Abstract
Sulforaphane (SF) is a phytochemical that displays both anticarcinogenic and anticancer activity. SF modulates many cancer-related events, including susceptibility to carcinogens, cell death, cell cycle, angiogenesis, invasion and metastasis. We review its discovery and development as a cancer chemopreventive agent with the intention of encouraging further research on this important compound and facilitating the identification and development of new phytochemicals for cancer prevention.
References
Tsuda H, Ohshima Y, Nomoto H, Fujita K, Matsuda E, Iigo M, et al. Cancer prevention by natural compounds. Drug Metab Pharmacokinet 2004; 19: 245–63.
Park E J, Pezzuto J M . Botanicals in cancer chemoprevention. Cancer Metastasis Rev 2002; 21: 231–55.
D'Incalci M, Steward WP, Gescher A J . Use of cancer chemo-preventive phytochemicals as antineoplastic agents. Lancet Oncol 2005; 6: 899–904.
Dorai T, Aggarwal B B . Role of chemopreventive agents in cancer therapy. Cancer Lett 2004; 215: 129–40.
Fimognari C, Hrelia P . Sulforaphane as a promising molecule for fighting cancer. Mutat Res 2007; 635: 90–104.
Myzak MC, Dashwood R H . Chemoprotection by sulforaphane: keep one eye beyond Keap1. Cancer Lett 2006; 233: 208–18.
Fahey J W, Talalay P . Antioxidant functions of sulforaphane: a potent inducer of Phase II detoxication enzymes. Food Chem Toxicol 1999; 37: 973–79.
Zhang Y . Cancer chemoprevention with sulforaphane, a dietary isothiocyanate. In: Bao Y, Fenwick G R, editors. Phytochemicals in health and disease. New York: Marcel Dekker, 2004. p 121–41.
Juge N, Mithen R F, Traka M . Molecular basis for chemopre-vention by sulforaphane: a comprehensive review. Cell Mol Life Sci 2007; 64: 1105–27.
Gamet-Payrastre L . Signaling pathways and intracellular targets of sulforaphane mediating cell cycle arrest and apoptosis. Curr Cancer Drug Targets 2006; 6: 135–45.
Prochaska HJ, Santamaria AB . Direct measurement of NAD(P) H:quinone reductase from cells cultured in microtiter wells: a screening assay for anticarcinogenic enzyme inducers. Anal Biochem 1988; 169: 328–36.
Fahey J W, Dinkova-Kostova AT, Stephenson KK, Talalay P . The “Prochaska” microtiter plate bioassay for inducers of NQO1. Methods Enzymol 2004; 382: 243–58.
Talalay P . Chemoprotection against cancer by induction of phase 2 enzymes. Biofactors 2000; 12: 5–11.
Talalay P . Mechanisms of induction of enzymes that protect against chemical carcinogenesis. Adv Enzyme Regul 1989; 28: 237–50.
IARC handbooks of cancer prevention. Vol 8. Fruit and vegetables. Vainio H, Bianchini F, editors. Lyon: IARC Press, 2003.
Prochaska HJ, Santamaria AB, Talalay P . Rapid detection of inducers of enzymes that protect against carcinogens. Proc Natl Acad Sci USA 1992; 89: 2394–8.
Fahey JW, Zhang Y, Talalay P . Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc Natl Acad Sci USA 1997; 94: 10367–72.
Zhang Y, Talalay P, Cho CG, Posner GH . A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proc Natl Acad Sci U S A, 1992; 89: 2399–403.
Procháska Z . Isolation of sulforaphane from hoary cress (Lepidium draba L.). Collect Czech Chem Commun 1959; 24: 2429–30.
Procháska Z, Komersová I . Isolation of sulforaphane from Cardaria draba and its antimicrobial effect. Cesk Farm 1995; 8: 373–6.
Fahey JW, Zalcmann AT, Talalay P . The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry 2001; 56: 5–51.
