通过抑制组蛋白脱乙酰酶抑制剂radiosensitize人类黑色素瘤细胞DNA修复活动。

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Munshi,当摩根富林明,田中Nishikawa T, T,霍布斯ML,塔克SL,伊斯梅尔年代,史蒂文斯C, Meyn再保险

通过抑制组蛋白脱乙酰酶抑制剂radiosensitize人类黑色素瘤细胞DNA修复活动。

癌症研究杂志2005年7月1;11(13):4912 - 22所示。doi: 10.1158 / 1078 - 0432. - ccr - 04 - 2088。

PubMed ID

16000590 (在PubMed

]

文摘

目的:组蛋白脱乙酰酶(HDAC抑制剂)出现在有前途的抗癌剂。他们逮捕细胞周期和诱导细胞分化和细胞死亡。HDAC抑制剂的抗肿瘤活性与诱导基因表达的能力通过乙酰化组蛋白和非组蛋白的蛋白质。但是,它最近建议HDAC抑制剂也可能增加其他癌症疗法的活动,包括放射治疗。本研究的目的是评估的能力HDAC抑制剂radiosensitize人类黑色素瘤细胞体外。实验设计:一个面板的HDAC抑制剂,包括丁酸钠(NaB) phenylbutyrate,三丁酸甘油酯,trichostatin检测能力radiosensitize两个人类黑色素瘤细胞系(A375和MeWo)使用单独的细胞生存分析。细胞凋亡和DNA修复衡量标准化验。结果:NaB诱导组蛋白H4的hyperacetylation两个黑素瘤细胞系和正常的人类成纤维细胞。NaB radiosensitized A375和MeWo黑色素瘤细胞系,大幅降低幸存的分数在2 Gy (SF2),而没有影响正常的人类成纤维细胞。其他HDAC抑制剂、phenylbutyrate三丁酸甘油酯,trichostatin有重要的机体影响黑素瘤细胞系进行测试。 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.

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药物靶点

药物	目标	类	生物	药理作用	行动
Phenylbutyric酸	组蛋白脱乙酰酶(蛋白质组)	蛋白质组	人类	未知的	抑制剂	细节