Neuroblastoma accounts for 7% of paediatric malignancies but is responsible for 15% of all childhood cancer deaths. Despite rigorous treatment involving chemotherapy, surgery, radiotherapy and immunotherapy, the 5-year overall survival rate of high-risk disease remains < 40%, highlighting the need for improved therapy. Since neuroblastoma cells exhibit aberrant metabolism, we determined whether their sensitivity to radiotherapy could be enhanced by drugs affecting cancer cell metabolism. Using a panel of neuroblastoma and glioma cells, we determined the radiosensitising effects of inhibitors of glycolysis (2-DG) and mitochondrial function (metformin). Mechanisms underlying radiosensitisation were determined by metabolomic and bioenergetic profiling, flow cytometry and live cell imaging and by evaluating different treatment schedules. The radiosensitising effects of 2-DG were greatly enhanced by combination with the antidiabetic biguanide, metformin. Metabolomic analysis and cellular bioenergetic profiling revealed this combination to elicit severe disruption of key glycolytic and mitochondrial metabolites, causing significant reductions in ATP generation and enhancing radiosensitivity. Combination treatment induced G2/M arrest that persisted for at least 24 h post-irradiation, promoting apoptotic cell death in a large proportion of cells. Our findings demonstrate that the radiosensitising effect of 2-DG was significantly enhanced by its combination with metformin. This clearly demonstrates that dual metabolic targeting has potential to improve clinical outcomes in children with high-risk neuroblastoma by overcoming radioresistance.

中文翻译：

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糖酵解和线粒体呼吸的抑制促进神经母细胞瘤和神经胶质瘤细胞的放射增敏


神经母细胞瘤占儿科恶性肿瘤的 7%，但占所有儿童癌症死亡的 15%。尽管经过化疗、手术、放疗和免疫治疗等严格治疗，但高危疾病的 5 年总体生存率仍然低于 40%，这凸显了治疗改进的必要性。由于神经母细胞瘤细胞表现出异常的代谢，我们确定影响癌细胞代谢的药物是否可以增强它们对放射治疗的敏感性。使用一组神经母细胞瘤和神经胶质瘤细胞，我们确定了糖酵解抑制剂 (2-DG) 和线粒体功能抑制剂（二甲双胍）的放射增敏作用。通过代谢组学和生物能分析、流式细胞术和活细胞成像以及评估不同的治疗方案来确定放射增敏的机制。与抗糖尿病双胍二甲双胍联合使用，2-DG 的放射增敏作用大大增强。代谢组学分析和细胞生物能量分析表明，这种组合会引起关键糖酵解和线粒体代谢物的严重破坏，导致 ATP 生成显着减少并增强放射敏感性。联合治疗诱导 G2/M 期停滞，并在照射后持续至少 24 小时，促进大部分细胞凋亡。我们的研究结果表明，2-DG 与二甲双胍联合使用可显着增强放射增敏作用。这清楚地表明，双重代谢靶向有可能通过克服放射抗性来改善高危神经母细胞瘤儿童的临床结果。