Fenwick GR, Heaney RK, Mullin WJ . Glucosinolates and their breakdown products in food and food plants. Crit Rev Food Sci Nutr 1983; 18: 123–201.
Zhang Y, Talalay P . Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanisms. Cancer Res 1994; 54: 1976s–81s.
Posner GH, Cho CG, Green J V, Zhang Y, Talalay P . Design and synthesis of bifunctional isothiocyanate analogs of sulforaphane: correlation between structure and potency as inducers of anticarcinogenic detoxication enzymes. J Med Chem 1994; 37: 170–6.
Moriarty RM, Naithani R, Kosmeder J, Prakash O . Cancer chemopreventive activity of sulforamate derivatives. Eur J Med Chem 2006; 41: 121–4.
Gerhauser C, You M, Liu J, Moriarty RM, Hawthorne M, Mehta RG, et al. Cancer chemopreventive potential of sulforamate, a novel analogue of sulforaphane that induces phase 2 drug-metabolizing enzymes. Cancer Res 1997; 57: 272–8.
Rabot S, Nugon-Baudon L, Raibaud P, Szylit O . Rape-seed meal toxicity in gnotobiotic rats: influence of a whole human faecal flora or single human strains of Escherichia coli and Bacteroides vulgatus. Br J Nutr 1993; 70: 323–31.
Shapiro TA, Fahey JW, Wade KL, Stephenson KK, Talalay P . Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables. Cancer Epidemiol Biomarkers Prev 1998; 7: 1091–100.
Getahun SM, Chung FL . Conversion of glucosinolates to isothiocyanates in humans after ingestion of cooked watercress. Cancer Epidemiol Biomarkers Prev 1999; 8: 447–51.
Bheemreddy RM, Jeffery EH . The Metabolic Fate of Purified Glucoraphanin in F344 Rats. J Agric Food Chem 2007; 55: 2861–6.
Jin Y, Wang M, Rosen RT, Ho CT . Thermal degradation of sulforaphane in aqueous solution. J Agric Food Chem 1999; 47: 3121–3.
Matusheski NV, Juvik JA, Jeffery EH . Heating decreases epithiospecifier protein activity and increases sulforaphane formation in broccoli. Phytochemistry 2004; 65: 1273–81.
Kensler TW, Chen JG, Egner PA, Fahey JW, Jacobson LP, Stephenson KK, et al . Effects of glucosinolate-rich broccoli sprouts on urinary levels of aflatoxin-DNA adducts and phenan-threne tetraols in a randomized clinical trial in He Zuo township, Qidong, People's Republic of China. Cancer Epidemiol Biomarkers Prev 2005; 14: 2605–13.
Tang L, Zhang Y, Jobson HE, Li J, Stephenson KK, Wade KL, et al. Potent activation of mitochondria-mediated apoptosis and arrest in S and M phases of cancer cells by a broccoli sprout extract. Mol Cancer Ther 2006; 5: 935–44.
Faulkner K, Mithen R, Williamson G . Selective increase of the potential anticarcinogen 4-methylsulphinylbutyl glucosinolate in broccoli. Carcinogenesis 1998; 19: 605–9.
Shapiro TA, Fahey JW, Wade KL, Stephenson KK, Talalay P . Chemoprotective glucosinolates and isothiocyanates of broccoli sprouts: metabolism and excretion in humans. Cancer Epidemiol Biomarkers Prev 2001; 10: 501–8.
Kim D J, Han BS, Ahn B, Hasegawa R, Shirai T, Ito N, et al. Enhancement by indole-3-carbinol of liver and thyroid gland neoplastic development in a rat medium-term multiorgan car-cinogenesis model. Carcinogenesis 1997; 18: 377–81.
Bjeldanes LF, Kim JY, Grose KR, Bartholomew JC, Bradfield CA . 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 1991; 88: 9543–7.
Zhang Y, Kensler TW, Cho CG, Posner GH, Talalay P . Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates. Proc Natl Acad Sci USA 1994; 91: 3147–50.
