced apoptosis in PC-3 cells. Clin Cancer Res 8:1228–1236Google Scholar
  15. 15.
    Ciska E, Martyniak-Przybyszewska B, Kozlowska H (2000) Content of glucosinolates in cruciferous vegetables grown at the same site for two years under different climatic conditions. J Agric Food Chem 48:2862–2867Google Scholar
  16. 16.
    Ciucci A, Gianferretti P, Piva R, Guyot T, Snape TJ, Roberts SM, Santoro MG (2006) Induction of apoptosis in estrogen receptor-negative breast cancer cells by natural and synthetic cyclopentenones: role of the IkappaB kinase/nuclear factor-kappaB pathway. Mol Pharmacol 70:1812–1821Google Scholar
  17. 17.
    Cole RA (1976) Isothiocyanates, nitriles and thiocyanates as products of autolysis of glucosinolates in Cruciferae. Phytochemistry 15:759–762Google Scholar
  18. 18.
    Conaway CC, Wang CX, Pittman B, Yang YM, Schwartz JE, Tian D, McIntee EJ, Hecht SS, Chung FL (2005) Phenethyl isothiocyanate and sulforaphane and their N-acetylcysteine conjugates inhibit malignant progression of lung adenomas induced by tobacco carcinogens in A/J mice. Cancer Res 65:8548–8557Google Scholar
  19. 19.
    Cover CM, Hsieh SJ, Cram EJ, Hong C, Riby JE, Bjeldanes LF, Firestone GL (1999) Indole-3-carbinol and tamoxifen cooperate to arrest the cell cycle of MCF-7 human breast cancer cells. Cancer Res 59:1244–1251Google Scholar
  20. 20.
    Cover CM, Hsieh SJ, Tran SH, Hallden G, Kim GS, Bjeldanes LF, Firestone GL (1998) Indole-3-carbinol inhibits the expression of cyclin-dependent kinase-6 and induces a G1 cell cycle arrest of human breast cancer cells independent of estrogen receptor signaling. J Biol Chem 273:3838–3847Google Scholar
  21. 21.
    Cram EJ, Liu BD, Bjeldanes LF, Firestone GL (2001) Indole-3-carbinol inhibits CDK6 expression in human MCF-7 breast cancer cells by disrupting Sp1 transcription factor interactions with a composite element in the CDK6 gene promoter. J Biol Chem 276:22332–22340Google Scholar
  22. 22.
    Dashwood RH, Myzak MC, Ho E (2006) Dietary HDAC inhibitors: time to rethink weak ligands in cancer chemoprevention? Carcinogenesis 27:344–349Google Scholar
  23. 23.
    Daxenbichler ME, Spencer GF, Carlson DG, Rose GB, Brinker AM, Powell RG (1991) Glucosinolate composition of seeds from 297 species of wild plants. Phytochemistry 30:2623–2638Google Scholar
  24. 24.
    Daxenbichler ME, VanEtten CH, Wolff IA (1968) Diastereomeric episulfides from epi-progoitrin upon autolysis of crambe seed meal. Phytochemistry 7:989–996Google Scholar
  25. 25.
    De Kruif CA, Marsman JW, Venekamp JC, Falke HE, Noordhoek J, Blaauboer BJ, Wortelboer HM (1991) Structure elucidation of acid reaction products of indole-3-carbinol: detection in vivo and enzyme induction in vitro. Chem Biol Interact 80:303–315Google Scholar
  26. 26.
    Devling TW, Lindsay CD, McLellan LI, McMahon M, Hayes JD (2005) Utility of siRNA against Keap1 as a strategy to stimulate a cancer chemopreventive phenotype. Proc Natl Acad Sci USA 102:7280–7285AGoogle Scholar
  27. 27.
    Dinkova-Kostova AT, Fahey JW, Talalay P (2004) Chemical structures of inducers of nicotinamide quinone oxidoreductase 1 (NQO1). Meth Enzymol 382:423–448Google Scholar
  28. 28.
    Dinkova-Kostova AT, Holtzclaw WD, Wakabayashi N (2005) Keap1, the sensor for electrophiles and oxidants that regulates the phase 2 response, is a zinc metalloprotein. Biochemistry 44:6889–6899Google Scholar
  29. 29.
    Dinkova-Kostova AT, Jenkins SN, Fahey JW, Ye L, Wehage SL, Liby KT, Stephenson KK, Wade KL, Talalay P (2006) Protection against UV-light-induced skin carcinogenesis in SKH-1 high-risk mice by sulforaphane-containing broccoli sprout extracts. Cancer Lett 240:243–252Google Scholar
  30. 30.
