Skip to main content

Molecular Targets of Dietary Phenethyl Isothiocyanate and Sulforaphane for Cancer Chemoprevention

Abstract

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Abbreviations

ARE/EpRE:

Antioxidant/electrophile response element

COX-2:

Cyclooxygenase-2

CYP:

Cytochrome P450

DME:

Drug-metabolizing enzyme

ERK:

Extracellular signal-regulated kinase

GST:

Glutathione-S-transferase

HO-1:

Heme-oxygenase 1

IAP:

Inhibitor of apoptosis

iNOS:

Inducible nitric oxide synthase

ITCs:

Isothiocyanates

IκB:

Inhibitor of kappa B

IκK:

IκB kinase

JNK:

c-Jun N-terminal kinase

MAPK:

Mitogen-activated protein kinase

NFκB:

Nuclear factor kappa B

NQO:

NAD(P)H:quinone oxidoreductase

Nrf2:

NF-E2-related factor-2

PEITC:

Penethyl isothiocyanate

RANKL:

Receptor activator of NFκB ligand

ROS:

Reactive oxygen species

RT-PCR:

Reverse-transcription polymerase chain reaction

SFN:

Sulforaphane

TNF:

Tumor necrosis factor

UGT:

UDP-glucuronosyltransferase

References

  1. 1.

    Wattenberg LW. Inhibition of chemical carcinogen-induced pulmonary neoplasia by butylated hydroxyanisole. J Natl Cancer Inst. 1973;50:1541–4.

    CAS  PubMed  Google Scholar 

  2. 2.

    Wattenberg LW. Chemoprevention of cancer. Cancer Res. 1985;45:1–8.

    Article  CAS  PubMed  Google Scholar 

  3. 3.

    Chen C, Kong AN. Dietary cancer-chemopreventive compounds: from signaling and gene expression to pharmacological effects. Trends Pharmacol Sci. 2005;26(6):318–26.

    Article  PubMed  Google Scholar 

  4. 4.

    Smart RC. Chemical carcinogenesis. In: Hodgson E, editor. A textbook of modern toxicology. 3rd ed. Hoboken: Wiley; 2004. p. 240–2.

    Google Scholar 

  5. 5.

    Weinstein IB. Cancer prevention: recent progress and future opportunities. Cancer Res. 1991;51:5080–5.

    Google Scholar 

  6. 6.

    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.

    CAS  PubMed  Google Scholar 

  7. 7.

    Hanausek M, Walaszek Z, Slaga TJ. Detoxifying cancer causing agents to prevent cancer. Integr Cancer Ther. 2003;2:139.

    Article  CAS  PubMed  Google Scholar 

  8. 8.

    Klaunig JE, Kamendulis LM. The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol. 2004;44:239–67.

    Article  CAS  PubMed  Google Scholar 

  9. 9.

    Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441:431–6.

    Article  CAS  PubMed  Google Scholar 

  10. 10.

    Jeong WS, Kong AN. Chemopreventive functions of isothiocyanates. Drug News Perspect. 2005;18:445–51.

    Article  PubMed  Google Scholar 

  11. 11.

    IARC. Cruciferous vegetables, isothiocyanates and indoles. Lyon: IARC; 2004.

    Google Scholar 

  12. 12.

    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.

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Hayes JD, Kelleher MO, Eggleston IM. The cancer chemopreventive actions of phytochemicals derived from glucosinolates. Eur J Nutr. 2008;47(Suppl 2):73–88.

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    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.

    CAS  PubMed  Google Scholar 

  15. 15.

    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.

    CAS  PubMed  Google Scholar 

  16. 16.

    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.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    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.

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Ji Y, Kuo Y, Morris ME. Pharmacokinetics of dietary phenethyl isothiocyanate in rats. Pharm Res. 2005;22:1658–66.

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Wogan GN, Hecht SS, Felton JS, Conney AH, Loeb LA. Environmental and chemical carcinogenesis. Semin Cancer Biol. 2004;14:473–86.

    Article  CAS  PubMed  Google Scholar 

  20. 20.

    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.

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    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.

    CAS  PubMed  Google Scholar 

  22. 22.

    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.

    PubMed  Google Scholar 

  23. 23.

    Barcelo S, Gardiner JM, Gescher A, Chipman JK. CYP2E1-mediated mechanism of anti-genotoxicity of the broccoli constituent sulforaphane. Carcinogenesis. 1996;17:277–82.

    Article  CAS  PubMed  Google Scholar 

  24. 24.

    Meunier B, de Visser SP, Shaik S. Mechanism of oxidation reactions catalyzed by cytochrome p450 enzymes. Chem Rev. 2004;104:3947–80.

    Article  CAS  PubMed  Google Scholar 

  25. 25.

    Kensler TW. Chemoprevention by inducers of carcinogen detoxication enzymes. Environ Health Perspect. 1997;105(Suppl 4):965–70.

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    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.

    CAS  PubMed  Google Scholar 

  27. 27.

    Saracino MR, Lampe JW. Phytochemical regulation of UDP-glucuronosyltransferases: implications for cancer prevention. Nutr Cancer. 2007;59:121–41.

    CAS  PubMed  Google Scholar 

  28. 28.

