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  • Title: Relative cytotoxic potencies and cell death mechanisms of α1 -adrenoceptor antagonists in prostate cancer cell lines.
    Author: Forbes A, Anoopkumar-Dukie S, Chess-Williams R, McDermott C.
    Journal: Prostate; 2016 Jun; 76(8):757-66. PubMed ID: 26880388.
    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.
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