Development of cancer is a long-term and multistep process which comprises initiation, progression, and promotion stages of carcinogenesis. Conceivably, it can be targeted and interrupted along these different stages. In this context, many naturally occurring dietary compounds from our daily consumption of fruits and vegetables have been shown to possess cancer preventive effects. Phenethyl isothiocyanate (PEITC) and sulforaphane (SFN) are two of the most widely investigated isothiocyanates from the crucifers. Both have been found to be very potent chemopreventive agents in numerous animal carcinogenesis models as well as cell culture models. They exert their chemopreventive effects through regulation of diverse molecular mechanisms. In this review, we will discuss the molecular targets of PEITC and SFN potentially involved in cancer chemoprevention. These include the regulation of drug-metabolizing enzymes phase I cytochrome P450s and phase II metabolizing enzymes. In addition, the signaling pathways including Nrf2–Keap 1, anti-inflammatory NFκB, apoptosis, and cell cycle arrest as well as some receptors will also be discussed. Furthermore, we will also discuss the similarities and their potential differences in the regulation of these molecular targets by PEITC and SFN.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Subscribe to journal
Immediate online access to all issues from 2019. Subscription will auto renew annually.
Tax calculation will be finalised during checkout.
Antioxidant/electrophile response element
Extracellular signal-regulated kinase
Inhibitor of apoptosis
Inducible nitric oxide synthase
Inhibitor of kappa B
c-Jun N-terminal kinase
Mitogen-activated protein kinase
Nuclear factor kappa B
Receptor activator of NFκB ligand
Reactive oxygen species
Reverse-transcription polymerase chain reaction
Tumor necrosis factor
Wattenberg LW. Inhibition of chemical carcinogen-induced pulmonary neoplasia by butylated hydroxyanisole. J Natl Cancer Inst. 1973;50:1541–4.
Wattenberg LW. Chemoprevention of cancer. Cancer Res. 1985;45:1–8.
Chen C, Kong AN. Dietary cancer-chemopreventive compounds: from signaling and gene expression to pharmacological effects. Trends Pharmacol Sci. 2005;26(6):318–26.
Smart RC. Chemical carcinogenesis. In: Hodgson E, editor. A textbook of modern toxicology. 3rd ed. Hoboken: Wiley; 2004. p. 240–2.
Weinstein IB. Cancer prevention: recent progress and future opportunities. Cancer Res. 1991;51:5080–5.
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.
Hanausek M, Walaszek Z, Slaga TJ. Detoxifying cancer causing agents to prevent cancer. Integr Cancer Ther. 2003;2:139.
Klaunig JE, Kamendulis LM. The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol. 2004;44:239–67.
Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441:431–6.
Jeong WS, Kong AN. Chemopreventive functions of isothiocyanates. Drug News Perspect. 2005;18:445–51.
IARC. Cruciferous vegetables, isothiocyanates and indoles. Lyon: IARC; 2004.
Kliebenstein DJ, Kroymann J, Mitchell-Olds T. The glucosinolate–myrosinase system in an ecological and evolutionary context. Curr Opin Plant Biol. 2005;8:264–71.
Hayes JD, Kelleher MO, Eggleston IM. The cancer chemopreventive actions of phytochemicals derived from glucosinolates. Eur J Nutr. 2008;47(Suppl 2):73–88.
Chung FL, Morse MA, Eklind KI, Lewis J. Quantitation of human uptake of the anticarcinogen phenethyl isothiocyanate after a watercress meal. Cancer Epidemiol Biomarkers Prev. 1992;1:383–8.
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.
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.
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.
Ji Y, Kuo Y, Morris ME. Pharmacokinetics of dietary phenethyl isothiocyanate in rats. Pharm Res. 2005;22:1658–66.
Wogan GN, Hecht SS, Felton JS, Conney AH, Loeb LA. Environmental and chemical carcinogenesis. Semin Cancer Biol. 2004;14:473–86.
Gross-Steinmeyer K, Stapleton PL, Liu F, Tracy JH, Bammler TK, Quigley SD, et al. Phytochemical-induced changes in gene expression of carcinogen-metabolizing enzymes in cultured human primary hepatocytes. Xenobiotica. 2004;34:619–32.
