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

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 > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
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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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
171879Exploitation of the elevated metabolic activity of cancer cells for combination with targeted radiotherapy of neuroblastoma 15-191Anthony ChalmersChildren with Cancer UK (CHILDCAN)15-191CS - Epigenetics
301290Two radiopharmaceuticals for treatment of neuroblastomaAnthony ChalmersChildren with Cancer UK (CHILDCAN)17-243CS - Epigenetics
173707Institutional Strategic Support Fund (2016)Anna DominiczakWellcome Trust (WELLCOTR)204820/Z/16/ZInstitute of Cardiovascular & Medical Sciences