Thymoquinone (TQ) is a highly perspective chemotherapeutic agent against gliomas and glioblastomas because of its ability to cross the blood-brain barrier and its selective cytotoxicity for glioblastoma cells compared to primary astrocytes. Here, we tested the hypothesis that TQ-induced mild oxidative stress provokes C6 glioma cell apoptosis through redox-dependent alteration of MAPK proteins. We showed that low concentrations of TQ (20-50 μM) promoted cell-cycle arrest and induced hydrogen peroxide generation as a result of NADH-quinone oxidoreductase 1-catalyzed two-electron reduction of this quinone. Similarly, low concentrations of TQ efficiently conjugated intracellular GSH disturbing redox state of glioma cells and provoking mitochondrial dysfunction. We demonstrated that high concentrations of TQ (70-100 μM) induced reactive oxygen species generation due to its one-electron reduction. TQ provoked apoptosis in C6 glioma cells through mitochondrial potential dissipation and permeability transition pore opening. The identified TQ modes of action on C6 glioma cells open up the possibility of considering it as a promising agent to enhance the sensitivity of cancer cells to standard chemotherapeutic drugs.

中文翻译：

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百里醌对大鼠 C6 胶质瘤细胞的细胞毒和抗增殖作用取决于氧化应激。

与原代星形胶质细胞相比，百里醌 (TQ) 是一种极具前景的针对胶质瘤和胶质母细胞瘤的化学治疗剂，因为它具有穿过血脑屏障的能力以及对胶质母细胞瘤细胞的选择性细胞毒性。在这里，我们测试了 TQ 诱导的轻度氧化应激通过 MAPK 蛋白的氧化还原依赖性改变引起 C6 胶质瘤细胞凋亡的假设。我们发现，由于 NADH-醌氧化还原酶 1 催化该醌的双电子还原，低浓度的 TQ (20-50 μM) 会促进细胞周期停滞并诱导过氧化氢的产生。同样，低浓度的 TQ 可有效地结合细胞内 GSH，从而扰乱胶质瘤细胞的氧化还原状态并引发线粒体功能障碍。我们证明了高浓度的 TQ (70-100 μM) 由于其单电子还原而诱导了活性氧的产生。TQ 通过线粒体电位耗散和通透性转换孔打开引起 C6 神经胶质瘤细胞凋亡。已确定的对 C6 神经胶质瘤细胞的 TQ 作用模式开辟了将其视为增强癌细胞对标准化疗药物敏感性的有希望的药物的可能性。