Dinkova-Kostova AT, Fahey J W, Wade KL, Jenkins SN, Shapiro TA, Fuchs EJ, et al. Induction of the Phase 2 Response in Mouse and Human Skin by Sulforaphane-containing Broccoli Sprout Extracts. Cancer Epidemiol Biomarkers Prev 2007; 16: 847–51.
Zhang Y, Munday R, Jobson HE, Munday CM, Lister C, Wilson P, et al. Induction of GST and NQO1 in cultured bladder cells and in the urinary bladders of rats by an extract of broccoli (Brassica oleracea italica) sprouts. J Agric Food Chem 2006; 54: 9370–6.
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.
Hu R, Xu C, Shen G, Jain MR, Khor TO, Gopalkrishnan A, et al. Gene expression profiles induced by cancer chemopreventive isothiocyanate sulforaphane in the liver of C57BL/6J mice and C57BL/6J/Nrf2 (-/-) mice. Cancer Lett 2006; 243: 170–192.
Zhang Y, Gonzalez V, Xu MJ . Expression and regulation of glutathione S-transferase P1-1 in cultured human epidermal cells. J Dermatol Sci 2002; 30: 205–14.
Wu L, Juurlink BH . The impaired glutathione system and its up-regulation by sulforaphane in vascular smooth muscle cells from spontaneously hypertensive rats. J Hypertens 2001; 19: 1819–25.
Cornblatt BS, Ye L, Dinkova-Kostova AT, Erb M, Fahey JW, Singh NK, et al. Preclinical and Clinical Evaluation of Sulforaphane for Chemoprevention in the Breast. Carcinogen-esis 2007; 28: 1485–90.
Bacon JR, Plumb GW, Howie A F, Beckett G J, Wang W, Bao Y . Dual action of sulforaphane in the regulation of thioredoxin reductase and thioredoxin in human HepG2 and Caco-2 cells. J Agric Food Chem 2007; 55: 1170–6.
Wang W, Wang S, Howie AF, Beckett GJ, Mithen R, Bao Y . Sulforaphane, erucin, and iberin up-regulate thioredoxin reduc-tase 1 expression in human MCF-7 cells. J Agric Food Chem 2005; 53: 1417–21.
Basten GP, Bao Y, Williamson G . Sulforaphane and its glu-tathione conjugate but not sulforaphane nitrile induce UDP-glucuronosyl transferase (UGT1A1) and glutathione transferase (GSTA1) in cultured cells. Carcinogenesis 2002; 23: 1399–404.
Wang M, Li YQ, Zhong N, Chen J, Xu XQ, Yuan MB . Induction of uridine 5′-diphosphate-glucuronosyltransferase gene expression by sulforaphane and its mechanism: experimental study in human colon cancel cells. Zhonghua Yi Xue Za Zhi 2005; 85: 819–24. Chinese.
Zhang Y, Gordon GB . A strategy for cancer prevention: stimulation of the Nrf2-ARE signaling pathway. Mol Cancer Ther 2004; 3: 885–93.
Dinkova-Kostova AT, Holtzclaw WD, Kensler TW . The role of Keap1 in cellular protective responses. Chem Res Toxicol 2005; 18: 1779–91.
Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, et al. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA 2002; 99: 11908–13.
Eggler AL, Liu G, Pezzuto JM, van Breemen RB, Mesecar AD . 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 2005; 102: 10070–5.
Yu R, Lei W, Mandlekar S, Weber MJ, Der CJ, Wu J, et al. Role of a mitogen-activated protein kinase pathway in the induction of phase II detoxifying enzymes by chemicals. J Biol Chem 1999; 274: 27545–52.
Yu R, Mandlekar S, Lei W, Fahl WE, Tan TH, Kong AN . p38 mitogen-activated protein kinase negatively regulates the induction of phase II drug-metabolizing enzymes that detoxify carcinogens. J Biol Chem 2000; 275: 2322–7.
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.
