DNA Methyltransferase-1 Inhibitors as Epigenetic Therapy for Cancer
DNA Methyltransferase-1 Inhibitors as Epigenetic Therapy for Cancer
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DOI：
10.2174/15680096113139990077
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发表时间：
2013-05-01
影响因子：
3
通讯作者：
Capalash, Neena
中科院分区：
文献类型：
--
作者：
Singh, Varinder;Sharma, Prince;Capalash, Neena
DNA甲基化是一种参与基因表达调节的表观遗传修饰。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经历启动子超甲基化并变得转录沉默。通过抑制DNA甲基转移酶（DNMT 1、DNMT 3A和DNMT 3B）来重新表达甲基化沉默的肿瘤抑制基因已经成为对抗癌症的有效策略。DNA甲基转移酶1（DNMT 1）在细胞周期的S期高表达，使其成为快速分裂细胞（如癌症）中甲基化抑制的特异性靶标。本文综述了核苷类似物（氮杂胞苷、地西他滨、zebularine、SGI-110、CP-4200）、非核苷类化合物（肼苯哒嗪、RG 108、普鲁卡因、普鲁卡因酰胺、IM 25、双硫仑）和天然化合物（姜黄素、染料木素、EGCG、白藜芦醇、雌马酚、小白菊素）通过不同的机制抑制DNMT。生物利用度、毒性、副作用、低甲基化抗性和组合疗法的问题也已突出。
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.