Shi Jinlong, Sun Baolan, Shi Wei, Zuo Hao, Cui Daming, Ni Lanchun, Chen Jian
Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu Province, 226001, People's Republic of China.
Tumour Biol. 2015 Feb;36(2):655-62. doi: 10.1007/s13277-014-2644-z. Epub 2014 Oct 5.
Gliomas are the most malignant and aggressive primary brain tumor in adults. Despite concerted efforts to improve therapies, their prognosis remains very poor. Isocitrate dehydrogenase 1 (IDH1) mutations have been discovered frequently in glioma patients and are strongly correlated with improved survival. However, the effect of IDH1 mutations on the chemosensitivity of gliomas remains unclear. In this study, we generated clonal U87 and U251 glioma cell lines overexpressing the R132H mutant protein (IDH1-R132H). Compared with control cells and cells overexpressing IDH wild type (IDH1-WT), both types of IDH1-R132H cells were more sensitive to temozolomide (TMZ) and cis-diamminedichloroplatinum (CDDP) in a time- and dose-dependent manner. The IDH1-R132H-induced higher chemosensitivity was associated with nicotine adenine disphosphonucleotide (NADPH), glutathione (GSH) depletion, and reactive oxygen species (ROS) generation. Accordingly, this IDH1-R132H-induced growth inhibition was effectively abrogated by GSH in vitro and in vivo. Our study provides direct evidence that the improved survival in patients with IDH1-R132H tumors may partly result from the effects of the IDH1-R132H protein on chemosensitivity. The primary cellular events associated with improved survival are the GSH depletion and increased ROS generation.
胶质瘤是成人中最恶性、侵袭性最强的原发性脑肿瘤。尽管人们齐心协力改进治疗方法，但其预后仍然很差。异柠檬酸脱氢酶1（IDH1）突变在胶质瘤患者中频繁被发现，且与生存率提高密切相关。然而，IDH1突变对胶质瘤化疗敏感性的影响仍不清楚。在本研究中，我们构建了过表达R132H突变蛋白（IDH1-R132H）的克隆U87和U251胶质瘤细胞系。与对照细胞和过表达IDH野生型（IDH1-WT）的细胞相比，两种类型的IDH1-R132H细胞对替莫唑胺（TMZ）和顺二氯二氨铂（CDDP）均表现出时间和剂量依赖性的更高敏感性。IDH1-R132H诱导的更高化疗敏感性与烟酰胺腺嘌呤二磷酸（NADPH）、谷胱甘肽（GSH）耗竭以及活性氧（ROS）生成有关。因此，在体外和体内，GSH均能有效消除IDH1-R132H诱导的生长抑制。我们的研究提供了直接证据，表明IDH1-R132H肿瘤患者生存率提高可能部分归因于IDH1-R132H蛋白对化疗敏感性的影响。与生存率提高相关的主要细胞事件是GSH耗竭和ROS生成增加。