Xu C, Huang MT, Shen G, Yuan X, Lin W, Khor TO, et al. Inhibition of 7,12-Dimethylbenz(a)anthracene-Induced Skin Tu-morigenesis in C57BL/6 Mice by Sulforaphane Is Mediated by Nuclear Factor E2-Related Factor 2. Cancer Res 2006; 66: 8293–6.
Hu R, Hebbar V, Kim BR, Chen C, Winnik B, Buckley B, et al. In vivo pharmacokinetics and regulation of gene expression profiles by isothiocyanate sulforaphane in the rat. J Pharmacol Exp Ther 2004; 310: 263–71.
Barcelo S, Gardiner JM, Gescher A, Chipman J K . CYP2E1-mediated mechanism of anti-genotoxicity of the broccoli constituent sulforaphane. Carcinogenesis 1996; 17: 277–82.
Barcelo S, Mace K, Pfeifer AM, Chipman JK . Production of DNA strand breaks by N-nitrosodimethylamine and 2-amino-3-methylimidazo[4,5-f]quinoline in THLE cells expressing human CYP isoenzymes and inhibition by sulforaphane. Mutat Res 1998; 402: 111–20.
Bacon JR, Williamson G, Garner RC, Lappin G, Langouet S, Bao Y . Sulforaphane and quercetin modulate PhIP-DNA adduct formation in human HepG2 cells and hepatocytes. Carcinogenesis 2003; 24: 1903–11.
Conaway CC, Jiao D, Chung FL . Inhibition of rat liver cyto-chrome P450 isozymes by isothiocyanates and their conjugates: a structure-activity relationship study. Carcinogenesis 1996; 17: 2423–7.
Maheo K, Morel F, Langouet S, Kramer H, Le Ferrec E, Ketterer B, Guillouzo A . Inhibition of cytochromes P-450 and induction of glutathione S-transferases by sulforaphane in primary human and rat hepatocytes. Cancer Res 1997; 57: 3649–3652.
Yoxall V, Kentish P, Coldham N, Kuhnert N, Sauer MJ, Ioannides C . Modulation of hepatic cytochromes P450 and phase II enzymes by dietary doses of sulforaphane in rats: Implications for its chemopreventive activity. Int J Cancer 2005; 117: 356–62.
Langouet S, Furge LL, Kerriguy N, Nakamura K, Guillouzo A, Guengerich FP . Inhibition of human cytochrome P450 enzymes by 1,2-dithiole-3-thione, oltipraz and its derivatives, and sulforaphane. Chem Res Toxicol 2000; 13: 245–52.
Paolini M, Perocco P, Canistro D, Valgimigli L, Pedulli GF, Iori R, et al. Induction of cytochrome P450, generation of oxidative stress and in vitro cell-transforming and DNA-damaging activities by glucoraphanin, the bioprecursor of the chemopreventive agent sulforaphane found in broccoli. Carcinogenesis 2004; 25: 61–67.
Tang L, Zhang Y . Dietary isothiocyanates inhibit the growth of human bladder carcinoma cells. J Nutr 2004; 134: 2004–10.
Shan Y, Sun C, Zhao X, Wu K, Cassidy A, Bao Y . Effect of sulforaphane on cell growth, G(0)/G(1) phase cell progression and apoptosis in human bladder cancer T24 cells. Int J Oncol 2006; 29: 883–8.
Fimognari C, Nusse M, Cesari R, Iori R, Cantelli-Forti G, Hrelia P . Growth inhibition, cell-cycle arrest and apoptosis in human T-cell leukemia by the isothiocyanate sulforaphane. Carcinogenesis 2002; 23: 581–6.
Fimognari C, Nusse M, Berti F, Iori R, Cantelli-Forti G, Hrelia P . Sulforaphane modulates cell cycle and apoptosis in transformed and non-transformed human T lymphocytes. Ann N Y Acad Sci 2003; 1010: 393–8.
