Etheridge Tyler, Damodaran Shivashankar, Schultz Adam, Richards Kyle A, Gawdzik Joseph, Yang Bing, Cryns Vincent, Jarrard David F
Department of Urology, University of Wisconsin-Madison, Madison, WI, USA.
Department of Medicine, University of Wisconsin-Madison, Madison, WI, USA.
Asian J Urol. 2019 Jan;6(1):57-64. doi: 10.1016/j.ajur.2018.09.001. Epub 2018 Sep 15.
Androgen deprivation therapy (ADT) has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer (PCa). However, this approach is rarely curative. Recent clinical trials have demonstrated that ADT combined with other agents, notably docetaxel and abiraterone, lead to improved survival. The mechanisms surrounding this improved cancer outcomes are incompletely defined. The response of cancer cells to ADT includes apoptosis and cell death, but a significant fraction remains viable. Our laboratory has demonstrated both and that cellular senescence occurs in a subset of these cells. Cellular senescence is a phenotype characterized by cell cycle arrest, senescence-associated β-galactosidase (SA-β-gal), and a hypermetabolic state. Positive features of cellular senescence include growth arrest and immune stimulation, although persistence may release cytokines and growth factors that are detrimental. Senescent tumor cells generate a catabolic state with increased glycolysis, protein turnover and other metabolic changes that represent targets for drugs, like metformin, to be applied in a synthetic lethal approach. This review examines the response to ADT and the putative role of cellular senescence as a biomarker and therapeutic target in this context.
在过去75年里，雄激素剥夺疗法（ADT）一直是转移性激素敏感性前列腺癌（PCa）的标准治疗方法。然而，这种方法很少能治愈。最近的临床试验表明，ADT与其他药物联合使用，尤其是多西他赛和阿比特龙，可提高生存率。围绕这种改善癌症预后的机制尚未完全明确。癌细胞对ADT的反应包括凋亡和细胞死亡，但仍有相当一部分细胞存活。我们实验室已经证明，在这些细胞的一个亚群中会发生细胞衰老。细胞衰老是一种以细胞周期停滞、衰老相关β-半乳糖苷酶（SA-β-gal）和高代谢状态为特征的表型。细胞衰老的积极特征包括生长停滞和免疫刺激，尽管持续存在可能会释放有害的细胞因子和生长因子。衰老的肿瘤细胞会产生一种分解代谢状态，糖酵解、蛋白质周转和其他代谢变化增加，这些变化代表了像二甲双胍这样的药物在合成致死方法中应用的靶点。本综述探讨了对ADT的反应以及细胞衰老在这种情况下作为生物标志物和治疗靶点的潜在作用。
