Inhibition of glycolysis and mitochondrial respiration promotes radiosensitisation of neuroblastoma and glioma cells

Donna L. Nile (Lead / Corresponding author), Colin Rae, David J. Walker, Joe Canning Waddington, Isabel Vincent, Karl Burgess, Mark N. Gaze, Robert J. Mairs, Anthony J. Chalmers

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    Abstract

    Background: 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.

    Methods: 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.

    Results: 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.

    Conclusion: 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.

    Original languageEnglish
    Article number24
    Pages (from-to)24
    Number of pages15
    JournalCancer & Metabolism
    Volume9
    Early online date19 May 2021
    DOIs
    Publication statusPublished - 19 May 2021

    Keywords

    • Neuroblastoma
    • Radiation
    • Metabolism
    • 2-DG
    • Metformin
    • 131I-MIBG
    • Research

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