Phenethyl isothiocyanate, a constituent of processed cruciferous vegetables, inhibits growth of PC-3 human prostate cancer xenografts in vivo in association with induction of Bax and Bid.

Abstract

5601

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.