Karmakar S, Weinberg MS, Banik NL, Patel SJ, Ray SK . Activation of multiple molecular mechanisms for apoptosis in human malignant glioblastoma T98G and U87MG cells treated with sulforaphane. Neuroscience 2006; 141: 1265–80.
Pledgie-Tracy A, Sobolewski MD, Davidson NE . Sulforaphane induces cell type-specific apoptosis in human breast cancer cell lines. Mol Cancer Ther 2007; 6: 1013–21.
Gamet-Payrastre L, Li P, Lumeau S, Cassar G, Dupont MA, Chevolleau S, et al. Sulforaphane, a naturally occurring isothiocyanate, induces cell cycle arrest and apoptosis in HT29 human colon cancer cells. Cancer Res 2000; 60: 1426–33.
Jakubikova J, Sedlak J, Mithen R, Bao Y . Role of PI3K/Akt and MEK/ERK signaling pathways in sulforaphane- and erucin-induced phase II enzymes and MRP2 transcription, G2/M arrest and cell death in Caco-2 cells. Biochem Pharmacol 2005; 69: 1543–52.
Chaudhuri D, Orsulic S, Ashok BT . Antiproliferative activity of sulforaphane in Akt-overexpressing ovarian cancer cells. Mol Cancer Ther 2007; 6: 334–45.
Pham NA, Jacobberger JW, Schimmer AD, Cao P, Gronda M, Hedley DW . The dietary isothiocyanate sulforaphane targets pathways of apoptosis, cell cycle arrest, and oxidative stress in human pancreatic cancer cells and inhibits tumor growth in severe combined immunodeficient mice. Mol Cancer Ther 2004; 3: 1239–48.
Chiao JW, Chung FL, Kancherla R, Ahmed T, Mittelman A, Conaway CC . Sulforaphane and its metabolite mediate growth arrest and apoptosis in human prostate cancer cells. Int J Oncol 2002; 20: 631–6.
Singh AV, Xiao D, Lew KL, Dhir R, Singh SV . Sulforaphane induces caspase-mediated apoptosis in cultured PC-3 human prostate cancer cells and retards growth of PC-3 xenografts in vivo. Carcinogenesis 2004; 25: 83–90.
Misiewicz I, Skupinska K, Kasprzycka-Guttman T . Sulforaphane and 2-oxohexyl isothiocyanate induce cell growth arrest and apoptosis in L-1210 leukemia and ME-18 melanoma cells. Oncol Rep 2003; 10: 2045–50.
Tang L, Zhang Y . Mitochondria are the primary target in isothiocyanate-induced apoptosis in human bladder cancer cells. Mol Cancer Ther 2005; 4: 1250–9.
Matsui TA, Sowa Y, Yoshid T, Murata H, Horinaka M, Wakada M, et al. Sulforaphane enhances TRAIL-induced apoptosis through the induction of DR5 expression in human osteosarcoma cells. Carcinogenesis 2006; 27: 1768–77.
Kim H, Kim EH, Eom YW, Kim WH, Kwon TK, Lee SJ, et al. Sulforaphane sensitizes tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant hepatoma cells to TRAIL-induced apoptosis through reactive oxygen species-mediated up-regulation of DR5. Cancer Res 2006; 66: 1740–50.
Singh S V, Srivastava SK, Choi S, Lew KL, Antosiewicz J, Xiao D, et al. Sulforaphane-induced cell death in human prostate cancer cells is initiated by reactive oxygen species. J Biol Chem 2005; 280: 19911–24.
Herman-Antosiewicz A, Johnson DE, Singh SV . Sulforaphane causes autophagy to inhibit release of cytochrome C and apoptosis in human prostate cancer cells. Cancer Res 2006; 66: 5828–35.
Wang L, Liu D, Ahmed T, Chung FL, Conaway C, Chiao JW . Targeting cell cycle machinery as a molecular mechanism of sulforaphane in prostate cancer prevention. Int J Oncol 2004; 24: 187–92.
