YM-155 potentiates the effect of ABT-737 in malignant human glioma cells via survivin and Mcl-1 downregulation in an EGFR-dependent context.
YM-155 potentiates the effect of ABT-737 in malignant human glioma cells via survivin and Mcl-1 downregulation in an EGFR-dependent context.
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DOI：
10.1158/1535-7163.mct-12-0901
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发表时间：
2013-03
影响因子：
5.7
通讯作者：
Pollack IF
中科院分区：
文献类型：
--
作者：
Jane EP;Premkumar DR;DiDomenico JD;Hu B;Cheng SY;Pollack IF
抗凋亡蛋白通常在胶质瘤中过表达，导致治疗抗性。我们最近报道，临床上可达到的浓度的Bcl-2/Bcl-xL抑制剂ABT-737未能诱导胶质瘤细胞凋亡，持续表达生存素和Mcl-1。为了阐明这些介质在胶质瘤细胞凋亡抵抗中的作用，我们分析了存活素抑制剂YM-155对一组胶质瘤细胞系存活的影响。YM-155以剂量和细胞系依赖性方式抑制生长，并下调生存素和Mcl-1。U373、LN 18、LNZ 428、T98 G、LN 229和LNZ 308细胞表现出10-75 nM的IC 50，而A172细胞具有抗性（IC 50 ~ 250 nM）。在对YM-155的敏感性和生存素或cIAP-1/cIAP-2/XIAP的基线表达之间没有发现相关性。然而，在EGFR活化水平和YM-155应答之间观察到强相关性，这使用EGFR转导的细胞与野生型细胞证实。因为我们假设降低Mcl-1表达可能增强胶质瘤对ABT-737的敏感性，所以我们检查了与YM-155共治疗是否促进ABT-737的疗效。YM-155协同增强ABT-737诱导的细胞毒性和caspase依赖性凋亡。使用shRNA下调Mcl-1也增强了ABT-737诱导的杀伤，证实了Mcl-1在介导ABT-737和YM-155之间的协同作用中的重要作用。与单独的YM-155一样，对YM-155和ABT-737的敏感性与EGFR活化状态负相关。然而，通过抑制EGFR或其下游通路，可以在高度耐药的U87-EGFRvIII细胞中恢复敏感性，突出了EGFR信号传导对Mcl-1表达的影响以及联合靶向治疗克服这些侵袭性肿瘤的多重耐药机制的相关性。
Antiapoptotic proteins are commonly overexpressed in gliomas, contributing to therapeutic resistance. We recently reported that clinically achievable concentrations of the Bcl-2/Bcl-xL inhibitor ABT-737 failed to induce apoptosis in glioma cells, with persistent expression of survivin and Mcl-1. To address the role of these mediators in glioma apoptosis resistance, we analyzed the effects of YM-155, a survivin suppressant, on survival on a panel of glioma cell lines. YM-155 inhibited growth, and downregulated survivin and Mcl-1 in a dose- and cell line-dependent manner. Whereas U373, LN18, LNZ428, T98G, LN229, and LNZ308 cells exhibited an IC50 of 10–75 nM, A172 cells were resistant (IC50 ~ 250 nM). No correlation was found between sensitivity to YM-155 and baseline expression of survivin or cIAP-1/cIAP-2/XIAP. However, strong correlation was observed between EGFR activation levels and YM-155 response, which was confirmed using EGFR-transduced versus wild-type cells. Because we postulated that decreasing Mcl-1 expression may enhance glioma sensitivity to ABT-737, we examined whether cotreatment with YM-155 promoted ABT-737 efficacy. YM-155 synergistically enhanced ABT-737-induced cytotoxicity and caspase-dependent apoptosis. Down-regulation of Mcl-1 using shRNA also enhanced ABT-737-inducing killing, confirming an important role for Mcl-1 in mediating synergism between ABT-737 and YM-155. As with YM-155 alone, sensitivity to YM-155 and ABT-737 inversely correlated with EGFR activation status. However, sensitivity could be restored in highly resistant U87-EGFRvIII cells by inhibition of EGFR or its downstream pathways, highlighting the impact of EGFR signaling on Mcl-1 expression and the relevance of combined targeted therapies to overcome the multiple resistance mechanisms of these aggressive tumors.