Reactive oxygen species contribute toward Smac mimetic/temozolomide-induced cell death in glioblastoma cells
Reactive oxygen species contribute toward Smac mimetic/temozolomide-induced cell death in glioblastoma cells
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DOI：
10.1097/cad.0000000000000412
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发表时间：
2016-11
影响因子：
2.3
通讯作者：
M. Seyfrid;V. Marschall;S. Fulda
中科院分区：
文献类型：
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作者：
M. Seyfrid;V. Marschall;S. Fulda
据报道，细胞凋亡抑制蛋白的小分子抑制剂如Smac模拟物提供了一种有前途的工具，使胶质母细胞瘤（GBM）细胞对包括化疗药物在内的细胞毒性疗法敏感。然而，潜在的分子作用机制尚未完全阐明。因此，在本研究中，我们研究了活性氧（ROS）在调节Smac模拟物/替莫唑胺（TMZ）诱导的GBM细胞死亡中的作用。在这里，我们表明，Smac模拟BV 6和TMZ的行动一致，以刺激细胞溶质和线粒体ROS的生产。这种ROS的积累有助于BV 6/TMZ共处理后促凋亡因子BAX的活化，因为几种ROS清除剂（即N-乙酰基-L-半胱氨酸、MnTBAP或-生育酚）保护GBM细胞免受BV 6/TMZ介导的BAX活化。此外，ROS清除剂显著地拯救GBM细胞免于BV 6/TMZ触发的细胞死亡，表明ROS产生是诱导细胞死亡所必需的。通过显示ROS在调节Smac模拟物/TMZ诱导的细胞死亡中起重要作用，我们的工作揭示了氧化系统在Smac模拟物/TMZ联合治疗对GBM细胞的协同抗肿瘤活性中的关键作用。
Small-molecule inhibitors of Inhibitor of Apoptosis proteins such as Smac mimetics have been reported to provide a promising tool to sensitize glioblastoma (GBM) cells to cytotoxic therapies including chemotherapeutic drugs. However, the underlying molecular mechanisms of action have not yet been fully unraveled. In the present study, we therefore investigated the role of reactive oxygen species (ROS) in the regulation of Smac mimetic/temozolomide (TMZ)-induced cell death in GBM cells. Here, we show that the Smac mimetic BV6 and TMZ act in concert to stimulate the production of both cytosolic and mitochondrial ROS. This accumulation of ROS contributes toward the activation of the proapoptotic factor BAX upon BV6/TMZ cotreatment as several ROS scavengers (i.e. N-acetyl-L-cysteine, MnTBAP, or -tocopherol) protect GBM cells against BV6/TMZ-mediated BAX activation. In addition, ROS scavengers significantly rescue GBM cells from BV6/TMZ-triggered cell death, indicating that ROS generation is required for the induction of cell death. By showing that ROS play an important role in the regulation of Smac mimetic/TMZ-induced cell death, our work sheds light on the crucial role of the oxidative system in the cooperative antitumor activity of Smac mimetic/TMZ combination therapy against GBM cells.