Parnaud G, Li P, Cassar G, Rouimi P, Tulliez J, Combaret L, et al. Mechanism of sulforaphane-induced cell cycle arrest and apoptosis in human colon cancer cells. Nutr Cancer 2004; 48: 198–206.
Jackson SJ, Singletary KW . Sulforaphane inhibits human MCF-7 mammary cancer cell mitotic progression and tubulin polymerization. J Nutr 2004; 134: 2229–36.
Xu C, Shen G, Yuan X, Kim JH, Gopalkrishnan A, Keum YS, et al. ERK and JNK signaling pathways are involved in the regulation of activator protein 1 and cell death elicited by three isothiocyanates in human prostate cancer PC-3 cells. Carcinogenesis 2006; 27: 437–45.
Cho SD, Li G, Hu H, Jiang C, Kang KS, Lee YS, et al. Involvement of c-Jun N-terminal kinase in G2/M arrest and caspase-mediated apoptosis induced by sulforaphane in DU145 prostate cancer cells. Nutr Cancer 2005; 52: 213–24.
Choi S, Singh SV . Bax and Bak are required for apoptosis induction by sulforaphane, a cruciferous vegetable-derived cancer chemopreventive agent. Cancer Res 2005; 65: 2035–43.
Myzak MC, Karplus PA, Chung FL, Dashwood RH . A novel mechanism of chemoprotection by sulforaphane: inhibition of histone deacetylase. Cancer Res 2004; 64: 5767–74.
Singh SV, Herman-Antosiewicz A, Singh AV, Lew KL, Srivastava SK, Kamath R, et al. Sulforaphane-induced G2/M phase cell cycle arrest involves checkpoint kinase 2-mediated phosphory-lation of cell division cycle 25C. J Biol Chem 2004; 279: 25813–22.
Fimognari C, Sangiorgi L, Capponcelli S, Nusse M, Fontanesi S, Berti F, et al. A mutated p53 status did not prevent the induction of apoptosis by sulforaphane, a promising anti-cancer drug. Invest New Drugs 2005; 23: 195–203.
Shen G, Xu C, Chen C, Hebbar V, Kong AN . p53-independent G1 cell cycle arrest of human colon carcinoma cells HT-29 by sulforaphane is associated with induction of p21CIP1 and inhibition of expression of cyclin D1. Cancer Chemother Pharmacol 2006; 57: 317–27.
Fimognari C, Nusse M, Lenzi M, Sciuscio D, Cantelli-Forti G, Hrelia P . Sulforaphane increases the efficacy of doxorubicin in mouse fibroblasts characterized by p53 mutations. Mutat Res 2006; 601: 92–101.
Fimognari C, Lenzi M, Sciuscio D, Cantelli-Forti G, Hrelia P . Combination of doxorubicin and sulforaphane for reversing doxo-rubicin-resistant phenotype in mouse fibroblasts with p53Ser220 mutation. Ann N Y Acad Sci 2007; 1095: 62–9.
Bertl E, Bartsch H, Gerhauser C . Inhibition of angiogenesis and endothelial cell functions are novel sulforaphane-mediated mechanisms in chemoprevention. Mol Cancer Ther 2006; 5: 575–85.
Asakage M, Tsuno NH, Kitayama J, Tsuchiya T, Yoneyama S, Yamada J, et al. Sulforaphane induces inhibition of human umbilical vein endothelial cells proliferation by apoptosis. Angiogenesis 2006; 9: 83–91.
Rose P, Huang Q, Ong CN, Whiteman M . Broccoli and watercress suppress matrix metalloproteinase-9 activity and invasiveness of human MDA-MB-231 breast cancer cells. Toxicol Appl Pharmacol 2005; 209: 105–13.
Westermarck J, Kahari VM . Regulation of matrix metallopro-teinase expression in tumor invasion. FASEB J 1999; 13: 781–92.
Jackson SJ, Singletary KW, Venema RC . Sulforaphane suppresses angiogenesis and disrupts endothelial mitotic progression and microtubule polymerization. Vascul Pharmacol 2007; 46: 77–84.