    Dinkova-Kostova AT, Massiah MA, Bozak RE, Hicks RJ, Talalay P (2001) Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups. Proc Natl Acad Sci USA 98:3404–3409Google Scholar
  31. 31.
    Eggler AL, Liu G, Pezzuto JM, van Breemen RB, Mesecar AD (2005) Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2. Proc Natl Acad Sci USA 102:10070–10075Google Scholar
  32. 32.
    Elfoul L, Rabot S, Khelifa N, Quinsac A, Duguay A, Rimbault A (2001) Formation of allyl isothiocyanate from sinigrin in the digestive tract of rats monoassociated with a human colonic strain of Bacteroides thetaiotaomicron. FEMS Microbiol Lett 197:99–103Google Scholar
  33. 33.
    Fahey JW, Haristoy X, Dolan PM, Kensler TW, Scholtus I, Stephenson KK, Talalay P, Lozniewski A (2002) Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Proc Natl Acad Sci USA 99:7610–7615Google Scholar
  34. 34.
    Fahey JW, Haristoy X, Dolan PM, Kensler TW, Scholtus I, Stephenson KK, Talalay P, Lozniewski A (2002) Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Proc Natl Acad Sci USA 99:7610–7615Google Scholar
  35. 35.
    Fahey JW, Zalcmann AT, Talalay P (2001) The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry 56:5–51Google Scholar
  36. 36.
    Farnham MW, Wilson PE, Stephenson KK, Fahey JW (2004) Genetic and environmental effects on glucosinolate content and chemopreventive potency of broccoli. Plant Breed 123:60–65Google Scholar
  37. 37.
    Fenwick GR, Heaney RK, Mullin WR (1983) Glucosinolates and their breakdown products in food and food plants. CRC Crit Rev Food Sci Technol 18:123–201Google Scholar
  38. 38.
    Fimognari C, Nusse M, Berti F, Cantelli-Forti G, Hrelia P (2003) Sulforaphane modulates cell cycle and apoptosis in transformed and non-transformed human T lymphocytes. Ann NY Acad Sci 1010:393–398Google Scholar
  39. 39.
    Foo HL, GrØnning LM, Goodenough L, Bones AM, Danielsen B, Whiting DA, Rossiter JT (2000) Purification and characterisation of epithiospecifier protein from Brassica napus: enzymic intramolecular sulphur addition within alkenyl thiohydroximates derived from alkenyl glucosinolate hydrolysis. FEBS Lett 468:243–246Google Scholar
  40. 40.
    Galletti S, Bernadi R, Leoni O, Rollin P, Palmieri S (2001) Preparation and biological activity of four epiprogoitrin myrosinase-derived products. J Agric Food Chem 49:471–476Google Scholar
  41. 41.
    Garcia HH, Brar GA, Nguyen DH, Bjeldanes LF, Firestone GL (2005) Indole-3-carbinol (I3C) inhibits cyclin-dependent kinase-2 function in human breast cancer cells by regulating the size distribution, associated cyclin E forms, and subcellular localization of the CDK2 protein complex. J Biol Chem 280:8756–8764Google Scholar
  42. 42.
    Giovannucci E, Rimm EB, Liu Y, Stampfer MJ, Willett WC (2003) A prospective study of cruciferous vegetables and prostate cancer. Cancer Epidemiol Biomarkers Prev 12:1403–1409Google Scholar
  43. 43.
    Graser G, Schneider B, Oldham NJ, Gershenzon J (2000) The methionine chain elongation pathway in the biosynthesis of glucosinolates in Eruca sativa (Brassicaceae). Arch Biochem Biophys 378:411–419Google Scholar
  44. 44.
    Hayes JD, Flanagan JU, Jowsey IR (2005) Glutathione transferases. Annu Rev Pharmacol Toxicol 45:51–88Google Scholar
  45. 45.
    Hayes JD, Pulford DJ (1995) The glutathione S-transferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 30:445–600Google Scholar
  46. 46.
    Hecht SS (2000) Inhibition of carcinogenesis by isothiocyanates. Drug Metab Rev 32:395–411Google Scholar
  47. 47.
    Heiss E, Herhaus C, Klimo K, Bartsch H, Gerhäuser C (2001) Nuclear factor kappa B is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms. J Biol Chem 276:32008–32015Google Scholar
  48. 48.
    Holst B, Williamson G (2004) A critical review of the bioavailability of glucosinolates and related compounds. Nat Prod Rep 21:425–447Google Scholar
  49. 49.
