AG490 influences UCN-01-induced cytotoxicity in Glioma cells in a p53-dependent fashion, correlating with effects on BAX cleavage and BAD phosphorylation
AG490 influences UCN-01-induced cytotoxicity in Glioma cells in a p53-dependent fashion, correlating with effects on BAX cleavage and BAD phosphorylation
复制标题
DOI：
10.1016/j.canlet.2007.06.020
复制
发表时间：
2007-11-08
期刊：
影响因子：
9.7
通讯作者：
Pollack, Ian F.
中科院分区：
文献类型：
--
作者：
Jane, Esther P.;Premkumar, Daniel R.;Pollack, Ian F.
我们测定了AG 490作为单一药剂以及与7-羟基星形孢菌素（UCN-01）组合在一组恶性人类神经胶质瘤细胞系中的细胞毒性。由于p53在细胞周期检查点中具有重要作用，因此已经预期检查点途径的调节应该使p53缺陷细胞敏感，同时保留正常细胞。从剂量-反应曲线确定细胞增殖。无论p53状态如何，AG 490单独作为细胞毒性剂是有效的。联合Chk 1抑制剂UCN-01显著增强了p53突变或缺失的胶质瘤细胞对AG 490的反应。在p53-野生型细胞中观察到相反的作用，其中UCN-01和AG 490对细胞增殖和活力具有拮抗作用。我们发现，AG 490增强BAD磷酸化的p53野生型胶质瘤细胞，这似乎保护UCN-01诱导的细胞毒性，而AG 490增强UCN-01诱导的细胞毒性在p53缺陷细胞系通过抑制BAD磷酸化和诱导BAX和PARP切割。这些观察结果强调了基因型依赖性因素强烈影响恶性胶质瘤信号靶向治疗反应的可能性，以及在这些药物的相关反应分析中考虑这些因素的重要性。(C)2007爱思唯尔爱尔兰有限公司保留所有权利。
We determined the cytotoxicity of AG490 as a single agent and in combination with 7-hydroxystaurosporine (UCN-01) in a panel of malignant human glioma cell lines. Because p53 has important roles in cell cycle checkpoints, it has been anticipated that modulation of checkpoint pathways should sensitize p53 defective cells while sparing the normal cells. Cell proliferation was determined from dose-response curves. AG490 was effective as a cytotoxic agent alone regardless of p53 status. Combining the Chk1 inhibitor UCN-01 dramatically enhanced the response to AG490 in p53-mutated or deleted glioma cells. An opposite effect was noted in p53-wild type cells, in which UCN-01 and AG490 had antagonistic effects on cell proliferation and viability. We found that AG490 enhanced BAD phosphorylation in p53 wild type glioma cells, which appeared to protect against UCN-01-induced cytotoxicity, whereas AG490 enhanced UCN-01-induced cytotoxicity in p53 defective cell lines by suppression of BAD phosphorylation and induction of BAX and PARP cleavage. These observations highlight the potential for genotype-dependent factors to strongly influence response to signa ling-targeted therapies in malignant gliomas and the importance of considering such factors in correlative response analyses for these agents. (C) 2007 Elsevier Ireland Ltd. All rights reserved.