Relative cytotoxic potency and cell death mechanisms of α1-adrenoceptor antagonists on prostate cancer cell lines — ASN Events
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Relative cytotoxic potency and cell death mechanisms of α1-adrenoceptor antagonists on prostate cancer cell lines (#216)

Amanda Forbes 1 , Russ Chess-Williams 1 , Shailendra Anoopkumar-Dukie 2 , Catherine McDermott 1
  1. Faculty of Health Sciences and Medicine, Bond University, Gold Coast, QLD
  2. School of Pharmacy, Griffith University, Gold Coast, QLD

 Alpha1-adrenoceptor antagonists increase apoptosis in the prostates of men with benign prostatic hyperplasia, while retrospective studies have shown that these agents also protect men against developing prostate cancer. The aim of this study was to assess the relative cytotoxic potencies and the cell death mechanisms (apoptosis and autophagy) of various α1-adrenoceptor antagonists against prostate cancer. Human castration-sensitive LNCaP and castration-resistant PC-3 prostate cancer cells were exposed to prazosin, doxazosin, alfuzosin, terazosin, tamsulosin (0.01-100 μM) and also the autophagy inhibitor 3-methyladenine (3-MA, 5 mM) for 24-72 h. Resazurin reduction assay was used as an indicator of cell viability, caspase-3 activity as an index of apoptosis and a CytoID autophagy detection kit to quantify change in autophagic activity. All α1-adrenoceptor antagonists tested, except tamsulosin, resulted in a time- and concentration-dependent reduction of LNCaP and PC-3 survival. Following 72h treatment, the most potent cytotoxic drug was prazosin in LNCaP (mean IC50 with 95% CI = 13 μM [8.6-19.6]) and PC-3 cells (IC50=21.3 μM [19.5-23.3]). Doxazosin was slightly less potent than prazosin (LNCaP IC50=17.2 μM [10.9-27.1] and PC-3 IC50=23.3 μM [21.0-25.7]). The relative cytotoxic potencies were found to be: prazosin > doxazosin > terazosin > alfuzosin > tamsulosin. Prazosin (30 μM) treatment resulted in a significant increase in autophagy and apoptosis (P<0.05). Prazosin-induced cytotoxicity and caspase-3 activity was enhanced following inhibition of autophagy in LNCaP cells (P<0.001). In contrast, autophagy inhibition partially protected PC-3 cells from prazosin-induced apoptotic cell death (P<0.05). In conclusion, these findings demonstrate that α1-adrenoceptor antagonists have cytotoxic actions, with prazosin exhibiting the greatest apoptotic potential. Prazosin-induced autophagy was found to play opposing roles, contributing to LNCaP survival and to PC-3 cell death. These findings suggest the anti-cancer activity of prazosin may be useful in mitigating early and advance stage prostate cancer.

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