    Hong F, Freeman ML, Liebler DC (2005) Identification of sensor cysteines in human keap1 modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol 18:1917–1926Google Scholar
  50. 50.
    Hsu JC, Zhang J, Dev A, Wing A, Bjeldanes LF, Firestone GL (2005) Indole-3-carbinol inhibition of androgen receptor expression and downregulation of androgen responsiveness in human prostate cancer cells. Carcinogenesis 26:1896–1904Google Scholar
  51. 51.
    Hu R, Hebbar V, Kim BR, Chen C, Winnik B, Buckley B, Soteropoulos P, Tolias P, Hart RP, Kong AN (2004) In vivo pharmacokinetics and regulation of gene expression profiles by isothiocyanate sulforaphane in the rat. J Pharmacol Exp Ther 310:263–271Google Scholar
  52. 52.
    Hu R, Khor TO, Shen G, Jeong WS, Hebbar V, Chen C, Xu C, Reddy B, Chada K, Kong AN (2006) Cancer chemoprevention of intestinal polyposis in ApcMin/+ mice by sulforaphane, a natural product derived from cruciferous vegetable. Carcinogenesis 27:2038–2046Google Scholar
  53. 53.
    Hu R, Kim BR, Chen C, Hebbar V, Kong AN (2003) The roles of JNK and apoptotic signaling pathways in PEITC-mediated responses in human HT-29 colon adenocarcinoma cells. Carcinogenesis 24:1361–1367Google Scholar
  54. 54.
    Hu R, Xu C, Shen G, Jain MR, Khor TO, Gopalkrishnan A, Lin W, Reddy B, Chan JY, Kong AN (2006) Gene expression profiles induced by cancer chemopreventive isothiocyanate sulforaphane in the liver of C57BL/6J mice and C57BL/6J/Nrf2 (-/-) mice. Cancer Lett 243:170–192Google Scholar
  55. 55.
    International Agency for Research on Cancer Workgroup (2004) Cruciferous vegetables, isothiocyanates and indoles, Handbooks of cancer prevention, vol 9. IARC Press, LyonGoogle Scholar
  56. 56.
    Jackson SJ, Singletary KW (2004) Sulforaphane: a naturally occurring mammary carcinoma mitotic inhibitor, which disrupts tubulin polymerization. Carcinogenesis 25:219–227Google Scholar
  57. 57.
    Jeong WS, Keum YS, Chen C, Jain MR, Shen G, Kim JH, Li W, Kong AN (2005) 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 38:167–176Google Scholar
  58. 58.
    Jiao D, Eklind KI, Choi CI, Desai DH, Amin SG, Chung FL (1994) Structure-activity relationships of isothiocyanates as mechanism-based inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone-induced lung tumorigenesis in A/J mice. Cancer Res 54:4327–4333Google Scholar
  59. 59.
    Johnson IT (2002) Glucosinolates: bioavailability and importance to health. Int J Vitam Nutr Res 72:26–31Google Scholar
  60. 60.
    Juan LJ, Shia WJ, Chen MH, Yang WM, Seto E, Lin YS, Wu CW (2000) Histone deacetylases specifically down-regulate p53-dependent gene activation. J Biol Chem 275:20436–20443Google Scholar
  61. 61.
    Keck AS, Staack R, Jeffery EH (2002) The cruciferous nitrile crambene has bioactivity similar to sulforaphane when administered to Fischer 344 rats but is far less potent in cell culture. Nutr Cancer 42:233–240Google Scholar
  62. 62.
    Kim BR, Hu R, Keum YS, Hebbar V, Shen G, Nair SS, Kong AN (2003) Effects of glutathione on antioxidant response element-mediated gene expression and apoptosis elicited by sulforaphane. Cancer Res 63:7520–7525Google Scholar
  63. 63.
    Kirk JTO, MacDonald CG (1974) 1-Cyano-3,4-epithiobutane: a major product of glucosinolate hydrolysis in seeds from certain varieties of Brassica campestris. Phytochemistry 13:2611Google Scholar
  64. 64.
    Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, Igarashi K, Yamamoto M (2004) Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 24:7130–7139Google Scholar
  65. 65.
    Krul C, Humblot C, Philippe C, Vermeulen M, van Nuenen M, Havenaar R, Rabot S (2002) Metabolism of sinigrin (2-propenyl glucosinolate) by the human colonic microflora in a dynamic in vitro large-intestinal model. Carcinogenesis 23:1009–1016Google Scholar
  66. 66.
