Autophagy and oxidative stress in gliomas with IDH1 mutations

Gilbert, Misty R.; Liu, Yinxing; Neltner, Janna H.; Peng, Hong; Morris, Andrew J.; Sunkara, Manjula; Pittman, Thomas; Kyprianou, Natasha; Horbinski, Craig

doi:10.1007/s00401-013-1194-6

Cited by 66 publications

(70 citation statements)

References 39 publications

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“…This is in agreement with the fact that mitochondrial inhibitors such as metformin depend on oxidative stress to induce cell death (44). Previous reports have shown that D-2HG induces cellular oxidative stress (37)(38)(39)(40), although the underlying mechanisms remained elusive thus far. Our data indicate that inhibition of IDH-mediated NADPH production capacity and aKGDH-mediated NADH production capacity by D-2HG and the resulting metabolic stress is, at least partly, responsible for this phenomenon.…”

Section: Idhsupporting

confidence: 85%

Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198

et al. 2015

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Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human cancer to IDH1 R132H , a structural alteration that leads to catalysis of a-ketoglutarate to the oncometabolite D-2-hydroxyglutarate. In this study, we present evidence that small-molecule inhibitors of IDH1 R132H that are being developed for cancer therapy may pose risks with coadministration of radiotherapy. Cancer cells heterozygous for the IDH1 R132H mutation exhibited less IDH-mediated production of NADPH, such that after exposure to ionizing radiation (IR), there were higher levels of reactive oxygen species, DNA double-strand breaks, and cell death compared with IDH1 wild-type cells. These effects were reversed by the IDH1 R132H inhibitor AGI-5198. Exposure of IDH1 wild-type cells to D-2-hydroxyglutarate was sufficient to reduce IDH-mediated NADPH production and increase IR sensitivity. Mechanistic investigations revealed that the radiosensitivity of heterozygous cells was independent of the well-described DNA hypermethylation phenotype in IDH1-mutated cancers. Thus, our results argue that altered oxidative stress responses are a plausible mechanism to understand the radiosensitivity of IDH1-mutated cancer cells. Further, they offer an explanation for the relatively longer survival of patients with IDH1-mutated tumors, and they imply that administration of IDH1 R132H inhibitors in these patients may limit irradiation efficacy in this setting.

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Section: Idhsupporting

confidence: 85%

Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198

et al. 2015

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“…Cells were cultured in humidified conditions at 37°C and 5% CO 2 . Vector and R132H mutant IDH1 stable U87MG, U138MG, and LN18 cell lines were generated as previously described (25). (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTS) cell viability assays were performed as previously described (25).…”

Section: Methodsmentioning

confidence: 99%

“…SDS-PAGE and Western immunoblotting were done on cell lysates as previously described (25) using the following antibodies: anti-tubulin, (Cell Signaling, 2125), anti R132H IDH1 (Dianova, DIA-H09), and anti-Par-4 (Santa Cruz, sc-1807).…”

Section: Methodsmentioning

confidence: 99%

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The tumor suppressor prostate apoptosis response-4 (Par-4) is regulated by mutant IDH1 and kills glioma stem cells

et al. 2014

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Prostate apoptosis response-4 (Par-4) is an endogenous tumor suppressor that selectively induces apoptosis in a variety of cancers. Although it has been the subject of intensive research in other cancers, less is known about its significance in gliomas, including whether it is regulated by key driver mutations, has therapeutic potential against glioma stem cells (GSCs), and/or is a prognostic marker. We found that patient-derived gliomas with mutant isocitrate dehydrogenase 1 have markedly lower Par-4 expression (P < 0.0001), which was validated by The Cancer Genome Atlas dataset (P = 2.0 E-13). The metabolic product of mutant IDH1, D-2-hydroxyglutarate (2-HG), can suppress Par-4 transcription in vitro via inhibition of promoter activity as well as enhanced mRNA degradation, but interestingly not by direct DNA promoter hypermethylation. The Selective for Apoptosis induction in Cancer cells (SAC) domain within Par-4 is highly active against glioma cells, including orthotopic xenografts of patient-derived primary GSCs (P < 0.0001). Among high-grade gliomas that are IDH1 wild-type, those that express more Par-4 have significantly longer median survival (18.4 versus 8.0 months, P = 0.002), a finding confirmed in two external GBM cohorts. Together, these data suggest that Par-4 is a significant component of the mutant IDH1 phenotype, that the activity of 2-HG is complex and can extend beyond direct DNA hypermethylation, and that Par-4 is a promising therapeutic strategy against GSCs. Furthermore, not every effect of mutant IDH1 necessarily contributes to the overall favorable prognosis seen in such tumors; inhibition of Par-4 may be one such effect.

