Abstract 1741: Mitotic catastrophe and inhibition of growth of Castration Resistant Prostate Cancers by a dietary agent Withaferin-A.

Abstract

Abstract Cell cycle deregulation has been strongly associated with the pathogenesis of prostate cancer. It has been well documented that an increased expression of cell cycle regulatory proteins (cyclin D1-25%, cyclin A-35% and cyclin B-75%) have been reported in castration resistant prostate cancer (CRPC) cells, when compared to normal prostate tissue. There are several cell cycle regulators undergoing clinical trials targeting either G0/G1 or G2/M phase of cell cycle to inhibit the growth of many cancers including prostate cancer. We previously published that Withaferin-A (WA); a natural compound effectively suppresses CRPC growth both in vitro and in vivo. Hence, in this study we intend to determine the cell-cycle regulatory potential of this agent on CRPC cells. WA caused irreversible G2/M arrest in both CRPC cell lines (PC-3 and C4-2B) till 72 hours . Phosphorylation of cdc2 by Wee1 and Myt1 is an important step to maintain an inactive state of cdc2 that lead to G2/M cell cycle arrest. Additionally decreased levels of phosphorylated Wee-1 and Myt1 followed by increase in the phosphorylation status of cdc2 (Tyr15 and Thr14) supported the G2/M phase of cell cycle arrest in both CRPC cell lines. Further checkpoint kinase assay showed increased activity in WA treated CRPC cells suggesting activation of CDC25C that activates cyclinB/cdc2 complex .We also observed down regulation of several cyclin family proteins in both CRPC cells. Altogether, these results conclude d that WA inhibits CRPC cell growth by induction of G2/M cell cycle arrest, highlighting the potential of WA could be a therapeutic agent for CRPC. Currently, we are investigating the effect of WA on cell cycle markers using both xenograft and TRAMP models. The outcome of our study may enable bringing WA to the mainstream of medicine for prevention and/or therapy for CRPC. Citation Format: Aditi Shirish Vadodkar, Suman Suman, Ram Vinod Roy, Chendil Damodaran. Mitotic catastrophe and inhibition of growth of Castration Resistant Prostate Cancers by a dietary agent Withaferin-A. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1741. doi:10.1158/1538-7445.AM2013-1741