Department of Biotechnology, Panjab University, Chandigarh, India.
Curr Cancer Drug Targets. 2013 May;13(4):379-99. doi: 10.2174/15680096113139990077.
DNA methylation is an epigenetic modification involved in gene expression regulation. In cancer, the DNA methylation pattern becomes aberrant, causing an array of tumor suppressor genes to undergo promoter hypermethylation and become transcriptionally silent. Reexpression of methylation silenced tumor suppressor genes by inhibiting the DNA methyltransferases (DNMT1, DNMT3A, and DNMT3B) has emerged as an effective strategy against cancer. The expression of DNA methyltransferase 1 (DNMT1) being high in S-phase of cell cycle makes it a specific target for methylation inhibition in rapidly dividing cells as in cancer. This review discusses nucleoside analogues (azacytidine, decitabine, zebularine, SGI-110, CP-4200), non-nucleoside ihibitors both synthetic (hydralazine, RG108, procaine, procainamide, IM25, disulfiram) and natural compounds (curcumin, genistein, EGCG, resveratrol, equol, parthenolide) which act through different mechanisms to inhibit DNMTs. The issues of bioavailability, toxicity, side effects, hypomethylation resistance and combinatorial therapies have also been highlighted.
DNA 甲基化是一种参与基因表达调控的表观遗传修饰。在癌症中，DNA 甲基化模式变得异常，导致一系列肿瘤抑制基因发生启动子过度甲基化，从而转录沉默。通过抑制 DNA 甲基转移酶（DNMT1、DNMT3A 和 DNMT3B）使甲基化沉默的肿瘤抑制基因重新表达，已成为对抗癌症的有效策略。DNA 甲基转移酶 1（DNMT1）在细胞周期的 S 期表达水平较高，使其成为癌症等快速分裂细胞中甲基化抑制的特异性靶点。本文综述了核苷类似物（阿扎胞苷、地西他滨、佐布勒林、SGI-110、CP-4200）、非核苷抑制剂（合成物：肼、RG108、普鲁卡因、普鲁卡因酰胺、IM25、双硫仑）和天然化合物（姜黄素、染料木黄酮、表没食子儿茶素没食子酸酯、白藜芦醇、雌马酚、紫菀酮）通过不同机制抑制 DNMTs 的作用。还强调了生物利用度、毒性、副作用、低甲基化耐药性和联合治疗等问题。
