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

Autor: Nile DL; Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK. Donna.Nile@nhs.net.; Present Address: Integrated Covid Hub North East (ICHNE) Innovation Laboratory, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE4 5BX, UK. Donna.Nile@nhs.net., Rae C; Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK., Walker DJ; Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK.; Present Address: School of Medicine, University of Dundee, Dundee, DD1 4HN, UK., Waddington JC; Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK., Vincent I; Glasgow Polyomics Facility, University of Glasgow, Glasgow, G61 1QH, UK.; Present Address: Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE, UK., Burgess K; Glasgow Polyomics Facility, University of Glasgow, Glasgow, G61 1QH, UK.; Present Address: School of Biological Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK., Gaze MN; Department of Oncology, University College London Hospitals NHS Foundation Trust, London, NW1 2BU, UK., Mairs RJ; Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK., Chalmers AJ; Institute of Cancer Sciences, University of Glasgow, Glasgow, G61 1QH, UK.
Jazyk: angličtina
Zdroj: Cancer & metabolism [Cancer Metab] 2021 May 19; Vol. 9 (1), pp. 24. Date of Electronic Publication: 2021 May 19.
DOI: 10.1186/s40170-021-00258-5
Abstrakt: 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 G 2 /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.
Databáze: MEDLINE
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