Impact of alpha-adrenoceptor antagonists on prostate cancer development, progression and prevention

Two decades following the discovery that alpha 1-adrenoceptor antagonists suppress prostate tumor growth at the molecular and cellular level, the impact of alpha-blockade as re-purposed treatment strategy in the medical management of prostate cancer is gradually being recognized. Prostate cancer is the second most common cause of cancer deaths among males in the United States, yet the disease maintains inconsistent recommendations for prevention and screening. The functional relationship between alpha-adrenergic signaling and smooth muscle cells in the stroma of the prostate gland and the bladder neck empowered the use of alpha-adrenoceptor antagonists for the relief of urethral obstruction and clinical symptoms associated with benign prostatic hyperplasia (BPH). Adrenoceptors are G-protein-coupled receptors (GCPRs) that are functionally bound by catecholamines: epinephrine (ER) and norepinephrine (NE). The alpha 1A adrenoceptor subtype is primarily responsible for smooth muscle contraction in the bladder neck and prostate gland. alpha 1-adrenoceptor antagonists are clinically indicated as first-line therapies for the relief of BPH, hypertension, and post-traumatic stress disorder (PTSD). Compelling evidence from cellular and pre-clinical models have identified additional effects of alpha 1-adrenoceptor antagonists regarding their ability to induce apoptosis-mediated suppression of prostate tumor growth and metastasis. Additionally, early epidemiologic data suggest that they may serve as a safe treatment to reduce the risk of prostate cancer. Optimization of quinazoline based compounds (doxazosin) to exploit pharmacologic targeting of tumor growth and vascularization revealed high efficacy of the lead novel compound DZ-50 against prostate tumors. This review discusses the experimental and pre-clinical evidence on the impact of alpha-blockade on prostate cancer.