Diallyl trisulfide (DATS) is a promising cancer chemopreventive constituent of processed garlic. The DATS administration not only inhibits chemical carcinogenesis in experimental rodents but also affords significant protection against cancer development in a transgenic mouse model of prostate cancer. We have shown previously that DATS inhibits growth of human prostate cancer cells by causing apoptosis, but the mechanism of cell death is not fully understood. Inhibitor of apoptosis (IAP) family proteins has emerged as critical regulators of apoptosis. In this study, we investigated the role of IAP family proteins in DATS-mediated apoptosis using PC-3 (an androgen-independent cell line lacking functional p53) and LNCaP (an androgen-responsive cell line with wild-type p53) human prostate cancer cells as a model. Protein level of X-linked inhibitor of apoptosis (XIAP) was decreased markedly upon 8-hour treatment with 20 and 40 µmol/L DATS in both PC-3 and LNCaP cells but this effect was somewhat reversible at the 16-hour time point. The DATS-mediated suppression of XIAP protein was not due to a decrease in its mRNA expression. Instead, the DATS-mediated decline in XIAP protein level was reversed in the presence of proteasomal inhibitor MG132. Ectopic expression of XIAP in PC-3 cells conferred modest yet statistically significant protection against DATS-induced apoptosis. Interestingly, the DATS treatment resulted in a marked and sustained induction of survivin protein in both cell types. The DATS-mediated induction of survivin protein correlated with an increase in its mRNA levels in PC-3 and LNCaP cells. RNA interference of survivin resulted in increased apoptosis even in absence of DATS treatment in PC-3 cells. However, the DATS-induced apoptosis was only marginally affected by siRNA knockdown of survivin. Inhibition of prostate cancer development in Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) mice by p.o. gavage with DATS correlated with a statistically significant decrease in the levels of XIAP protein and induction of survivin protein expression. The results of the present study indicate differential effect of DATS treatment on IAP family protein expression, which may serve as biomarkers of DATS response. This study was supported by the USPHS grant 2 RO1 CA113363-06, awarded by the National Cancer Institute.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3688. doi:10.1158/1538-7445.AM2011-3688