Chemoprevention of Prostate Cancer by Phenethyl Isothiocyanate

Abstract : There are epidemiological conclusions for potential prevention of prostate cancer with the intake of cruciferous vegetables. The responsible dietary factors were not identified. Now, we have demonstrated that isothiocyanates, such as phenethyl isothiocyanate (PEITC), from these vegetables inhibits growth of prostate cancer cells by targeting cell cycle regulators, like up-regulating p21. Analyses of the mechanism indicated that it involves a regulation at the epigenetic level. PEITC was found to be a dual inhibitor of histone deacetylases (HDACs) and aberrant CpG island methylation. Due to HDAC inhibition, PEITC modifies histones for transcription competent chromatins to activate p21. We demonstrated, for the first time, that PEITC reverses hypermethylation and reactivates GSTP1 that is silenced in prostate tumor. The silencing of GSTP1 occurs in the vast majority of clinical tumors and is a risk factor. We also determined that PEITC represses androgen receptor (AR) via down-regulation of Sp1 and increase protein degradation. The bioassay showed that PEITC regulates the activity of testosterone, via down-regulation of AR. Thus we have demonstrated several molecular targets relevant for inhibiting prostate carcinogenesis by PEITC. They include repressing AR, inhibiting HDACs, inhibiting aberrant CpG island methylation, and activating cell cycle regulators. The chemopreventive mechanisms of isothiocyanates revealed.