Rana Zohaib, Diermeier Sarah, Hanif Muhammad, Rosengren Rhonda J
Department of Pharmacology and Toxicology, School of Biomedical Sciences, University of Otago, 18 Frederick Street, Dunedin 9016, New Zealand.
Department of Biochemistry, School of Biomedical Sciences, University of Otago, 710 Cumberland Street, Dunedin 9016, New Zealand.
Biomedicines. 2020 Jan 30;8(2):22. doi: 10.3390/biomedicines8020022.
Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and enzalutamide. Histone deacetylase (HDAC) inhibitors showed promising results in hematological malignancies, but they failed in solid tumors such as prostate cancer, despite the overexpression of HDACs in CRPC. Four HDAC inhibitors, vorinostat, pracinostat, panobinostat and romidepsin, underwent phase II clinical trials for prostate cancers; however, phase III trials were not recommended due to a majority of patients exhibiting either toxicity or disease progression. In this review, the pharmacodynamic reasons for the failure of HDAC inhibitors were assessed and placed in the context of the advancements in the understanding of CRPCs, HDACs and resistance mechanisms. The review focuses on three themes: evolution of androgen receptor-negative prostate cancers, development of resistance mechanisms and differential effects of HDACs. In conclusion, advancements can be made in this field by characterizing HDACs in prostate tumors more extensively, as this will allow more specific drugs catering to the specific HDAC subtypes to be designed.
对于对多西他赛和恩杂鲁胺等标准治疗无反应的去势抵抗性前列腺癌（CRPC），需要新的治疗方案。组蛋白脱乙酰酶（HDAC）抑制剂在血液系统恶性肿瘤中显示出有前景的结果，但在前列腺癌等实体瘤中却失败了，尽管CRPC中HDACs过表达。四种HDAC抑制剂，伏立诺他、普拉西诺司他、帕比司他和罗米地辛，进行了前列腺癌的II期临床试验；然而，由于大多数患者出现毒性或疾病进展，不建议进行III期试验。在本综述中，评估了HDAC抑制剂失败的药效学原因，并结合对CRPC、HDACs和耐药机制的理解进展进行了分析。该综述聚焦于三个主题：雄激素受体阴性前列腺癌的演变、耐药机制的发展以及HDACs的不同作用。总之，通过更广泛地表征前列腺肿瘤中的HDACs，可以在该领域取得进展，因为这将使设计出更针对特定HDAC亚型的药物成为可能。
