Chemosensitization of rhabdomyosarcoma cells by the histone deacetylase inhibitor SAHA
Chemosensitization of rhabdomyosarcoma cells by the histone deacetylase inhibitor SAHA
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组蛋白去乙酰化酶抑制剂 SAHA 对横纹肌肉瘤细胞的化疗增敏作用
DOI：
10.1016/j.canlet.2014.04.021
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发表时间：
2014-08-28
期刊：
影响因子：
9.7
通讯作者：
Fulda, Simone
中科院分区：
文献类型：
--
作者：
Heinicke, Ulrike;Fulda, Simone
横纹肌肉瘤（RMS）是儿童期最常见的软组织肉瘤，预后不佳，凸显了对新治疗策略的需求。在这里，我们发现了 RMS 细胞中组蛋白脱乙酰酶抑制剂 (HDACI) SAHA 和抗癌药物之间的新型合成致死相互作用。重要的是，SAHA 显着增加胚胎和肺泡 RMS 细胞系中化疗药物诱导的细胞凋亡，包括临床上用于治疗 RMS 的几种抗癌药物，如阿霉素、依托泊苷、长春新碱和环磷酰胺。组合指数（CI）的计算表明SAHA与阿霉素或依托泊苷的相互作用是协同的。从机制上讲，SAHA 会导致 RMS 细胞中组蛋白 H3 蛋白乙酰化，表明 SAHA 会改变染色质背景。此外，SAHA 和多柔比星联合处理会改变促凋亡和抗凋亡 Bcl-2 蛋白的比例，下调 McI-1 和 Bcl-x(L)、Bcl-2 去磷酸化和上调 Bim(EL)，从而将平衡转向细胞凋亡。一致地，SAHA 和阿霉素协同刺激 Bax 和 Bak 的激活、caspase 激活和 caspase 依赖性细胞凋亡。 Bc1-2 的过表达可显着挽救 SAHA/阿霉素介导的细胞凋亡，强调了线粒体凋亡途径对 SAHA 和阿霉素协同诱导细胞凋亡的要求。使用广泛的 caspase 抑制剂 N-苄氧基羰基-Val-Ala-Asp-氟甲基酮 (zVAD.fmk) 证实了 Caspase 依赖性细胞凋亡，该抑制剂可显着减少 SAHA/阿霉素触发的细胞凋亡。总之，这些研究结果表明，HDACI SAHA 代表了一种有前途的策略，可以为 RMS 细胞做好化疗诱导的细胞凋亡的准备，并值得在联合治疗方案中进行进一步研究。 (C) 2014 年，爱思唯尔爱尔兰有限公司出版。
Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma in childhood with a dismal prognosis, highlighting the need for novel treatment strategies. Here, we identify a novel synthetic lethal interaction between the histone deacetylase inhibitor (HDACI) SAHA and anticancer drugs in RMS cells. Importantly, SAHA significantly increases chemotherapeutic drug-induced apoptosis in both embryonal and alveolar RMS cell lines, including several anticancer agents that are used in the clinic for the treatment of RMS such as Doxorubicin, Etoposide, Vincristine and Cyclophosphamide. Calculation of combination index (CI) reveals that the interaction of SAHA and Doxorubicin or Etoposide is synergistic. Mechanistically, SAHA causes acetylation of histone H3 protein in RMS cells, indicating that SAHA alters the chromatin context. Also, cotreatment with SAHA and Doxorubicin changes the ratio of pro- and antiapoptotic Bcl-2 proteins with downregulation of McI-1 and Bcl-x(L), dephosphorylation of Bcl-2 and upregulation of Bim(EL), thus shifting the balance towards apoptosis. Consistently, SAHA and Doxorubicin cooperate to stimulate activation of Bax and Bak, caspase activation and caspase-dependent apoptosis. Overexpression of Bc1-2 significantly rescues SAHA/Doxorubicin-mediated apoptosis, underscoring the requirement of the mitochondrial apoptotic pathway for the synergistic induction of apoptosis by SAHA and Doxorubicin. Caspase-dependent apoptotic cell death is confirmed by the use of the broad-range caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk), which significantly decreases SAHA/Doxorubicin-triggered apoptosis. In conclusion, these findings demonstrate that the HDACI SAHA represents a promising strategy to prime RMS cells for chemotherapy-induced apoptosis and warrants further investigation in combination regimens. (C) 2014 Published by Elsevier Ireland Ltd.