Decreasing GSH and increasing ROS in chemosensitivity gliomas with IDH1 mutation.

Abstract

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.

• Authors: Jinlong Shi, Baolan Sun, Wei Shi, Hao Zuo, Daming Cui, Lanchun Ni, Jian Chen
• Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine (Tumour Biol) Vol. 36 Issue 2 Pg. 655-62 (Feb 2015) ISSN: 1423-0380 [Electronic] Netherlands
• PMID: 25283382 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Reactive Oxygen Species
• Dacarbazine
• Isocitrate Dehydrogenase
• IDH1 protein, human
• Cisplatin
• Temozolomide

Topics

• Cell Proliferation
• Cisplatin (administration & dosage)
• Dacarbazine (administration & dosage, analogs & derivatives)
• Gene Expression Regulation, Neoplastic (drug effects)
• Glioma (drug therapy, genetics, pathology)
• Humans
• Isocitrate Dehydrogenase (biosynthesis, genetics)
• Mutation
• Prognosis
• Reactive Oxygen Species (metabolism)
• Temozolomide