Differential response of cancer cells to HDAC inhibitors trichostatin A and depsipeptide.
Differential response of cancer cells to HDAC inhibitors trichostatin A and depsipeptide.
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DOI：
10.1038/bjc.2011.532
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发表时间：
2012-01-03
影响因子：
8.8
通讯作者：
Martinez, E. D.
中科院分区：
文献类型：
--
作者：
Chang, J.;Varghese, D. S.;Gillam, M. C.;Peyton, M.;Modi, B.;Schiltz, R. L.;Girard, L.;Martinez, E. D.
在过去的十年中，已经鉴定出几种抑制 I 类和/或 II 类组蛋白脱乙酰酶 (HDAC) 的药物，包括曲古抑菌素 A、环缩酚肽 FR901228 和抗生素 apicidin。这些化合物因其能够重新激活异常沉默的肿瘤抑制基因和/或阻止肿瘤细胞生长而立即应用于癌症研究。尽管许多 HDAC 抑制剂正在临床前癌症模型和临床试验中进行评估，但人们对其具体作用机制的差异以及癌细胞对每种抑制剂敏感性的独特决定因素知之甚少。通过结合细胞活力测定、HDAC 酶活性测量、组蛋白修饰的蛋白质印迹、微阵列基因表达分析和 qRT-PCR，我们表征了肺癌、乳腺癌和皮肤癌细胞以及正常细胞中曲古抑菌素 A 与缩酚肽诱导表型的差异，然后将这些研究扩展到其他 HDAC 抑制剂。与 1 类选择性抑制剂缩酚肽相比，肺癌、乳腺癌和黑色素瘤细胞系的细胞活力谱显示出对泛抑制剂 TSA 的不同敏感性。在一些情况下，对一种抑制剂最敏感的细胞系对另一种抑制剂最有抵抗力，这表明这些药物至少作用于一些不重叠的细胞靶标。这些差异不能仅用这些抑制剂的 HDAC 选择性来解释，因为 apicidin（一种类似于缩酚肽的 1 类选择性化合物）也显示出其自身独特的药物敏感性特征。与其他 HDAC 抑制剂相比，TSA 对癌症细胞和正常细胞具有更高的特异性。此外，在阻断癌细胞活力的浓度下，TSA 有效抑制纯化的重组 HDAC 1、2 和 5，并适度抑制 HDAC8，而缩酚肽在体外不会抑制纯化的 HDAC 的活性，但在细胞提取物中会抑制，表明该药物可能具有间接作用。尽管缩酚肽和 TSA 都增加了癌细胞中组蛋白乙酰化的水平，但只有缩酚肽降低了转录抑制组蛋白甲基化标记的整体水平。对显示出对缩酚肽敏感性不同的同基因细胞系对的基因表达谱的分析表明，对这种抑制剂的耐药性可能是由暴露于化疗引发的多药耐药基因表达增加介导的，维拉帕米研究证实了这一点。尽管通常认为具有相似的活性，但 HDAC 调节剂曲古抑菌素 A 和缩酚肽在抑制癌细胞活力和 HDAC 活性、对癌症细胞与正常细胞的选择性以及对组蛋白修饰的影响方面表现出不同的表型。这些作用方式的差异可能会影响这些抑制剂的未来治疗和研究应用。
Over the last decade, several drugs that inhibit class I and/or class II histone deacetylases (HDACs) have been identified, including trichostatin A, the cyclic depsipeptide FR901228 and the antibiotic apicidin. These compounds have had immediate application in cancer research because of their ability to reactivate aberrantly silenced tumour suppressor genes and/or block tumour cell growth. Although a number of HDAC inhibitors are being evaluated in preclinical cancer models and in clinical trials, little is known about the differences in their specific mechanism of action and about the unique determinants of cancer cell sensitivity to each of these inhibitors. Using a combination of cell viability assays, HDAC enzyme activity measurements, western blots for histone modifications, microarray gene expression analysis and qRT–PCR, we have characterised differences in trichostatin A vs depsipeptide-induced phenotypes in lung cancer, breast cancer and skin cancer cells and in normal cells and have then expanded these studies to other HDAC inhibitors. Cell viability profiles across panels of lung cancer, breast cancer and melanoma cell lines showed distinct sensitivities to the pan-inhibitor TSA compared with the class 1 selective inhibitor depsipeptide. In several instances, the cell lines most sensitive to one inhibitor were most resistant to the other inhibitor, demonstrating these drugs act on at least some non-overlapping cellular targets. These differences were not explained by the HDAC selectivity of these inhibitors alone since apicidin, which is a class 1 selective compound similar to depsipeptide, also showed a unique drug sensitivity profile of its own. TSA had greater specificity for cancer vs normal cells compared with other HDAC inhibitors. In addition, at concentrations that blocked cancer cell viability, TSA effectively inhibited purified recombinant HDACs 1, 2 and 5 and moderately inhibited HDAC8, while depsipeptide did not inhibit the activity of purified HDACs in vitro but did in cellular extracts, suggesting a potentially indirect action of this drug. Although both depsipeptide and TSA increased levels of histone acetylation in cancer cells, only depsipeptide decreased global levels of transcriptionally repressive histone methylation marks. Analysis of gene expression profiles of an isogenic cell line pair that showed discrepant sensitivity to depsipeptide, suggested that resistance to this inhibitor may be mediated by increased expression of multidrug resistance genes triggered by exposure to chemotherapy as was confirmed by verapamil studies. Although generally thought to have similar activities, the HDAC modulators trichostatin A and depsipeptide demonstrated distinct phenotypes in the inhibition of cancer cell viability and of HDAC activity, in their selectivity for cancer vs normal cells, and in their effects on histone modifications. These differences in mode of action may bear on the future therapeutic and research application of these inhibitors.
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影响因子：
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