人EGFR-2、EGFR和HDAC三重抑制剂CUDC-101增强GBM细胞的放射敏感性

C. Schlaff, W. Arscott, I. Gordon, K. Camphausen, A. Tandle
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引用次数: 4

摘要

放疗仍然是手术切除后多形性胶质母细胞瘤(GBM)的标准治疗方法。鉴于人表皮生长因子受体2 (HER2)和表皮生长因子受体(EGFR)的异常表达可能在受体酪氨酸激酶抑制剂的治疗抗性中发挥作用,以及组蛋白去乙酰化酶(HDAC)抑制剂作为放射增敏剂的新应用,我们确定了HER2、EGFR和HDAC的三抑制剂CUDC-101对GBM细胞放射敏感性的影响。克隆存活测定了CUDC-101对GBM、乳腺癌和正常成纤维细胞系的体外放射增敏潜力。用免疫印迹法测定抑制活性,用yH2AX法评价DNA双链断裂。采用流式细胞术和荧光显微镜观察CUDC-101对细胞周期和辐射诱导细胞杀伤的影响。CUDC-101抑制HER2、EGFR和HDAC,增强GBM和乳腺癌细胞系的体外放射敏感性,对正常成纤维细胞无影响。单独使用CUDC-101及联合照射24 h均可增加yH2AX病灶的保留率。CUDC-101可使G2期和M期细胞数量增加,仅M期细胞数量增加有统计学意义。在联合治疗中,有丝分裂突变的增加呈时间依赖性。结果表明,肿瘤特异性CUDC-101增强了GBM的放射致敏,并提示其作用涉及抑制DNA修复。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Human EGFR-2, EGFR and HDAC triple-inhibitor CUDC-101 enhances radiosensitivity of GBM cells
Radiotherapy remains the standard treatment for glioblastoma multiforme (GBM) following surgical resection. Given the aberrant expression of human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR) which may play a role in therapeutic resistance to receptor tyrosine kinase inhibitors, and the emerging use of histone deacetylase (HDAC) inhibitors as radiosensitizers, we defined the effects of CUDC-101, a triple inhibitor of HER2, EGFR and HDAC on the radiosensitivity of GBM cells. Clonogenic survival was used to determine the in vitro radiosensitizing potential of CUDC-101 on GBM, breast cancer, and normal fibroblast cell lines. Inhibitory activity was defined using immunoblots and DNA double strand breaks were evaluated using yH2AX foci. Effects of CUDC-101 on cell cycle and radiation-induced cell kill were determined using flow cytometry and fluorescent microscopy. CUDC-101 inhibited HER2, EGFR and HDAC and enhanced in vitro radiosensitivity of both GBM and breast cancer cell lines, with no effect on normal fibroblasts. Retention of yH2AX foci was increased by CUDC-101 alone and in combination with irradiation for 24 h. Treatment with CUDC-101 increased the number of cells in G2 and M phase, with only increase in M phase statistically significant. An increase in mitotic catastrophe was seen in a time-dependent fashion with combination treatment. The results indicate the tumor specific CUDC-101 enhanced radiosensitization in GBM, and suggest that the effect involves inhibition of DNA repair.
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