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“…21 The conversion of glutamate to αKG is catalysed by glutamate dehydrogenase, which is the final step of glutaminolysis and can be inhibited by the antimalaria drug chloroquine and the antidiabetic drug metformin 20 22–24. In addition, IDH1 -mutated glioma cells show increased levels of autophagy, likely as a survival mechanism of cells to metabolic stress by catabolising proteins in order to provide substrates for energy production in stress/starvation contexts 25. Autophagy is inhibited by chloroquine26 and the anticancer properties of chloroquine may thus be selective for IDH1/2 -mutated cells because it inhibits glutaminolysis and autophagy on which the cells are dependent.…”

Section: Introductionmentioning

confidence: 99%

Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients withIDH1-mutated orIDH2-mutated solid tumours

et al. 2017

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IntroductionHigh-grade chondrosarcoma, high-grade glioma and intrahepatic cholangiocarcinoma are aggressive types of cancer with a dismal outcome. This is due to the lack of effective treatment options, emphasising the need for novel therapies. Mutations in the genes IDH1 and IDH2 (isocitrate dehydrogenase 1 and 2) occur in 60% of chondrosarcoma, 80% of WHO grade II–IV glioma and 20% of intrahepatic cholangiocarcinoma. IDH1/2-mutated cancer cells produce the oncometabolite D-2-hydroxyglutarate (D-2HG) and are metabolically vulnerable to treatment with the oral antidiabetic metformin and the oral antimalarial drug chloroquine.Methods and analysisWe describe a dose-finding phase Ib/II clinical trial, in which patients with IDH1/2-mutated chondrosarcoma, glioma and intrahepatic cholangiocarcinoma are treated with a combination of metformin and chloroquine. Dose escalation is performed according to a 3+3 dose-escalation scheme. The primary objective is to determine the maximum tolerated dose to establish the recommended dose for a phase II clinical trial. Secondary objectives of the study include (1) determination of pharmacokinetics and toxic effects of the study therapy, for which metformin and chloroquine serum levels will be determined over time; (2) investigation of tumour responses to metformin plus chloroquine in IDH1/2-mutated cancers using CT/MRI scans; and (3) whether tumour responses can be measured by non-invasive D-2HG measurements (mass spectrometry and magnetic resonance spectroscopy) of tumour tissue, serum, urine, and/or bile or next-generation sequencing of circulating tumour DNA (liquid biopsies). This study may open a novel treatment avenue for IDH1/2-mutated high-grade chondrosarcoma, glioma and intrahepatic cholangiocarcinoma by repurposing the combination of two inexpensive drugs that are already approved for other indications.Ethics and disseminationThis study has been approved by the medical-ethical review committee of the Academic Medical Center, Amsterdam, The Netherlands. The report will be submitted to a peer-reviewed journal.Trial registration numberThis article was registered at ClinicalTrials.gov identifier (NCT02496741): Pre-results.

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Autophagy and oxidative stress in gliomas with IDH1 mutations

Cited by 66 publications

References 39 publications

Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198

Radioprotection of IDH1-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198

The tumor suppressor prostate apoptosis response-4 (Par-4) is regulated by mutant IDH1 and kills glioma stem cells

Study protocol of a phase IB/II clinical trial of metformin and chloroquine in patients withIDH1-mutated orIDH2-mutated solid tumours

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