Nakajima M, Yoshida R, Shimada N, Yamazaki H, Yokoi T. Inhibition and inactivation of human cytochrome P450 isoforms by phenethyl isothiocyanate. Drug Metab Dispos. 2001;29:1110–3.
Mahéo K, Morel F, Langouët 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.
Barcelo S, Gardiner JM, Gescher A, Chipman JK. CYP2E1-mediated mechanism of anti-genotoxicity of the broccoli constituent sulforaphane. Carcinogenesis. 1996;17:277–82.
Meunier B, de Visser SP, Shaik S. Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes. Chem Rev. 2004;104:3947–80.
Kensler TW. Chemoprevention by inducers of carcinogen detoxication enzymes. Environ Health Perspect. 1997;105(Suppl 4):965–70.
Pool-Zobel B, Veeriah S, Böhmer FD. Modulation of xenobiotic metabolising enzymes by anticarcinogens – focus on glutathione S-transferases and their role as targets of dietary chemoprevention in colorectal carcinogenesis. Mutat Res. 2005;591:74–92.
Saracino MR, Lampe JW. Phytochemical regulation of UDP-glucuronosyltransferases: implications for cancer prevention. Nutr Cancer. 2007;59:121–41.
Vasiliou V, Ross D, Nebert DW. Update of the NAD(P)H:quinone oxidoreductase (NQO) gene family. Hum Genomics. 2006;2(5):329–35.
Dingley KH, Ubick EA, Chiarappa-Zucca ML, Nowell S, Abel S, Ebeler SE, et al. Effect of dietary constituents with chemopreventive potential on adduct formation of a low dose of the heterocyclic amines PhIP and IQ and phase II hepatic enzymes. Nutr Cancer. 2003;46:212–21.
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.
Konsue N, Ioannides C. Tissue differences in the modulation of rat cytochromes P450 and phase II conjugation systems by dietary doses of phenethyl isothiocyanate. Food Chem Toxicol. 2008;46:3677–83.
Xu C, Yuan X, Pan Z, Shen G, Kim JH, Yu S, et al. Mechanism of action of isothiocyanates: the induction of ARE-regulated genes is associated with activation of ERK and JNK and the phosphorylation and nuclear translocation of Nrf2. Mol Cancer Ther. 2006;5:1918–26.
Cheung KL, Khor TO, Kong AN. Synergistic effect of combination of phenethyl isothiocyanate and sulforaphane or curcumin and sulforaphane in the inhibition of inflammation. Pharm Res. 2009;26:224–31.
Dinkova-Kostova AT, Fahey JW, 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.
Bacon JR, Williamson G, Garner RC, Lappin G, Langouët S, Bao Y. Sulforaphane and quercetin modulate PhIP-DNA adduct formation in human HepG2 cells and hepatocytes. Carcinogenesis. 2003;24:1903–11.
Munday R, Munday CM. Induction of phase II detoxification enzymes in rats by plant-derived isothiocyanates: comparison of allyl isothiocyanate with sulforaphane and related compounds. J Agric Food Chem. 2004;52:1867–71.
Matusheski NV, Jeffery EH. Comparison of the bioactivity of two glucoraphanin hydrolysis products found in broccoli, sulforaphane and sulforaphane nitrile. J Agric Food Chem. 2001;49:5743–9.
Jones SB, Brooks JD. Modest induction of phase 2 enzyme activity in the F-344 rat prostate. BMC Cancer. 2006;6:62.
Prestera T, Talalay P. Electrophile and antioxidant regulation of enzymes that detoxify carcinogens. Proc Natl Acad Sci USA. 1995;92:8965–9.
Jiang ZQ, Chen C, Yang B, Hebbar V, Kong AN. Differential responses from seven mammalian cell lines to the treatments of detoxifying enzyme inducers. Life Sci. 2003;72:2243–53.
Basten GP, Bao Y, Williamson G. Sulforaphane and its glutathione conjugate but not sulforaphane nitrile induce UDP-glucuronosyl transferase (UGT1A1) and glutathione transferase (GSTA1) in cultured cells. Carcinogenesis. 2002;23:1399–404.
Svehlíková V, Wang S, Jakubíková J, Williamson G, Mithen R, Bao Y. Interactions between sulforaphane and apigenin in the induction of UGT1A1 and GSTA1 in CaCo-2 cells. Carcinogenesis. 2004;25:1629–37.
