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Decreasing GSH and increasing ROS in chemosensitivity gliomas with IDH1 mutation

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Tumor Biology

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.

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Acknowledgments

This study was supported by the Youth Fund of the National Natural Science Foundation of China (81201975; 81201979; 81201349), the Youth Fund of the Natural Science Foundation of Jiangsu Province (BK2012224), the Natural Science Foundation of China Ministry of Health (2010-2-025), the Natural Science Foundation of Jiangsu Department of Health (H201124), the Six Major Human Resources Project of Jiangsu Province (2011-WS-065; 2010-WS-038), and the Natural Science Foundation of Jiangsu Colleges and Universities Grant (11KJB320010).

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Authors and Affiliations

  1. Department of Neurosurgery, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, Jiangsu Province, 226001, China

    Jinlong Shi, Baolan Sun, Wei Shi, Hao Zuo, Lanchun Ni & Jian Chen

  2. Department of Neurosurgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 301 Yanchang Road, Shanghai, 200072, China

    Daming Cui

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  1. Jinlong Shi
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  2. Baolan Sun
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  3. Wei Shi
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  4. Hao Zuo
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Correspondence to Lanchun Ni or Jian Chen.

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Animal experiments were performed in strict compliance with the institutional animal care guidelines.

Jinlong Shi and Baolan Sun contributed equally to the work.

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Fig. S1

U251-IDH1-R132H cells increased the sensitivity to TMZ and CDDP. Cells were treated with varying doses of TMZ (A), CDDP (B), VCR (C), and VP-16 (D) for different incubation periods. Viability was quantitated with WST-1 assay and expressed as mean percentage of untreated control cells (mean ± SEM, n = 3). *P < 0.05, **P < 0.01 compared with control, IDH1-WT cells. (JPEG 43 kb)

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Shi, J., Sun, B., Shi, W. et al. Decreasing GSH and increasing ROS in chemosensitivity gliomas with IDH1 mutation. Tumor Biol. 36, 655–662 (2015). https://doi.org/10.1007/s13277-014-2644-z

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