Histone-Deacetylase Inhibitors for the Treatment of Cancer
Histone-Deacetylase Inhibitors for the Treatment of Cancer
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DOI：
10.4161/cc.3.6.927
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发表时间：
2004-04
期刊：
影响因子：
4.3
通讯作者：
R. Lindemann;B. Gabrielli;R. Johnstone
中科院分区：
文献类型：
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作者：
R. Lindemann;B. Gabrielli;R. Johnstone
组蛋白去乙酰化酶抑制剂（HDACi）是一种很有前途的新型化疗药物，目前正处于早期临床试验阶段。已经纯化或合成了大量结构不同的HDACi，其主要抑制所有11种I类和II类HDAC的活性。虽然这些药物表现出抗癌活性所需的许多特征，如对正常细胞的低毒性和在纳摩尔浓度下抑制肿瘤细胞生长和存活的能力，但它们的作用机制在很大程度上是未知的。最初，提出了一种模型，其中HDACi介导的特定基因或一组基因的反式激活负责抑制细胞周期进程或诱导细胞凋亡。考虑到HDACs可以调节许多非组蛋白蛋白的活性，并且组蛋白乙酰化对于不直接涉及基因转录的DNA复制和有丝分裂等事件很重要，因此HDACi的初始机制模型似乎过于简单。在此，我们提供了一个更新的转录依赖性和非依赖性的事件，可能是重要的HDACi的抗肿瘤活性，并讨论这些化合物与其他化疗药物的组合使用。
Histone deacetylase inhibitors (HDACi) are a promising new class of chemotherapeutic drug currently in early phase clinical trials. A large number of structurally diverse HDACi have been purified or synthesised that mostly inhibit the activity of all eleven class I and II HDACs. While these agents demonstrate many features required for anti-cancer activity such as low toxicity against normal cells and an ability to inhibit tumor cell growth and survival at nanomolar concentrations, their mechanisms of action are largely unknown. Initially, a model was proposed whereby HDACi-mediated transactivation of a specific gene or set of genes was responsible for the inhibition of cell cycle progression or induction of apoptosis. Given that HDACs can regulate the activity of a number of non-histone proteins and that histone acetylation is important for events such as DNA replication and mitosis that do not directly involve gene transcription, it appears that the initial mechanistic model for HDACi may have been too simple. Herein, we provide an update on the transcription-dependent and –independent events that may be important for the anti-tumor activities of HDACi and discuss the use of these compounds in combination with other chemotherapeutic drugs.