    Kushad MM, Brown AF, Kurilich AC, Juvik JA, Klein BP, Wallig MA, Jeffery EH (1999) Variation of glucosinolates in vegetable crops of Brassica oleracea. J Agric Food Chem 47:1541–1548Google Scholar
  67. 67.
    Kwak MK, Wakabayashi N, Itoh K, Motohashi H, Yamamoto M, Kensler TW (2003) Modulation of gene expression by cancer chemopreventive dithiolethiones through the Keap1-Nrf2 pathway. Identification of novel gene clusters for cell survival. J Biol Chem 278:8135–8145Google Scholar
  68. 68.
    Kyung KH, Fleming HP, Young CT, Haney CA (1995) 1-Cyano-2,3-epithiopropane as the primary sinigrin hydrolysis product of fresh cabbage. J Food Sci 60:157–159Google Scholar
  69. 69.
    Lambrix V, Reichelt M, Mitchell-Olds T, Kliebenstein DJ, Gershenzon J (2001) The Arabidopsis epithiospecifier protein promotes the hydrolysis of glucosinolates to nitriles and influences Trichoplusia ni herbivory. Plant Cell 13:2793–2807Google Scholar
  70. 70.
    Lee SH, Kim JS, Yamaguchi K, Eling TE, Baek SJ (2005) Indole-3-carbinol and 3,3’-diindolylmethane induce expression of NAG-1 in a p53-independent manner. Biochem Biophys Res Commun 328:63–69Google Scholar
  71. 71.
    Li Y, Li X, Sarkar FH (2003) Gene expression profiles of I3C- and DIM-treated PC3 human prostate cancer cells determined by cDNA microarray analysis. J Nutr 133:1011–1019Google Scholar
  72. 72.
    Link LB, Potter JD (2004) Raw versus cooked vegetables and cancer risk. Cancer Epidemiol Biomarkers Prev 13:1422–1435Google Scholar
  73. 73.
    London SJ, Yuan J-M, Chung F-L, Gao Y-T, Coetzee GA, Ross RK, Yu MC (2000) Isothiocyanates, glutathione S-transferase M1 and T1 polymorphisms, and lung-cancer risk: a prospective study of men in Shanghai, China. Lancet 356:724–729Google Scholar
  74. 74.
    Lund E (2003) Non-nutritive bioactive constituents of plants: dietary sources and health benefits of glucosinolates. Int J Vitam Nutr Res 73:135–143Google Scholar
  75. 75.
    Ma Q, Kinneer K, Bi Y, Chan JY, Kan YW (2004) Induction of murine NAD(P)H:quinone oxidoreductase by 2,3,7,8-tetrachlorodibenzo-p-dioxin requires the CNC (cap ‘n’ collar) basic leucine zipper transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2): cross-interaction between AhR (aryl hydrocarbon receptor) and Nrf2 signal transduction. Biochem J 377:205–213Google Scholar
  76. 76.
    MacLeod AJ, Rossiter JT (1987) Degradation of 2-hydroxybut-3-enyl-glucosinolate (progoitrin). Phytochemistry 26:669–673Google Scholar
  77. 77.
    Maheo K, Morel F, Langouet S, Kramer H, Le Ferrec E, Ketterer B, Guillouzo A (1997) Inhibition of cytochromes P-450 and induction of glutathione S-transferases by sulforaphane in primary human and rat hepatocytes. Cancer Res 57:3649–3652Google Scholar
  78. 78.
    March TH, Jeffery EH, Wallig MA (1998) The cruciferous nitrile, crambene, induces rat hepatic and pancreatic glutathione S-transferases. Toxicol Sci 42:82–90Google Scholar
  79. 79.
    Matsuzaki Y, Koyama M, Hitomi T, Kawanaka M, Sakai T (2004) Indole-3-carbinol activates the cyclin-dependent kinase inhibitor p15(INK4b) gene. FEBS Lett 576:137–140Google Scholar
  80. 80.
    Matusheski NV, Jeffery EH (2001) Comparison of the bioactivity of two glucoraphanin hydrolysis products found in broccoli, sulforaphane and sulforaphane nitrile. J Agric Food Chem 49:5743–5749Google Scholar
  81. 81.
    Matusheski NV, Juvik JA, Jeffery EH (2004) Heating decreases epithiospecifier protein activity and increases sulforaphane formation in broccoli. Phytochemistry 65:1273–1281Google Scholar
  82. 82.
