Relative cytotoxic potencies and cell death mechanisms of 1-adrenoceptor antagonists in prostate cancer cell lines

BACKGROUNDSome (1)-adrenoceptor antagonists possess anti-cancer actions that are independent of (1)-adrenoceptors and the aim of these studies was to assess the relative cytotoxic potencies of (1)-adrenoceptor antagonists and the mechanisms involved in these actions. METHODSPC-3 and LNCap human prostate cancer cells were exposed to (1)-adrenoceptor antagonists (0.01-100M) and cell survival assessed after 24-72hr. The levels of apoptosis, autophagy and stress related proteins were also determined. RESULTSThe relative cytotoxic potency order was prazosin=doxazosin>terazosin=silodosin=alfuzosin>tamsulosin on both cell types, but LNCaP cells were significantly more sensitive to these effects than PC-3 cells. Prazosin and doxazosin increased levels of apoptotsis and autophagy in both cell lines, and activated EphA2 receptors in PC-3 cells. Autophagy contributed to survival of LNCaP, but promoted cell death in PC-3 cells. Treatment with prazosin (30M) altered the expression of several cell stress-related proteins: elevating phospho-p38 and reducing S6 kinase in both cell lines. Surprisingly some proteins were differentially affected in the two prostate cancer cell lines: Akt and p27 increasing and HIF-1 decreasing in LNCap cells but not PC-3, while ADAMTS1 was increased in PC-3 cells only. CONCLUSIONSPrazosin and doxazosin demonstrated cytotoxic actions on both castration-resistant PC-3 and androgen-sensitive LNCap prostate cancer cells. The mechanisms involved included changes in a number of proliferation and apoptosis regulatory proteins. The role of autophagy depended on the cell type, but contributed to cell death in PC3 cells. Prostate 76:757-766, 2016. (c) 2016 Wiley Periodicals, Inc.