Epidemiological studies continue to support the premise that dietary intake of cruciferous vegetables may be protective against the risk of various types of malignancies including cancer of the prostate. Anti-carcinogenic effect of cruciferous vegetables is attributed to organic isothiocyanates (ITCs), such as phenethyl-ITC (PEITC), that are highly effective in affording protection against chemically induced cancers in animal models. More recent studies have indicated that PEITC can cause G2/M phase cell cycle arrest and/or apoptosis induction to suppress proliferation of cancer cells in culture, but the mechanism of PEITC-induced cell death is not fully defined. The present study was undertaken to determine the role of Bcl-xL in regulation of apoptosis induction by PEITC using PC-3 human prostate cancer cells as a model, and to determine the effect of oral administration of PEITC on PC-3 xenograft growth in athymic mice. The viability of PC-3 cells was reduced significantly in the presence of PEITC in a concentration-dependent manner as revealed by sulforhodamine B assay. Structure-activity analysis indicated a marked effect of alkyl chain length on activity of PEITC against proliferation of PC-3 cells. Ectopic expression of Bcl-xL, whose protein level is reduced markedly on treatment of PC-3 cells with PEITC, conferred partial yet statistically significant protection against PEITC-induced apoptosis in PC-3 cells at higher drug concentrations (10 and 20 μM) as revealed by analysis of cytoplasmic histone associated DNA fragmentation, sub-diploid cells, and cleavage of caspase-3 and poly(ADP-ribose)polymerase. Oral administration of 12 μmol PEITC/day (Monday through Friday) significantly inhibited PC-3 xenograft growth in athymic mice. For instance, 31 days after initiation of the therapy, the average tumor volume in control mice was approximately 1.9-fold higher (P < 0.05) compared with mice treated with 12 μmol PEITC/day. The PEITC-mediated inhibition of PC-3 xenograft growth in vivo was associated with induction of Bax and cleavage of Bid. These results suggest that PEITC, which is a constituent of many edible cruciferous vegetables such as watercress, may be used to delay onset and/or progression of prostate cancer. This study was supported in part by NCI grants CA101753 and CA115498.
[Proc Amer Assoc Cancer Res, Volume 47, 2006]