    Matusheski NV, Swarup R, Juvik JA, Mithen R, Bennett M, Jeffery EH (2006) Epithiospecifier protein from Broccoli (Brassica oleracea L. ssp. italica) inhibits formation of the anticancer agent sulforaphane. J Agric Food Chem 54:2069–2076Google Scholar
  83. 83.
    McDanell R, McLean AE, Hanley AB, Heaney RK, Fenwick GR (1988) Chemical and biological properties of indole glucosinolates (glucobrassicins): a review. Food Chem Toxicol 26:59–70Google Scholar
  84. 84.
    McMahon M, Itoh K, Yamamoto M, Chanas SA, Henderson CJ, McLellan LI, Wolf CR, Cavin C, Hayes JD (2001) The Cap‘n’Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res 61:3299–3307Google Scholar
  85. 85.
    McMahon M, Itoh K, Yamamoto M, Hayes JD (2003) Keap1-dependent proteasomal degradation of transcription factor Nrf2 contributes to the negative regulation of antioxidant response element-driven gene expression. J Biol Chem 278:21592–21600Google Scholar
  86. 86.
    McMahon M, Thomas N, Itoh K, Yamamoto M, Hayes JD (2006) Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a “tethering” mechanism: a two-site interaction model for the Nrf2-Keap1 complex. J Biol Chem 281:24756–24768Google Scholar
  87. 87.
    McWalter GK, Higgins LG, McLellan LI, Henderson CJ, Song L, Thornalley PJ, Itoh K, Yamamoto M, Hayes JD (2004) Transcription factor Nrf2 is essential for induction of NAD(P)H:quinone oxidoreductase 1, glutathione S-transferases, and glutamate cysteine ligase by broccoli seeds and isothiocyanates. J Nutr 134:3499S–3506SGoogle Scholar
  88. 88.
    Miao W, Hu L, Scrivens PJ, Batist G (2005) Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes. J Biol Chem 280:20340–20348Google Scholar
  89. 89.
    Mithen R (2001) Glucosinolates and their degradation products. Adv Bot Res 35:214–262Google Scholar
  90. 90.
    Mithen R, Faulkner K, Magrath R, Rose P, Williamson G, Marquez J (2003) Development of isothiocyanate-enriched broccoli, and its enhanced ability to induce phase 2 detoxification enzymes in mammalian cells. Theor Appl Genet 106:727–734Google Scholar
  91. 91.
    Morimitsu Y, Nakagawa Y, Hayashi K, Fujii H, Kumagai T, Nakamura Y, Osawa T, Horio F, Itoh K, Iida K, Yamamoto M, Uchida K (2002) A sulforaphane analogue that potently activates the Nrf2-dependent detoxification pathway. J Biol Chem 277:3456–3463Google Scholar
  92. 92.
    Myzak MC, Dashwood WM, Orner GA, Ho E, Dashwood RH (2006) Sulforaphane inhibits histone deacetylase in vivo and suppresses tumorigenesis in Apc min mice. FASEB J 20:506–508Google Scholar
  93. 93.
    Myzak MC, Hardin K, Wang R, Dashwood RH, Ho E (2006) Sulforaphane inhibits histone deacetylase activity in BPH-1, LnCaP and PC-3 prostate epithelial cells. Carcinogenesis 27:811–819Google Scholar
  94. 94.
    Myzak MC, Karplus PA, Chung FL, Dashwood RH (2004) A novel mechanism of chemoprotection by sulforaphane: inhibition of histone deacetylase. Cancer Res 64:5767–5774Google Scholar
  95. 95.
    Nakajima M, Yoshida R, Shimada N, Yamazaki H, Yokoi T (2001) Inhibition and inactivation of human cytochrome P450 isoforms by phenethyl isothiocyanate. Drug Metab Dispos 29:1110–1113Google Scholar
  96. 96.
    Nakamura Y, Morimitsu Y, Uzu T, Ohigashi H, Murakami A, Naito Y, Nakagawa Y, Osawa T, Uchida K (2000) A glutathione S-transferase inducer from papaya: rapid screening, identification and structure-activity relationship of isothiocyanates. Cancer Lett 157:193–200Google Scholar
  97. 97.
    Nakamura Y, Ohigashi H, Masuda S, Murakami A, Morimitsu Y, Kawamoto Y, Osawa T, Imagawa M, Uchida K (2000) Redox regulation of glutathione S-transferase induction by benzyl isothiocyanate: correlation of enzyme induction with the formation of reactive oxygen intermediates. Cancer Res 60:219–225Google Scholar
  98. 98.