Brooks JD, Paton VG, Vidanes G. Potent induction of phase 2 enzymes in human prostate cells by sulforaphane. Cancer Epidemiol Biomarkers Prev. 2001;10:949–54.
Lin W, Wu RT, Wu T, Khor TO, Wang H, Kong AN. Sulforaphane suppressed LPS-induced inflammation in mouse peritoneal macrophages through Nrf2 dependent pathway. Biochem Pharmacol. 2008;76:967–73.
Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009;284:13291–5.
Itoh K, Wakabayashi N, Katoh Y, Ishii T, O'Connor T, Yamamoto M. Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes Cells. 2003;8:379–91.
Kong AN, Owuor E, Yu R, Hebbar V, Chen C, Hu R, et al. Induction of xenobiotic enzymes by the MAP kinase pathway and the antioxidant or electrophile response element (ARE/EpRE). Drug Metab Rev. 2001;33:255–71.
Chen YR, Han J, Kori R, Kong AN, Tan TH. Phenylethyl isothiocyanate induces apoptotic signaling via suppressing phosphatase activity against c-Jun N-terminal kinase. J Biol Chem. 2002;277:39334–42.
Rushmore TH, Kong AN. Pharmacogenomics, regulation and signaling pathways of phase I and II drug metabolizing enzymes. Curr Drug Metab. 2002;3:481–90.
Keum YS, Owuor ED, Kim BR, Hu R, Kong AN. Involvement of Nrf2 and JNK1 in the activation of antioxidant responsive element (ARE) by chemopreventive agent phenethyl isothiocyanate (PEITC). Pharm Res. 2003;20:1351–6.
Sun Z, Huang Z, Zhang DD. Phosphorylation of Nrf2 at multiple sites by MAP kinases has a limited contribution in modulating the Nrf2-dependent antioxidant response. PLoS One. 2009;4:e6588.
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.
Hong F, Freeman ML, Liebler DC. Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chem Res Toxicol. 2005;18:1917–26.
Banning A, Deubel S, Kluth D, Zhou Z, Brigelius-Flohé R. The GI-GPx gene is a target for Nrf2. Mol Cell Biol. 2005;25:4914–23.
Rose P, Won YK, Ong CN, Whiteman M. Beta-phenylethyl and 8-methylsulphinyloctyl isothiocyanates, constituents of watercress, suppress LPS induced production of nitric oxide and prostaglandin E2 in RAW 264.7 macrophages. Nitric Oxide. 2005;12:237–43.
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.
Xu C, Shen G, Chen C, Gélinas 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.
Heiss E, Herhaus C, Klimo K, Bartsch H, Gerhäuser C. Nuclear factor kappa B is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms. J Biol Chem. 2001;276:32008–15.
Heiss E, Gerhäuser C. Time-dependent modulation of thioredoxin reductase activity might contribute to sulforaphane-mediated inhibition of NF-kappaB binding to DNA. Antioxid Redox Signal. 2005;7:1601–11.
Kim SJ, Kang SY, Shin HH, Choi HS. Sulforaphane inhibits osteoclastogenesis by inhibiting nuclear factor-kappaB. Mol Cells. 2005;20:364–70.
Woo KJ, Kwon TK. Sulforaphane suppresses lipopolysaccharide-induced cyclooxygenase-2 (COX-2) expression through the modulation of multiple targets in COX-2 gene promoter. Int Immunopharmacol. 2007;7:1776–83.
Reed JC. Apoptosis-based therapies. Nat Rev Drug Discov. 2002;1:111–21.
Park SY, Kim GY, Bae SJ, Yoo YH, Choi YH. Induction of apoptosis by isothiocyanate sulforaphane in human cervical carcinoma HeLa and hepatocarcinoma HepG2 cells through activation of caspase-3. Oncol Rep. 2007;18:181–7.
Choi S, Lew KL, Xiao H, Herman-Antosiewicz A, Xiao D, Brown CK, et al. D, L-Sulforaphane-induced cell death in human prostate cancer cells is regulated by inhibitor of apoptosis family proteins and Apaf-1. Carcinogenesis. 2007;28:151–62.
