Effects of alpha₁-adrenoceptor (α₁-AR) antagonists on cell proliferation and apoptosis in the prostate: Therapeutic implications in prostatic disease

BACKGROUND. Benign prostate hyperplasia (BPH) and prostate cancer established that disruption of the molecular mechanisms that regulate apoptosis and cell proliferation among the stromal and epithelial cell populations, may underlie the neoplastic development that characterizes the aging gland. This work examined the effects of selected alpha₁-adrenoceptor (α1-AR) antagonists (blockers) on cellular dynamics to determine whether induction of apoptosis or inhibition of proliferation could contribute to the overall clinical profile. METHODS. Our efforts were focused on investigating whether α₁-AR antagonists of two different chemical classes affect prostate pathophysiology via mechanisms other than smooth muscle contraction. In in vitro experiments, the two clinically used quinazoline α₁-adrenoceptor antagonists terazosin and doxazosin and the chemically-distinct sulphonamide, tamsulosin, were examined for effects on prostatic tumor growth, by inhibiting cell proliferation and/or inducing apoptosis. RESULTS. Our findings suggest that α₁-AR antagonists, terazosin and doxazosin, suppress prostatic growth by inducing apoptosis in a dose-dependent manner and without affecting cell proliferation. Tamsulosin exerted no effect on prostate cancer cell growth. The apoptotic effect of terazosin and doxazosin appears to be independent of the α1-adrenoceptor block. CONCLUSIONS. Taken together, our findings demonstrate the ability of the quinazoline alpha-blockers, terazosin and doxazosin, but not the sulphonamide, tamsulosin, to suppress prostate growth by inducing apoptosis among the epithelial cells in the benign and malignant prostate. These studies underwrite the durability of the response seen in long-term studies with terazosin, and suggest the potential of this drug in the treatment of prostate carcinoma. (C) 2000 Wiley-Liss, Inc.