Apoptotic impact of α1‐blockers on prostate cancer growth: A myth or an inviting reality?

Abstract

BACKGROUND Pharmacological manipulation or genetic targeting of the major apoptosis regulators, such as bcl‐2, caspases, and inhibitors of apoptosis (IAPs), represent clinically attractive avenues towards effective therapeuti strategies for advanced prostate cancer. A wealth of evidence established the α₁‐adrenoceptor antagonists to be clinically effective in relieving the symptoms associated with benign prostatic hyperplasia (BPH) by relaxing prostatic smooth muscle tone. This action alone however does not fully account for the long‐term clinical response to these drugs in BPH patients. METHODS Experimental and retrospective clinical studies provided new evidence supporting a differential growth‐suppressing function of two α₁‐adrenoceptor antagonists against prostate cancer, independent of an α₁‐adrenoceptor mechanism. RESULTS The quinazoline‐based antagonists, doxazosin and terazosin, induce apoptosis, inhibit cell adhesion to the extracellular matrix (by activating anoikis), and prevent cell invasion and migration of prostate tumor epithelial cells and vascular endothelial cells. Tamsulosin, a sulphonamide‐based, clinically effective α₁‐adrenoceptor antagonist for BPH treatment, fails to exert a similar apoptotic action against prostate cells. Furthermore, at pharmacologically relevant doses, doxazosin suppresses benign and malignant prostate growth in in vivo experimental models. The effect is characterized by three intriguing features: (a) it is mediated by an α₁‐adrenoceptor‐independent action, (possibly related to the quinazoline nucleus); (b) it is targeted at the apoptotic process without affecting cell proliferation; and (c) the elevated apoptotic index correlated with symptom score improvement in BPH patients. CONCLUSIONS This evidence challenges conventional knowledge of the mechanism of action of α₁‐adrenoceptor antagonists, and points to a new therapeutic value for these drugs by providing a differential molecular basis for their anti‐tumor efficacy. The present review focuses on the characterization of the apoptotic/anti‐angiogenic effect of quinazoline‐based α₁‐adrenoceptor antagonists against prostate cancer cells and discusses the clinical significance of this action in the prevention and treatment of prostate cancer.