Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hněvotínská 5, 77900 Olomouc, Czech Republic; Cancer Research Czech Republic, Hněvotínská 5, 77900 Olomouc, Czech Republic.
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, 21205 Baltimore, MD, United States.
Pharmacol Ther. 2018 Aug;188:45-79. doi: 10.1016/j.pharmthera.2018.02.006. Epub 2018 Feb 15.
DNA methylation plays a pivotal role in the etiology of cancer by mediating epigenetic silencing of cancer-related genes. Since the relationship between aberrant DNA methylation and cancer has been understood, there has been an explosion of research at developing anti-cancer therapies that work by inhibiting DNA methylation. From the discovery of first DNA hypomethylating drugs in the 1980s to recently discovered second generation pro-drugs, exceedingly large number of studies have been published that describe the DNA hypomethylation-based anti-neoplastic action of these drugs in various stages of the pre-clinical investigation and advanced stages of clinical development. This review is a comprehensive report of the literature published in past 40 years, on so far discovered nucleosidic DNA methylation inhibitors in chronological order. The review will provide a complete insight to the readers about the mechanisms of action, efficacy to demethylate and re-express various cancer-related genes, anti-tumor activity, cytotoxicity profile, stability, and bioavailability of these drugs. The review further presents the far known mechanisms of primary and secondary resistance to azanucleoside drugs. Finally, the review highlights the ubiquitous role of DNA hypomethylating epi-drugs as chemosensitizers and/or priming agents, and recapitulate the combinatorial cancer preventive effects of these drugs with other epigenetic agents, conventional chemo-drugs, or immunotherapies. This comprehensive review analyzes the beneficial characteristics and drawbacks of nucleosidic DNA methylation inhibitors, which will assist the pre-clinical and clinical researchers in the design of future experiments to improve the therapeutic efficacy of these drugs and circumvent the challenges in the path of successful epigenetic therapy.
DNA 甲基化通过介导癌症相关基因的表观遗传沉默，在癌症的发病机制中起着关键作用。自异常 DNA 甲基化与癌症之间的关系被理解以来，开发通过抑制 DNA 甲基化来治疗癌症的疗法的研究呈爆炸式增长。从 20 世纪 80 年代首次发现 DNA 低甲基化药物到最近发现的第二代前药，已经发表了大量研究描述了这些药物在临床前研究的各个阶段和临床开发的后期阶段基于 DNA 低甲基化的抗肿瘤作用。这篇综述是对过去 40 年来发表的文献的全面报道，按时间顺序描述了迄今为止发现的核苷类 DNA 甲基化抑制剂。该综述将为读者提供关于这些药物的作用机制、去甲基化和重新表达各种癌症相关基因的疗效、抗肿瘤活性、细胞毒性特征、稳定性和生物利用度的完整见解。该综述进一步介绍了对氮杂核苷药物的原发性和继发性耐药的已知机制。最后，该综述强调了 DNA 低甲基化表型药物作为化疗增敏剂和/或引发剂的普遍作用，并总结了这些药物与其他表观遗传药物、常规化疗药物或免疫疗法联合的癌症预防作用。本综述分析了核苷类 DNA 甲基化抑制剂的有益特征和缺点，这将有助于临床前和临床研究人员设计未来的实验，以提高这些药物的治疗效果，并克服成功进行表观遗传治疗的挑战。
