DNA methyltransferase inhibitors in cancer: From pharmacology to translational studies
DNA methyltransferase inhibitors in cancer: From pharmacology to translational studies
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DOI：
10.1016/j.bcp.2016.12.004
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发表时间：
2017-04-01
影响因子：
5.8
通讯作者：
Arimondo, Paola B.
中科院分区：
文献类型：
--
作者：
Pechalrieu, Dany;Etievant, Chantal;Arimondo, Paola B.
DNA甲基化是哺乳动物的表观遗传标记，它参与定义基因在正常细胞和疾病背景下表达的地点和时间。与其他表观遗传标记一样，它是可逆的，可以被化学试剂调节。由于它通过沉默某些基因，如肿瘤抑制基因，在癌症中发挥着重要作用，因此它是一个有希望的治疗靶点。两种化合物已被批准用于治疗血液病癌症，并已进行了许多努力来发现抑制DNA甲基转移酶的新分子，DNA甲基转移酶是负责DNA甲基化的酶。本文分析了这些抑制剂的分子机制和细胞药理学，指出了新的药理学模型和范例的必要性。药理反应的参数需要重新定义：目标是细胞重新编程，而不是一般的细胞毒性。因此，定义了“表观遗传”剂量，而不是细胞毒性剂量。另一个问题是反应的延迟：细胞重新编程可能需要几代人才能产生可观察到的表型。这与实验室规模的实验兼容吗？最后，重要的是要考虑癌细胞与正常细胞相比的特异性和耐药性的出现。我们还讨论了使用的不同技术和药理模型的选择。(C)2016 Elsevier Inc.保留所有权利。
DNA methylation is a mammalian epigenetic mark that participates to define where and when genes are expressed, both in normal cells and in the context of diseases. Like other epigenetic marks, it is reversible and can be modulated by chemical agents. Because it plays an important role in cancer by silencing certain genes, such as tumour suppressor genes, it is a promising therapeutic target. Two compounds are already approved to treat haematological cancers, and many efforts have been carried out to discover new molecules that inhibit DNA methyltransferases, the enzymes responsible for DNA methylation.Here, we analyse the molecular mechanisms and cellular pharmacology of these inhibitors, pointing out the necessity for new pharmacological models and paradigms. The parameters of pharmacological responses need to be redefined: the aim is cellular reprogramming rather than general cytotoxicity. Thus, "epigenetic" rather than cytotoxic dosages are defined. Another issue is the delay of the response: cellular reprogramming can take several generations to produce observable phenotypes. Is this compatible with laboratory scale experiments? Finally, it is important to consider the specificity for cancer cells compared to normal cells and the appearance of resistance. We also discuss different techniques that are used and the selection of pharmacological models. (C) 2016 Elsevier Inc. All rights reserved.