    Vasiliou V, Ross D, Nebert DW. Update of the NAD(P)H:quinone oxidoreductase (NQO) gene family. Hum Genomics. 2006;2(5):329–35.

    CAS  PubMed  Google Scholar 

  29. 29.

    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.

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    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.

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    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.

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    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.

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    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.

    Article  CAS  PubMed  Google Scholar 

  34. 34.

    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.

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    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.

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    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.

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    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.

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Jones SB, Brooks JD. Modest induction of phase 2 enzyme activity in the F-344 rat prostate. BMC Cancer. 2006;6:62.

    Article  PubMed  Google Scholar 

  39. 39.

    Prestera T, Talalay P. Electrophile and antioxidant regulation of enzymes that detoxify carcinogens. Proc Natl Acad Sci USA. 1995;92:8965–9.

    Article  CAS  PubMed  Google Scholar 

  40. 40.

    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.

    Article  CAS  PubMed  Google Scholar 

  41. 41.

    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.

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    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.

    Article  PubMed  Google Scholar 

  43. 43.

    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.

    CAS  PubMed  Google Scholar 

  44. 44.

    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.

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    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.

    Article  CAS  PubMed  Google Scholar 

  46. 46.

    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.

    Article  CAS  PubMed  Google Scholar 

  47. 47.

    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.

    Article  CAS  PubMed  Google Scholar 

  48. 48.

    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.

    Article  CAS  PubMed  Google Scholar 

  49. 49.

    Rushmore TH, Kong AN. Pharmacogenomics, regulation and signaling pathways of phase I and II drug metabolizing enzymes. Curr Drug Metab. 2002;3:481–90.

    Article  CAS  PubMed  Google Scholar 

  50. 50.

    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.

    Article  CAS  PubMed  Google Scholar 

  51. 51.

    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.

    Article  PubMed  Google Scholar 

  52. 52.

    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.

    Article  CAS  PubMed  Google Scholar 

  53. 53.

    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.

    Article  CAS  PubMed  Google Scholar 

  54. 54.

    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.

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    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.

    Article  CAS  PubMed  Google Scholar 

  56. 56.

    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.

    Article  CAS  PubMed  Google Scholar 

  57. 57.

    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.

    Article  CAS  PubMed  Google Scholar 

  58. 58.

    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.

    Article  CAS  PubMed  Google Scholar 

  59. 59.

    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.

    Article  CAS  PubMed  Google Scholar 

  60. 60.

    Kim SJ, Kang SY, Shin HH, Choi HS. Sulforaphane inhibits osteoclastogenesis by inhibiting nuclear factor-kappaB. Mol Cells. 2005;20:364–70.

    CAS  PubMed  Google Scholar 

  61. 61.

    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.

    Article  CAS  PubMed  Google Scholar 

  62. 62.

    Reed JC. Apoptosis-based therapies. Nat Rev Drug Discov. 2002;1:111–21.

    Article  CAS  PubMed  Google Scholar 

  63. 63.

    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.

    CAS  PubMed  Google Scholar 

  64. 64.

    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.

    Article  CAS  PubMed  Google Scholar 

  65. 65.

    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.

    CAS  PubMed  Google Scholar 

  66. 66.

    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.

    Article  CAS  PubMed  Google Scholar 

  67. 67.

    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.

    Article  PubMed  Google Scholar 

  68. 68.

    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.

    Article  CAS  PubMed  Google Scholar 

  69. 69.

    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.

    CAS  PubMed  Google Scholar 

  70. 70.

    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.

    Article  CAS  PubMed  Google Scholar 

  71. 71.

    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.

    Article  CAS  PubMed  Google Scholar 

  72. 72.

    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.

    Article  CAS  PubMed  Google Scholar 

  73. 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.

    Article  CAS  PubMed  Google Scholar 

  74. 74.

    Zhang Y, Tang L, Gonzalez V. Selected isothiocyanates rapidly induce growth inhibition of cancer cells. Mol Cancer Ther. 2003;2:1045–52.

    CAS  PubMed  Google Scholar 

  75. 75.

    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.

    Article  CAS  PubMed  Google Scholar 

  76. 76.

    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.

    Article  CAS  PubMed  Google Scholar 

  77. 77.

    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.

    CAS  PubMed  Google Scholar 

  78. 78.

    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.

    Article  CAS  PubMed  Google Scholar 

  79. 79.

    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.

    CAS  PubMed  Google Scholar 

  80. 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.

    Article  CAS  PubMed  Google Scholar 

  81. 81.

    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.

    Article  CAS  PubMed  Google Scholar 

  82. 82.

    Ramirez MC, Singletary K. Regulation of estrogen receptor alpha expression in human breast cancer cells by sulforaphane. J Nutr Biochem. 2009;20:195–201.

    Article  CAS  PubMed  Google Scholar 

  83. 83.

    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.

    Article  CAS  PubMed  Google Scholar 

  84. 84.

    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.

    Article  CAS  PubMed  Google Scholar 

  85. 85.

    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.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgement

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).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Ah-Ng Kong.

Additional information

Guest Editor: Marilyn E. Morris

Rights and permissions

Reprints and Permissions

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

Download citation

Key words

  • dietary cancer chemoprevention
  • NF-kB
  • Nrf2
  • phenethyl isothiocyanate
  • sulforaphane