Targeted histone deacetylase inhibition for cancer therapy

被引:83
作者
Vigushin, DM [1 ]
Coombes, RC [1 ]
机构
[1] Univ London Imperial Coll Sci Technol & Med, Dept Canc Med, London W12 0NN, England
关键词
D O I
10.2174/1568009043481560
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The histone deacetylase inhibitors are a new class of cytostatic agents that inhibit the proliferation of tumor cells in culture and in vivo by inducing cell cycle arrest, differentiation and/or apoptosis. Historic acetylation and deacetylation play important roles in the modulation of chromatin topology and the regulation of gene transcription. Histone deacetylase inhibition induces the accumulation of hyperacetylated nucleosome core histories in most regions of chromatin but affects the expression of only a small subset of genes, leading to transcriptional activation of some genes' but repression of an equal or larger number of other genes. Non-histone proteins such as transcription factors are also targets for acetylation with varying functional effects. Acetylation enhances the activity of some transcription factors such as the tumor suppressor p53 and the erythroid differentiation factor GATA-1 but may repress transcriptional activity of others including T cell factor and the co-activator ACTR. Recent studies in our laboratory and others have shown that the estrogen receptor alpha (ERalpha) can be hyperacetylated in response to histone deacetylase inhibition, suppressing ligand sensitivity and regulating transcriptional activation by histone deacetylase inhibitors. Conservation of the acetylated ERalpha motif in other nuclear receptors suggests that acetylation may play an important regulatory role in diverse nuclear receptor signaling functions. A number of structurally diverse histone deacetylase inhibitors have shown potent antitumor efficacy with little toxicity in vivo in animal models. Several compounds are currently in early phase clinical development as potential treatments for solid and hematological cancers both as monotherapy and in combination with cytotoxics and differentiation agents. This report reviews the biology and clinical development of historic deacetylase inhibitors for cancer therapy.
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页码:205 / 218
页数:14
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