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Updated: Apr 23, 2026
A Protocol for Explant Cultures of IDH1-mutant Diffuse Low-grade Gliomas
Published on: May 9, 2025
Decreasing GSH and increasing ROS in chemosensitivity gliomas with IDH1 mutation
Jinlong Shi1, Baolan Sun, Wei Shi
1Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu Province, 226001, People's Republic of China.
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.
Insights
Isocitrate dehydrogenase 1 (IDH1) mutations in glioma patients enhance sensitivity to chemotherapy drugs like temozolomide. This improved chemosensitivity is linked to glutathione depletion and increased reactive oxygen species, contributing to better survival rates.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Cancer Research
Background:
- Gliomas are aggressive adult primary brain tumors with poor prognosis.
- Isocitrate dehydrogenase 1 (IDH1) mutations are common in glioma patients and correlate with improved survival.
- The impact of IDH1 mutations on glioma chemosensitivity is not well understood.
Purpose of the Study:
- To investigate the effect of IDH1-R132H mutations on glioma chemosensitivity.
- To elucidate the cellular mechanisms underlying IDH1-R132H-mediated chemosensitivity.
Main Methods:
- Generated U87 and U251 glioma cell lines overexpressing IDH1-R132H mutant protein.
- Assessed chemosensitivity to temozolomide (TMZ) and cis-diamminedichloroplatinum (CDDP).
- Measured levels of nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), and reactive oxygen species (ROS).
Main Results:
- IDH1-R132H-overexpressing cells showed increased sensitivity to TMZ and CDDP.
- Enhanced chemosensitivity correlated with GSH depletion and increased ROS generation.
- GSH supplementation abrogated the IDH1-R132H-induced growth inhibition in vitro and in vivo.
Conclusions:
- IDH1-R132H mutations enhance glioma chemosensitivity, potentially explaining improved patient survival.
- GSH depletion and increased ROS are key cellular events mediating this effect.
- Targeting these pathways could offer new therapeutic strategies for IDH1-mutant gliomas.
