Translational Neuro-Oncology Group, Leeds Institute of Molecular Medicine, University of Leeds, St James's University Hospital, Leeds, United Kingdom.
PLoS One. 2013 May 17;8(5):e64051. doi: 10.1371/journal.pone.0064051. Print 2013.
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.
儿科高级别神经胶质瘤对传统的多模式治疗具有抗性，这突出表明需要开发新的有效治疗方法。我们使用二甲双胍和 2-脱氧葡萄糖研究了一系列不同的儿科神经胶质瘤细胞系（SF188、KNS42、UW479 和 RES186）中的肿瘤代谢作为潜在的治疗靶点。作为单一药物，二甲双胍对细胞活力的总体影响不大。然而，SF188 细胞对 2-脱氧葡萄糖高度敏感，与单独使用任何一种药物相比，二甲双胍与 2-脱氧葡萄糖联合使用可显著降低所有测试细胞系的细胞增殖。此外，两种药物的联合使用与细胞内 ATP 的快速减少和随后的 AMPK 激活有关。然而，只有在延长暴露于药物联合后，才会观察到某些细胞系中细胞死亡增加，并且这种增加与 Caspase 无关。抗凋亡 BCL-2 家族蛋白已被表明是代谢应激抗性的介导物。因此，我们试图确定用 ABT-263 抑制 BCL-2/BCL-xL 是否可以增强这些药物的细胞凋亡。我们发现，ABT-263 增加了对 2-脱氧葡萄糖的敏感性，并促进了对 2-脱氧葡萄糖和二甲双胍联合使用的快速和广泛的细胞死亡。此外，用 pan-caspase 抑制剂 z-VAD-FMK 抑制细胞死亡，这表明 ABT-263 增强了 2-脱氧葡萄糖或其与二甲双胍联合使用时 Caspase 依赖性细胞死亡。总的来说，这些数据为靶向代谢和抗凋亡途径可能是儿科神经胶质瘤的有效治疗策略这一概念提供了支持。