    Nebert DW, Dalton TP, Okey AB, Gonzalez FJ (2004) Role of aryl hydrocarbon receptor-mediated induction of the CYP1 enzymes in environmental toxicity and cancer. J Biol Chem 279:23847–23850Google Scholar
  99. 99.
    Nioi P, Hayes JD (2004) Contribution of NAD(P)H:quinone oxidoreductase 1 to protection against carcinogenesis, and regulation of its gene by the Nrf2 basic-region leucine zipper and the arylhydrocarbon receptor basic helix-loop-helix transcription factors. Mutat Res 555:149–171Google Scholar
  100. 100.
    Nioi P, McMahon M, Itoh K, Yamamoto M, Hayes JD (2003) Identification of a novel Nrf2-regulated antioxidant response element (ARE) in the mouse NAD(P)H:quinone oxidoreductase 1 gene: reassessment of the ARE consensus sequence. Biochem J 374:337–348Google Scholar
  101. 101.
    Noda S, Harada N, Hida A, Fujii-Kuriyama Y, Motohashi H, Yamamoto M (2003) Gene expression of detoxifying enzymes in AhR and Nrf2 compound null mutant mouse. Biochem Biophys Res Commun 303:105–111Google Scholar
  102. 102.
    Petroski RJ, Tookey HV (1982) Interactions of thioglucoside glucosinolase and epithiospecifier protein of cruciferous plants to form 1-cyano-epithioalkanes. Phytochemistry 21:1903–1905Google Scholar
  103. 103.
    Plummer SM, Holloway KA, Manson MM, Munks RJ, Kaptein A, Farrow S, Howells L (1999) 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 18:6013–6020Google Scholar
  104. 104.
    van Poppel G, Verhoeven DT, Verhagen H, Goldbohm RA (1999) Brassica vegetables and cancer prevention. Epidemiology and mechanisms. Adv Exp Med Biol 472:159–168Google Scholar
  105. 105.
    Preobrazhenskaya MN, Bukhman VM, Korolev AM, Efimov SA (1993) Ascorbigen and other indole-derived compounds from Brassica vegetables and their analogs as anticarcinogenic and immunomodulating agents. Pharmacol Ther 60:301–313Google Scholar
  106. 106.
    Prochaska HJ, Talalay P (1988) Regulatory mechanisms of monofunctional and bifunctional anticarcinogenic enzyme inducers in murine liver. Cancer Res 48:4776–4782Google Scholar
  107. 107.
    Rahman KM, Li Y, Sarkar FH (2004) Inactivation of Akt and NF-κB plays important roles during I3C-induced apoptosis in breast cancer cells. Nutr Cancer 48:84–94Google Scholar
  108. 108.
    Rahman KW, Sarkar FH (2005) Inhibition of nuclear translocation of nuclear factor-κB contributes to 3,3′-diindolylmethane-induced apoptosis in breast cancer cells. Cancer Res 65:364–371Google Scholar
  109. 109.
    Ramsdell HS, Eaton DL (1988) Modification of aflatoxin B1 biotransformation in vitro and DNA binding in vivo by dietary broccoli in rats. J Toxicol Environ Health 25:269–284Google Scholar
  110. 110.
    Rosa EA, Heaney RK, Fenwick GR, Portas CA (1997) Glucosinolates in crop plants. Hortic Rev 19:99–215Google Scholar
  111. 111.
    Rossi A, Kapahi P, Natoli G, Takahashi T, Chen Y, Karin M, Santoro MG (2000) Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IkappaB kinase. Nature 403:103–108Google Scholar
  112. 112.
    Sanderson JT, Slobbe L, Lansbergen GWA, Safe S, van den Berg M (2001) 2,3,7,8-Tetrachlorodibenzo-p-dioxin and diindolylmethanes differentially induce cytochrome P450 1A1, 1B1 and 19 in H295R adrenocortital carcinoma cells. Toxicol Sci 61:40–48Google Scholar
  113. 113.
    Shen G, Khor TO, Hu R, Yu S, Nair S, Ho CT, Reddy BS, Huang MT, Newmark HL, Kong AN (2007) Chemoprevention of familial adenomatous polyposis by natural dietary compounds sulforaphane and dibenzoylmethane alone and in combination in ApcMin/+ mouse. Cancer Res 67:9937–9944Google Scholar
  114. 114.
    Shin S, Wakabayashi N, Misra V, Biswal S, Lee GH, Agoston ES, Yamamoto M, Kensler TW (2007) NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis. Mol Cell Biol 27:7188–7197Google Scholar
  115. 115.
