Doxazosin and Terazosin Suppress Prostate Growth by Inducing Apoptosis: Clinical Significance

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Abstract
Doxazosin and terazosin are known to relax prostate smooth muscle through blockade of alpha 1-adrenergic innervation to the prostate. This action alone however does not fully account for the long-term clinical responses exerted by these drugs in the treatment of patients with benign prostatic hyperplasia (BPH). Experimental and clinical studies were done to establish the induction of prostate cell apoptosis by alpha 1-adrenoceptor antagonists as a molecular mechanism contributing to their long-term efficacy in the management of lower urinary tract symptoms associated with BPH and to potential suppression of prostate cancer growth. The data indicate that both doxazosin and terazosin induce apoptosis in prostate cancer cells in vitro and in vivo. The apoptotic effect of doxazosin and terazosin is mediated by a mechanism independent of the alpha1-adrenoceptor blockade, potentially under the direction of the quinazoline nucleus, since the nonquinazoline alpha 1-adrenoceptor antagonist tamsulosin does not elicit an apoptotic response. Recent experimental evidence points to deregulation of signal transduction pathways involving transforming growth factor-beta and disruption of cell attachment to the extracellular matrix (anoikis) as potential mechanisms underlying this apoptotic action of quinazoline based alpha 1-adrenoceptor antagonists against prostate cells. The correlation of induced prostate smooth muscle cell apoptosis with improvement of urinary symptoms in patients with BPH treated with doxazosin and terazosin, identifies apoptosis as an additional molecular mechanism for the long term therapeutic impact of these drugs in BPH. Moreover, the apoptotic effect elicited by quinazolines may have high clinical significance in the prevention and treatment of prostate cancer.