Thejass P, Kuttan G . Antimetastatic activity of Sulforaphane. Life Sci 2006; 78: 3043–50.
Thejass P, Kuttan G . Augmentation of natural killer cell and antibody-dependent cellular cytotoxicity in BALB/c mice by sulforaphane, a naturally occurring isothiocyanate from broccoli through enhanced production of cytokines IL-2 and IFN-gamma. Immunopharmacol Immunotoxicol 2006; 28: 443–57.
Heiss E, Herhaus C, Klimo K, Bartsch H, Gerhauser C . Nuclear factor kappa B is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms. J Biol Chem 2001; 276: 32008–15.
Ritz SA, Wan J, Diaz-Sanchez D . Sulforaphane-stimulated phase II enzyme induction inhibits cytokine production by airway epithelial cells stimulated with diesel extract. Am J Physiol Lung Cell Mol Physiol 2007; 292: L33–9.
Xu C, Shen G, Chen C, Gelinas C, Kong AN . Suppression of NF-kappaB and NF-kappaB-regulated gene expression by sulfora-phane and PEITC through IkappaBalpha, IKK pathway in human prostate cancer PC-3 cells. Oncogene 2005; 24: 4486–95.
Niture SK, Velu CS, Smith QR, Bhat G J, Srivenugopal KS . Increased expression of the MGMT repair protein mediated by cysteine prodrugs and chemopreventative natural products in human lymphocytes and tumor cell lines. Carcinogenesis 2007; 28: 378–89.
Lee SK, Song L, Mata-Greenwood E, Kelloff GJ, Steele VE, Pezzuto JM . Modulation of in vitro biomarkers of the carcinogenic process by chemopreventive agents. Anticancer Res 1999; 19: 35–44.
Payen L, Courtois A, Loewert M, Guillouzo A, Fardel O . Reactive oxygen species-related induction of multidrug resistance-associated protein 2 expression in primary hepatocytes exposed to sulforaphane. Biochem Biophys Res Commun 2001; 282: 257–63.
Nabekura T, Kamiyama S, Kitagawa S . Effects of dietary chemo-preventive phytochemicals on P-glycoprotein function. Biochem Biophys Res Commun 2005; 327: 866–70.
Haristoy X, Angioi-Duprez K, Duprez A, Lozniewski A . Efficacy of sulforaphane in eradicating Helicobacter pylori in human gastric xenografts implanted in nude mice. Antimicrob Agents Chemother 2003; 47: 3982–4.
Chung FL, Conaway CC, Rao CV, Reddy BS . Chemoprevention of colonic aberrant crypt foci in Fischer rats by sulforaphane and phenethyl isothiocyanate. Carcinogenesis 2000; 21: 2287–91.
Conaway CC, Wang CX, Pittman B, Yang YM, Schwartz JE, Tian D, et al. 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 2005; 65: 8548–57.
Kuroiwa Y, Nishikawa A, Kitamura Y, Kanki K, Ishii Y, Umemura T, et al. Protective effects of benzyl isothiocyanate and sulforaphane but not resveratrol against initiation of pancreatic car-cinogenesis in hamsters. Cancer Lett 2006; 241: 275–80.
Gills JJ, Jeffery EH, Matusheski NV, Moon RC, Lantvit DD, Pezzuto JM . Sulforaphane prevents mouse skin tumorigenesis during the stage of promotion. Cancer Lett 2006; 236: 72–9.
Dinkova-Kostova AT, Jenkins SN, Fahey JW, Ye L, Wehage SL, Liby KT, et al. Protection against UV-light-induced skin car-cinogenesis in SKH-1 high-risk mice by sulforaphane-containing broccoli sprout extracts. Cancer Lett 2006; 240: 243–52.
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.
Su LK, Kinzler KW, Vogelstein B, Preisinger AC, Moser AR, Luongo C, et al. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science 1992; 256: 668–70.
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.