    Singh SV, Herman-Antosiewicz A, Singh AV, Lew KL, Srivastava SK, Kamath R, Brown KD, Zhang L, Baskaran R (2004) Sulforaphane-induced G2/M phase cell cycle arrest involves checkpoint kinase 2-mediated phosphorylation of cell division cycle 25C. J Biol Chem 279:25813–25822Google Scholar
  116. 116.
    Singh SV, Srivastava SK, Choi S, Lew KL, Antosiewicz J, Xiao D, Zeng Y, Watkins SC, Johnson CS, Trump DL, Lee YJ, Xiao H, Herman-Antosiewicz A (2005) Sulforaphane-induced cell death in human prostate cancer cells is initiated by reactive oxygen species. J Biol Chem 280:19911–19924Google Scholar
  117. 117.
    Smith TK, Lund EK, Parker ML, Clarke RG, Johnson IT (2004) Allyl-isothiocyanate causes mitotic block, loss of cell adhesion and disrupted cytoskeletal structure in HT29 cells. Carcinogenesis 25:1409–1415Google Scholar
  118. 118.
    Song L, Morrison JJ, Botting NP, Thornalley PJ (2005) Analysis of glucosinolates, isothiocyanates and amine degradation products in vegetable extracts and blood plasm by LC-MS/MS. Anal Biochem 347:234–243Google Scholar
  119. 119.
    Srivastava SK, Singh SV (2004) Cell cycle arrest, apoptosis induction and inhibition of nuclear factor kappa B activation in anti-proliferative activity of benzyl isothiocyanate against human pancreatic cancer cells. Carcinogenesis 25:1701–1709Google Scholar
  120. 120.
    Staub RE, Feng C, Onisko B, Bailey GS, Firestone GL, Bjeldanes LF (2002) Fate of indole-3-carbinol in cultured human breast tumor cells. Chem Res Toxicol 15:101–109Google Scholar
  121. 121.
    Talalay P, Fahey JW, Healy ZR, Wehage SL, Benedict AL, Min C, Dinkova-Kostova AT (2007) Sulforaphane mobilizes cellular defenses that protect skin against damage by UV radiation. Proc Natl Acad Sci USA 104:17500–17505Google Scholar
  122. 122.
    Tang L, Zhang Y (2004) Dietary isothiocyanates inhibit the growth of human bladder carcinoma cells. J Nutr 134:2004–2010Google Scholar
  123. 123.
    Tang L, Zhang Y (2005) Mitochondria are the primary target in isothiocyanate-induced apoptosis in human bladder cancer cells. Mol Cancer Ther 4:1250–1259Google Scholar
  124. 124.
    Thimmulappa RK, Mai KH, Srisuma S, Kensler TW, Yamamoto M, Biswal S (2002) Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 62:5196–5203Google Scholar
  125. 125.
    Tijet N, Boutros PC, Moffat ID, Okey AB, Tuomisto J, Pohjanvirta R (2006) Aryl hydrocarbon receptor regulates distinct dioxin-dependent and dioxin-independent gene batteries. Mol Pharmacol 69:140–153Google Scholar
  126. 126.
    Wakabayashi N, Dinkova-Kostova AT, Holtzclaw WD, Kang MI, Kobayashi A, Yamamoto M, Kensler TW, Talalay P (2005) Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers. Proc Natl Acad Sci USA 101:2040–2045Google Scholar
  127. 127.
    Wang XJ, Hayes JD, Henderson CJ, Wolf CR (2007) Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha. Proc Natl Acad Sci USA 104:19589–19594Google Scholar
  128. 128.
    Wentzell AM, Rowe HC, Hansen BG, Ticconi C, Halkier BA, Kliebenstein DJ (2007) Linking metabolic QTLs with network and cis-eQTLs controlling biosynthetic pathways. PLoS Genet 3:1687–701Google Scholar
  129. 129.
    World Cancer Research Fund/American Institute for Cancer Research (1997) Food, nutrition and the prevention of cancer. AICR, Washington, DCGoogle Scholar
  130. 130.
    Xiao D, Johnson CS, Trump DL, Singh SV (2004) Proteasome-mediated degradation of cell division cycle 25C and cyclin-dependent kinase 1 in phenethyl isothiocyanate-induced G2-M-phase cell cycle arrest in PC-3 human prostate cancer cells. Mol Cancer Ther 3:567–575Google Scholar
  131. 131.
    Xiao D, Singh SV (2002) Phenethyl isothiocyanate-induced apoptosis in p53-deficient PC-3 human prostate cancer cell line is mediated by extracellular signal-regulated kinases. Cancer Res 62:3615–3619Google Scholar
  132. 132.
