Nile, D. L., Rae, C. , Walker, D. J. , Canning Waddington, J., Vincent, I. , Burgess, K., Gaze, M. N., Mairs, R. J. and Chalmers, A. J. (2021) Inhibition of glycolysis and mitochondrial respiration promotes radiosensitisation of neuroblastoma and glioma cells. Cancer and Metabolism, 9, 24. (doi: 10.1186/s40170-021-00258-5) (PMID:34011385) (PMCID:PMC8136224)
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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.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Burgess, Dr Karl and Rae, Dr Colin and Nile, Dr Donna and Chalmers, Professor Anthony and Vincent, Dr Isabel and Walker, Dr David and Mairs, Professor Robert |
| Authors: | Nile, D. L., Rae, C., Walker, D. J., Canning Waddington, J., Vincent, I., Burgess, K., Gaze, M. N., Mairs, R. J., and Chalmers, A. J. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Infection & Immunity |
| Journal Name: | Cancer and Metabolism |
| Publisher: | BioMed Central |
| ISSN: | 2049-3002 |
| ISSN (Online): | 2049-3002 |
| Copyright Holders: | Copyright © 2021 The Authors |
| First Published: | First published in Cancer and Metabolism 9: 24 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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