Relative cytotoxic potencies and cell death mechanisms of α1-adrenoceptor antagonists in prostate cancer cell lines

Abstract

BACKGROUND Some α1-adrenoceptor antagonists possess anti-cancer actions that are independent of α1-adrenoceptors and the aim of these studies was to assess the relative cytotoxic potencies of α1-adrenoceptor antagonists and the mechanisms involved in these actions.

METHODS PC-3 and LNCap human prostate cancer cells were exposed to α1-adrenoceptor antagonists (0.01–100 μM) and cell survival assessed after 24–72 hr. The levels of apoptosis, autophagy and stress related proteins were also determined.

RESULTS The 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 (30 μM) altered the expression of several cell stress-related proteins: elevating phospho-p38α 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-1α decreasing in LNCap cells but not PC-3, while ADAMTS1 was increased in PC-3 cells only.

CONCLUSIONS Prazosin 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. © 2016 Wiley Periodicals, Inc.