组蛋白去乙酰化酶抑制剂通过抑制DNA修复活性放射致敏人类黑素瘤细胞。

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Munshi A, Kurland JF，西川T，田中T, Hobbs ML, Tucker SL, Ismail S, Stevens C, Meyn RE

组蛋白去乙酰化酶抑制剂通过抑制DNA修复活性放射致敏人类黑素瘤细胞。

临床癌症杂志2005年7月1日;11(13):4912-22。doi: 10.1158 / 1078 - 0432. - ccr - 04 - 2088。

PubMed ID

16000590 (PubMed视图

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摘要

目的:组蛋白去乙酰化酶(HDAC)抑制剂最近作为一种有前途的抗癌药物出现。它们在细胞周期中阻止细胞，诱导分化和细胞死亡。HDAC抑制剂的抗肿瘤活性与它们通过组蛋白和非组蛋白乙酰化诱导基因表达的能力有关。然而，最近有研究表明，HDAC抑制剂也可能增强其他癌症治疗方法的活性，包括放疗。本研究的目的是评估HDAC抑制剂在体外对人类黑素瘤细胞放射增敏的能力。实验设计:一组HDAC抑制剂，包括丁酸钠(NaB)、苯丁酸、三丁酸和曲古霉素A，通过克隆原性细胞生存试验测试它们对两种人类黑素瘤细胞系(A375和MeWo)的放射增敏能力。采用标准法检测细胞凋亡和DNA修复。结果:NaB诱导两种黑素瘤细胞系和正常人成纤维细胞组蛋白H4的高乙酰化。NaB放射致敏A375和MeWo黑素瘤细胞系，在2 Gy (SF2)下大大降低了存活分数，而它对正常的人成纤维细胞没有影响。其他HDAC抑制剂，苯丁酸酯，三丁酸酯和曲古霉素A对两种黑色素瘤细胞系都有显著的放射增敏作用。 NaB modestly enhanced radiation-induced apoptosis that did not correlate with survival but did correlate with functional impairment of DNA repair as determined based on the host cell reactivation assay. Moreover, NaB significantly reduced the expression of the repair-related genes Ku70 and Ku86 and DNA-dependent protein kinase catalytic subunit in melanoma cells at the protein and mRNA levels. Normal human fibroblasts showed no change in DNA repair capacity or levels of DNA repair proteins following NaB treatment. We also examined gamma-H2AX phosphorylation as a marker of radiation response to NaB and observed that compared with controls, gamma-H2AX foci persisted long after ionizing exposure in the NaB-treated cells. CONCLUSIONS: HDAC inhibitors radiosensitize human tumor cells by affecting their ability to repair the DNA damage induced by ionizing radiation and that gamma-H2AX phosphorylation can be used as a predictive marker of radioresponse.

引用本文的药物库数据

药物靶点

药物	目标	种类	生物	药理作用	行动
Phenylbutyric酸	组蛋白去乙酰化酶(蛋白质组)	蛋白质组	人类	未知的	抑制剂	细节