Department of Surgery, Division of Neurosurgery, University of Alabama at Birmingham, Alabama 35294-0006, USA.
J Biol Chem. 2010 Dec 17;285(51):39759-67. doi: 10.1074/jbc.M110.147504. Epub 2010 Sep 24.
Temozolomide (TMZ) is an oral alkylating agent used for the treatment of high-grade gliomas. Acquired chemoresistance is a severe limitation to this therapy with more than 90% of recurrent gliomas showing no response to a second cycle of chemotherapy. Efforts to better understand the underlying mechanisms of acquired chemoresistance to TMZ and potential strategies to overcome chemoresistance are, therefore, critically needed. TMZ methylates nuclear DNA and induces cell death; however, the impact on mitochondria DNA (mtDNA) and mitochondrial bioenergetics is not known. Herein, we tested the hypothesis that TMZ-mediated alterations in mtDNA and respiratory function contribute to TMZ-dependent acquired chemoresistance. Using an in vitro model of TMZ-mediated acquired chemoresistance, we report 1) a decrease in mtDNA copy number and the presence of large heteroplasmic mtDNA deletions in TMZ-resistant glioma cells, 2) remodeling of the entire electron transport chain with significant decreases of complexes I and V and increases of complexes II/III and IV, and 3) pharmacologic and genetic manipulation of cytochrome c oxidase, which restores sensitivity to TMZ-dependent apoptosis in resistant glioma cells. Importantly, human primary and recurrent pairs of glioblastoma multiforme (GBM) biopsies as well as primary and TMZ-resistant GBM xenograft lines exhibit similar remodeling of the ETC. Overall these results suggest that TMZ-dependent acquired chemoresistance may be due to a mitochondrial adaptive response to TMZ genotoxic stress with a major contribution from cytochrome c oxidase. Thus, abrogation of this adaptive response may reverse chemoresistance and restore sensitivity to TMZ, providing a strategy for improved therapeutic outcomes in GBM patients.
替莫唑胺（TMZ）是一种用于治疗高级别神经胶质瘤的口服烷化剂。获得性化疗耐药性是该治疗方法的严重限制，超过 90%的复发性神经胶质瘤对第二轮化疗没有反应。因此，迫切需要努力更好地了解 TMZ 获得性耐药的潜在机制和克服耐药性的潜在策略。TMZ 使核 DNA 甲基化并诱导细胞死亡；然而，其对线粒体 DNA（mtDNA）和线粒体生物能学的影响尚不清楚。在此，我们检验了 TMZ 介导的 mtDNA 改变和呼吸功能改变是否有助于 TMZ 依赖性获得性耐药的假设。通过 TMZ 介导的获得性耐药的体外模型，我们报告了 1）mtDNA 拷贝数减少和 TMZ 耐药神经胶质瘤细胞中存在大异质 mtDNA 缺失，2）整个电子传递链重塑，复合物 I 和 V 显著减少，复合物 II/III 和 IV 增加，3）细胞色素 c 氧化酶的药理学和遗传操作，可恢复耐药神经胶质瘤细胞对 TMZ 依赖性细胞凋亡的敏感性。重要的是，人原发性和复发性多形性胶质母细胞瘤（GBM）活检以及原发性和 TMZ 耐药性 GBM 异种移植系均表现出电子传递链的类似重塑。总的来说，这些结果表明 TMZ 依赖性获得性耐药性可能是由于 TMZ 遗传毒性应激的线粒体适应性反应引起的，其中细胞色素 c 氧化酶的贡献很大。因此，阻断这种适应性反应可能会逆转耐药性并恢复对 TMZ 的敏感性，为提高 GBM 患者的治疗效果提供了一种策略。
