Abstract
Pediatric high grade glioma is refractory to conventional multimodal treatment, highlighting a need to develop novel efficacious therapies. We investigated tumor metabolism as a potential therapeutic target in a panel of diverse pediatric glioma cell lines (SF188, KNS42, UW479 and RES186) using metformin and 2-deoxyglucose. As a single agent, metformin had little effect on cell viability overall. SF188 cells were highly sensitive to 2-deoxyglucose however, combination of metformin with 2-deoxyglucose significantly reduced cell proliferation compared to either drug alone in all cell lines tested. In addition, the combination of the two agents was associated with a rapid decrease in cellular ATP and subsequent AMPK activation. However, increased cell death was only observed in select cell lines after prolonged exposure to the drug combination and was caspase independent. Anti-apoptotic BCL-2 family proteins have been indicated as mediators of resistance against metabolic stress. Therefore we sought to determine whether pharmacological inhibition of BCL-2/BCL-xL with ABT-263 could potentiate apoptosis in response to these agents. We found that ABT-263 increased sensitivity to 2-deoxyglucose and promoted rapid and extensive cell death in response to the combination of 2-deoxyglucose and metformin. Furthermore, cell death was inhibited by the pan-caspase inhibitor, z-VAD-FMK suggesting that ABT-263 potentiated caspase-dependent cell death in response to 2-deoxyglucose or its combination with metformin. Overall, these data provide support for the concept that targeting metabolic and anti-apoptotic pathways may be an effective therapeutic strategy in pediatric glioma.
Highlights
Pediatric high grade glioma comprises a heterogeneous group of brain tumors which are refractory to conventional multimodal therapy [1,2,3,4]
In order to examine the potential of cellular metabolism as a therapeutic target in pediatric glioma, we investigated the effect of the drugs metformin and 2DG on a diverse panel of previously characterized cell lines (SF188 and KNS42; grade IV glioblastoma multiforme, UW479; grade III anaplastic astrocytoma and RES186; grade I pilocytic astrocytoma) [24]
In this study we examined the concept of targeting tumour metabolism in a diverse panel of pediatric glioma cell lines using the glycolysis inhibitor 2DG, and metformin, a diabetes drug which has emerged as a promising anti-cancer agent
Summary
Pediatric high grade glioma comprises a heterogeneous group of brain tumors which are refractory to conventional multimodal therapy [1,2,3,4]. Recent studies in intact brain tumors and human orthotopic mouse models of glioblastoma have demonstrated that their metabolism in vivo involves extensive mitochondrial oxidation of glucose [8,9] These findings indicate both glycolysis and mitochondrial glucose oxidation are necessary to support the rapid and aggressive growth observed in high grade glioma [10]. Mitochondrial metabolism has been linked to drug resistance in glioblastoma, as DNA damaging agents have been shown to induce a cytoprotective ATP surge via oxidative phosphorylation [11] These data indicate that therapeutic strategies directed against the metabolism of these tumors may need to target both glycolysis and mitochondrial oxidative phosphorylation in order to be effective
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