Fimognari C, Lenzi M, Sciuscio D, Cantelli-Forti G, Hrelia P. Cell-cycle specificity of sulforaphane-mediated apoptosis in Jurkat T-leukemia cells. In Vivo. 2007;21:377–80.
Singh SV, 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.
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.
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.
Xiao D, Johnson CS, Trump DL, Singh SV. 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. 2004;3:567–75.
Mi L, Chung FL. Binding to protein by isothiocyanates: a potential mechanism for apoptosis induction in human nonsmall lung cancer cells. Nutr Cancer. 2008;60(Suppl 1):12–20.
Mi L, Xiao Z, Hood BL, Dakshanamurthy S, Wang X, Govind S, et al. Covalent binding to tubulin by isothiocyanates. A mechanism of cell growth arrest and apoptosis. J Biol Chem. 2008;283:22136–46.
Hu J, Straub J, Xiao D, Singh SV, Yang HS, Sonenberg N, et al. Phenethyl isothiocyanate, a cancer chemopreventive constituent of cruciferous vegetables, inhibits cap-dependent translation by regulating the level and phosphorylation of 4E-BP1. Cancer Res. 2007;67:3569–73.
Hasegawa T, Nishino H, Iwashima A. Isothiocyanates inhibit cell cycle progression of HeLa cells at G2/M phase. Anticancer Drugs. 1993;4:273–9.
Zhang Y, Tang L, Gonzalez V. Selected isothiocyanates rapidly induce growth inhibition of cancer cells. Mol Cancer Ther. 2003;2:1045–52.
Pappa G, Bartsch H, Gerhäuser C. Biphasic modulation of cell proliferation by sulforaphane at physiologically relevant exposure times in a human colon cancer cell line. Mol Nutr Food Res. 2007;51:977–84.
Cheung KL, Khor TO, Yu S, Kong AN. PEITC induces G1 cell cycle arrest on HT-29 cells through the activation of p38 MAPK signaling pathway. AAPS J. 2008;10:277–81.
Visanji JM, Duthie SJ, Pirie L, Thompson DG, Padfield PJ. Dietary isothiocyanates inhibit Caco-2 cell proliferation and induce G2/M phase cell cycle arrest, DNA damage, and G2/M checkpoint activation. J Nutr. 2004;134:3121–6.
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 phosphorylation of cell division cycle 25C. J Biol Chem. 2004;279:25813–22.
Wang LG, Liu XM, Fang Y, Dai W, Chiao FB, Puccio GM, et al. De-repression of the p21 promoter in prostate cancer cells by an isothiocyanate via inhibition of HDACs and c-Myc. Int J Oncol. 2008;33:375–80.
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.
Beklemisheva AA, Feng J, Yeh YA, Wang LG, Chiao JW. Modulating testosterone stimulated prostate growth by phenethyl isothiocyanate via Sp1 and androgen receptor down-regulation. Prostate. 2007;67:863–70.
Ramirez MC, Singletary K. Regulation of estrogen receptor alpha expression in human breast cancer cells by sulforaphane. J Nutr Biochem. 2009;20:195–201.
Matsui TA, Sowa Y, Yoshida 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.
Mastrangelo L, Cassidy A, Mulholland F, Wang W, Bao Y. Serotonin receptors, novel targets of sulforaphane identified by proteomic analysis in Caco-2 cells. Cancer Res. 2008;68:5487–91.
We thank all the members in Dr. Tony Kong’s lab for their help in the discussion and preparation of this manuscript. We also thank Drs. Siwang Yu (Beijing University, People Republic of China) and Young-Sam Keum (Hormel Institute, Austin, MN) for their helpful discussions. This study was supported in part by Institutional Funds and by R01-CA073674, R01-CA094828 and R01-CA118947 to Dr Ah-Ng Tony Kong from the National Institutes of Health (NIH).
Guest Editor: Marilyn E. Morris
About this article
Cite this article
Cheung, K.L., Kong, AN. Molecular Targets of Dietary Phenethyl Isothiocyanate and Sulforaphane for Cancer Chemoprevention. AAPS J 12, 87–97 (2010). https://doi.org/10.1208/s12248-009-9162-8
- dietary cancer chemoprevention
- phenethyl isothiocyanate