Acquisition of chemoresistance in gliomas is associated with increased mitochondrial coupling and decreased ROS production.
Acquisition of chemoresistance in gliomas is associated with increased mitochondrial coupling and decreased ROS production.
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神经胶质瘤中化学抗性的获取与线粒体耦合增加和ROS产生减少有关。
DOI：
10.1371/journal.pone.0024665
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Griguer CE
中科院分区：
文献类型：
--
作者：
Oliva CR;Moellering DR;Gillespie GY;Griguer CE
替莫唑胺（TMZ）是一种用于治疗胶质瘤的烷基化剂。化疗耐药是TMZ治疗的严重限制；我们迫切需要了解决定肿瘤对TMZ反应的潜在机制。我们最近报道了TMZ的化学耐药与整个电子传递链的重塑有关，与复合物II/III和细胞色素c氧化酶（CcO）的活性显著增加有关。此外，CcO的药理学和遗传学操作可以逆转化学耐药。因此，为了验证tmz耐药源于线粒体偶联更紧密和活性氧（ROS）产生减少的假设，我们评估了tmz敏感和耐药胶质瘤细胞以及tmz耐药多形性胶质母细胞瘤（GBM）异种移植物系（xenolines）的线粒体功能。在tmz耐药细胞和xenoline细胞中，adp刺激的最大线粒体耗氧率（状态3）更高，而在tmz耐药细胞中，基础呼吸（状态2）、质子泄漏（状态4）和线粒体ROS生成显著降低。此外，抗tmz细胞消耗更少的葡萄糖，产生更少的乳酸。化疗耐药细胞对TMZ和过氧化氢诱导的氧化应激不敏感，但用氧化剂l -丁硫氨酸-s、r -亚砜处理可增加TMZ依赖性ROS的生成，逆转化疗耐药。重要的是，用抗氧化剂n -乙酰半胱氨酸处理可抑制化学敏感细胞中TMZ依赖性ROS的产生，从而防止TMZ毒性。最后，我们发现线粒体dna缺失细胞（ρ°）对TMZ具有抗性，并且与亲本细胞相比，TMZ暴露后细胞内ROS水平较低。带线粒体的ρ°细胞的再生恢复了ROS的产生和对TMZ的敏感性。综上所述，我们的研究结果表明，TMZ的化疗耐药与线粒体偶联更紧密和ROS产生低有关，并提示胶质瘤中TMZ化疗耐药的一种新的线粒体ROS依赖机制。因此，线粒体功能的扰动和氧化还原状态的改变可能构成一种使胶质瘤细胞对治疗方法敏感的新策略。
Temozolomide (TMZ) is an alkylating agent used for treating gliomas. Chemoresistance is a severe limitation to TMZ therapy; there is a critical need to understand the underlying mechanisms that determine tumor response to TMZ. We recently reported that chemoresistance to TMZ is related to a remodeling of the entire electron transport chain, with significant increases in the activity of complexes II/III and cytochrome c oxidase (CcO). Moreover, pharmacologic and genetic manipulation of CcO reverses chemoresistance. Therefore, to test the hypothesis that TMZ-resistance arises from tighter mitochondrial coupling and decreased production of reactive oxygen species (ROS), we have assessed mitochondrial function in TMZ-sensitive and -resistant glioma cells, and in TMZ-resistant glioblastoma multiform (GBM) xenograft lines (xenolines). Maximum ADP-stimulated (state 3) rates of mitochondrial oxygen consumption were greater in TMZ-resistant cells and xenolines, and basal respiration (state 2), proton leak (state 4), and mitochondrial ROS production were significantly lower in TMZ-resistant cells. Furthermore, TMZ-resistant cells consumed less glucose and produced less lactic acid. Chemoresistant cells were insensitive to the oxidative stress induced by TMZ and hydrogen peroxide challenges, but treatment with the oxidant L-buthionine-S,R-sulfoximine increased TMZ-dependent ROS generation and reversed chemoresistance. Importantly, treatment with the antioxidant N-acetyl-cysteine inhibited TMZ-dependent ROS generation in chemosensitive cells, preventing TMZ toxicity. Finally, we found that mitochondrial DNA-depleted cells (ρ°) were resistant to TMZ and had lower intracellular ROS levels after TMZ exposure compared with parental cells. Repopulation of ρ° cells with mitochondria restored ROS production and sensitivity to TMZ. Taken together, our results indicate that chemoresistance to TMZ is linked to tighter mitochondrial coupling and low ROS production, and suggest a novel mitochondrial ROS-dependent mechanism underlying TMZ-chemoresistance in glioma. Thus, perturbation of mitochondrial functions and changes in redox status might constitute a novel strategy for sensitizing glioma cells to therapeutic approaches.
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影响因子：
3.7
作者：
Griguer CE;Oliva CR;Gobin E;Marcorelles P;Benos DJ;Lancaster JR Jr;Gillespie GY
通讯作者：
Gillespie GY
影响因子：
3.9
作者：
Griguer, Corinne E.;Oliva, Claudia R.;Marcorelles, Pascale
通讯作者：
Marcorelles, Pascale
影响因子：
158.5
作者：
Hegi, ME;Diserens, A;Stupp, R
通讯作者：
Stupp, R
影响因子：
4.1
作者：
BOVERIS, A;CHANCE, B
通讯作者：
CHANCE, B
DOI：
10.1016/j.ijrobp.2009.04.026
发表时间：
2009-09-01
影响因子：
7
作者：
Carlson, Brett L.;Grogan, Patrick T.;Sarkaria, Jann N.
通讯作者：
Sarkaria, Jann N.