Shapiro TA, Fahey JW, Dinkova-Kostova AT, Holtzclaw WD, Stephenson KK, Wade KL, et al. Safety, tolerance, and metabolism of broccoli sprout glucosinolates and isothiocyanates: a clinical phase I study. Nutr Cancer 2006; 55: 53–62.
Kassahun K, Davis M, Hu P, Martin B, Baillie T . Biotransformation of the naturally occurring isothiocyanate sulforaphane in the rat: identification of phase I metabolites and glutathione conjugates. Chem Res Toxicol 1997; 10: 1228–33.
Ye L, Dinkova-Kostova AT, Wade KL, Zhang Y, Shapiro TA, Talalay P . Quantitative determination of dithiocarbamates in human plasma, serum, erythrocytes and urine: pharmacokinetics of broccoli sprout isothiocyanates in humans. Clin Chim Acta 2002; 316: 43–53.
Petri N, Tannergren C, Holst B, Mellon FA, Bao Y, Plumb G W, et al. Absorption/metabolism of sulforaphane and quercetin, and regulation of phase II enzymes, in human jejunum in vivo. Drug Metab Dispos 2003; 31: 805–13.
Gasper AV, Al-Janobi A, Smith JA, Bacon JR, Fortun P, Atherton C, et al. Glutathione S-transferase M1 polymorphism and metabolism of sulforaphane from standard and high-glucosinolate broccoli. Am J Clin Nutr 2005; 82: 1283–91.
Al Janobi AA, Mithen RF, Gasper AV, Shaw PN, Middleton RJ, Ortori CA, et al. Quantitative measurement of sulforaphane, iberin and their mercapturic acid pathway metabolites in human plasma and urine using liquid chromatography-tandem electro-spray ionisation mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 2006; 844: 223–34.
Conaway CC, Krzeminski J, Amin S, Chung FL . Decomposition rates of isothiocyanate conjugates determine their activity as inhibitors of cytochrome p450 enzymes. Chem Res Toxicol 2001; 14: 1170–6.
Tang L, Li G, Song L, Zhang Y . The principal urinary metabolites of dietary isothiocyanates, N-acetylcysteine conjugates, elicit the same anti-proliferative response as their parent compounds in human bladder cancer cells. Anticancer Drugs 2006; 17: 297–305.
Hwang ES, Jeffery EH . Induction of quinone reductase by sulforaphane and sulforaphane N-acetylcysteine conjugate in murine hepatoma cells. J Med Food 2005; 8: 198–203.
Zhang Y, Talalay P . Mechanism of differential potencies of isothiocyanates as inducers of anticarcinogenic Phase 2 enzymes. Cancer Res 1998; 58: 4632–9.
Zhang Y . Role of glutathione in the accumulation of anticarcinogenic isothiocyanates and their glutathione conjugates by murine hepatoma cells. Carcinogenesis 2000; 21: 1175–82.
Zhang Y . Molecular mechanism of rapid cellular accumulation of anticarcinogenic isothiocyanates. Carcinogenesis 2001; 22: 425–31.
Zhang Y, Callaway EC . High cellular accumulation of sulphoraphane, a dietary anticarcinogen, is followed by rapid transporter-mediated export as a glutathione conjugate. Biochem J 2002; 364: 301–7.
Callaway EC, Zhang Y, Chew W, Chow HH . Cellular accumulation of dietary anticarcinogenic isothiocyanates is followed by transporter-mediated export as dithiocarbamates. Cancer Lett 2004; 204: 23–31.
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Studies carried out in the authors' laboratory were supported in part by US Public Service Grants CA80962 and CA100623.
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Zhang, Y., Tang, L. Discovery and development of sulforaphane as a cancer chemopreventive phytochemical. Acta Pharmacol Sin 28, 1343–1354 (2007). https://doi.org/10.1111/j.1745-7254.2007.00679.x
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DOI: https://doi.org/10.1111/j.1745-7254.2007.00679.x
Keywords
- chemoprevention
- phytochemical
- isothiocyanate
- sulforaphane
- broccoli
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