Wade Cameron A, Goodwin Jeffrey, Preston David, Kyprianou Natasha
Department of Urology, University of Kentucky College of Medicine Lexington, Kentucky 40536, USA.
Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine Lexington, Kentucky 40536, USA.
Am J Clin Exp Urol. 2019 Feb 18;7(1):46-60. eCollection 2019.
Two decades following the discovery that α1-adrenoceptor antagonists suppress prostate tumor growth at the molecular and cellular level, the impact of α-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 α-adrenergic signaling and smooth muscle cells in the stroma of the prostate gland and the bladder neck empowered the use of α-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 α1A adrenoceptor subtype is primarily responsible for smooth muscle contraction in the bladder neck and prostate gland. α1-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 α1-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 α-blockade on prostate cancer.
在发现α1-肾上腺素能受体拮抗剂在分子和细胞水平上抑制前列腺肿瘤生长二十年之后，α-阻滞剂作为一种重新定位的治疗策略在前列腺癌医学管理中的作用正逐渐得到认可。前列腺癌是美国男性癌症死亡的第二大常见原因，但对于该疾病的预防和筛查建议仍不一致。前列腺和膀胱颈基质中α-肾上腺素能信号与平滑肌细胞之间的功能关系，使得α-肾上腺素能受体拮抗剂被用于缓解尿道梗阻以及与良性前列腺增生（BPH）相关的临床症状。肾上腺素能受体是G蛋白偶联受体（GCPRs），其功能上与儿茶酚胺结合：肾上腺素（ER）和去甲肾上腺素（NE）。α1A肾上腺素能受体亚型主要负责膀胱颈和前列腺中的平滑肌收缩。α1-肾上腺素能受体拮抗剂在临床上被用作缓解BPH、高血压和创伤后应激障碍（PTSD）的一线治疗药物。来自细胞和临床前模型的有力证据表明，α1-肾上腺素能受体拮抗剂在诱导凋亡介导的抑制前列腺肿瘤生长和转移方面还有其他作用。此外，早期的流行病学数据表明，它们可能是降低前列腺癌风险的一种安全治疗方法。对基于喹唑啉的化合物（多沙唑嗪）进行优化以利用对肿瘤生长和血管生成的药理靶向作用，结果显示先导新型化合物DZ-50对前列腺肿瘤具有高效性。本综述讨论了关于α-阻滞剂对前列腺癌影响的实验和临床前证据。