    Xiao D, Zeng Y, Choi S, Lew KL, Nelson JB, Singh SV (2005) Caspase-dependent apoptosis induction by phenethyl isothiocyanate, a cruciferous vegetable-derived cancer chemopreventive agent, is mediated by Bak and Bax. Clin Cancer Res 11:2670–2679Google Scholar
  133. 133.
    Xu C, Huang MT, Shen G, Yuan X, Lin W, Khor TO, Conney AH, Kong AN (2006) 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 66:8293–8296Google Scholar
  134. 134.
    Xu C, Shen G, Chen C, Gélinas C, Kong AN (2005) 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 24:4486–4495Google Scholar
  135. 135.
    Xu K, Thornalley PJ (2000) Studies on the mechanism of the inhibition of human leukaemia cell growth by dietary isothiocyanates and their cysteine adducts in vitro. Biochem Pharmacol 60:221–231Google Scholar
  136. 136.
    Xu K, Thornalley PJ (2001) Involvement of glutathione metabolism in the cytotoxicity of the phenethyl isothiocyanate and its cysteine conjugate to human leukaemia cells in vitro. Biochem Pharmacol 61:165–177Google Scholar
  137. 137.
    Xu K, Thornalley PJ (2001) Signal transduction activated by the cancer chemopreventive isothiocyanates: cleavage of BID protein, tyrosine phosphorylation and activation of JNK. Br J Cancer 84:670–673Google Scholar
  138. 138.
    Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9:47–59Google Scholar
  139. 139.
    Zabala M de T, Grant M, Bones AM, Bennett R, Lim YS, Kissen R, Rossiter JT (2005) Characterisation of recombinant epithiospecifier protein and its over-expression in Arabidopsis thaliana. Phytochemistry 66:859–867Google Scholar
  140. 140.
    Zhang Y (2000) Role of glutathione in the accumulation of anticarcinogenic ITCs and their glutathione conjugates by murine hepatoma cells. Carcinogenesis 21:1175–1182Google Scholar
  141. 141.
    Zhang DD, Hannink M (2003) Distinct cysteine residues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol Cell Biol 23:8137–8151Google Scholar
  142. 142.
    Zhang Y, Kensler TW, Cho CG, Posner GH, Talalay P (1994) Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates. Proc Natl Acad Sci USA 91:3147–3150Google Scholar
  143. 143.
    Zhang DD, Lo SC, Cross JV, Templeton DJ, Hannink M (2004) Keap1 is a redox-regulated substrate adaptor protein for a Cul3-dependent ubiquitin ligase complex. Mol Cell Biol 24:10941–10953Google Scholar
  144. 144.
    Zhang Z, Ober JA, Kliebenstein DJ (2006) The gene controlling the quantitative trait locus EPITHIOSPECIFIER MODIFIER1 alters glucosinolate hydrolysis and insect resistance in Arabidopsis. Plant Cell 18:1524–1536Google Scholar
  145. 145.
    Zhang J, Svehlíková V, Bao Y, Howie AF, Beckett GJ, Williamson G (2003) Synergy between sulforaphane and selenium in the induction of thioredoxin reductase 1 requires both transcriptional and translational modulation. Carcinogenesis 24:497–503Google Scholar
  146. 146.
    Zhang Y, Talalay P (1998) Mechanism of differential potencies of isothiocyanates as inducers of anticarcinogenic Phase 2 enzymes. Cancer Res 58:4632–4639Google Scholar
  147. 147.
    Zhang Y, Talalay P, Cho CG, Posner GH (1992) A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc Natl Acad Sci USA 89:2399–2403Google Scholar
  148. 148.
    Zhang Y, Tang L, Gonzalez V (2003) Selected isothiocyanates rapidly induce growth inhibition of cancer cells. Mol Cancer Ther 2:1045–1052Google Scholar
  149. 149.
    Zhou W, Lo SC, Liu JH, Hannink M, Lubahn DB (2007) ERRbeta: a potent inhibitor of Nrf2 transcriptional activity. Mol Cell Endocrinol 278:52–62Google Scholar

Copyright information

© Spinger 2008

Authors and Affiliations

  • John D. Hayes
    • 1
    Email author
  • Michael O. Kelleher
    • 1
  • Ian M. Eggleston
    • 2
  1. 1.Biomedical Research Centre, Ninewells Hospital and Medical SchoolUniversity of DundeeDundeeScotland, UK
  2. 2.Dept. of Pharmacy and PharmacologyUniversity of BathBathUK

Personalised recommendations