Inhibition of glycolysis and mitochondrial respiration promotes radiosensitisation of neuroblastoma and glioma cells
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%,...
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doaj-18c074a3dffa4f188c780def00713faa2021-05-23T11:10:49ZengBMCCancer & Metabolism2049-30022021-05-019111510.1186/s40170-021-00258-5Inhibition of glycolysis and mitochondrial respiration promotes radiosensitisation of neuroblastoma and glioma cellsDonna L. Nile0Colin Rae1David J. Walker2Joe Canning Waddington3Isabel Vincent4Karl Burgess5Mark N. Gaze6Robert J. Mairs7Anthony J. Chalmers8Institute of Cancer Sciences, University of GlasgowInstitute of Cancer Sciences, University of GlasgowInstitute of Cancer Sciences, University of GlasgowInstitute of Cancer Sciences, University of GlasgowGlasgow Polyomics Facility, University of GlasgowGlasgow Polyomics Facility, University of GlasgowDepartment of Oncology, University College London Hospitals NHS Foundation TrustInstitute of Cancer Sciences, University of GlasgowInstitute of Cancer Sciences, University of GlasgowAbstract 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.https://doi.org/10.1186/s40170-021-00258-5NeuroblastomaRadiationMetabolism2-DGMetformin131I-MIBG |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Donna L. Nile Colin Rae David J. Walker Joe Canning Waddington Isabel Vincent Karl Burgess Mark N. Gaze Robert J. Mairs Anthony J. Chalmers |
spellingShingle |
Donna L. Nile Colin Rae David J. Walker Joe Canning Waddington Isabel Vincent Karl Burgess Mark N. Gaze Robert J. Mairs Anthony J. Chalmers Inhibition of glycolysis and mitochondrial respiration promotes radiosensitisation of neuroblastoma and glioma cells Cancer & Metabolism Neuroblastoma Radiation Metabolism 2-DG Metformin 131I-MIBG |
author_facet |
Donna L. Nile Colin Rae David J. Walker Joe Canning Waddington Isabel Vincent Karl Burgess Mark N. Gaze Robert J. Mairs Anthony J. Chalmers |
author_sort |
Donna L. Nile |
title |
Inhibition of glycolysis and mitochondrial respiration promotes radiosensitisation of neuroblastoma and glioma cells |
title_short |
Inhibition of glycolysis and mitochondrial respiration promotes radiosensitisation of neuroblastoma and glioma cells |
title_full |
Inhibition of glycolysis and mitochondrial respiration promotes radiosensitisation of neuroblastoma and glioma cells |
title_fullStr |
Inhibition of glycolysis and mitochondrial respiration promotes radiosensitisation of neuroblastoma and glioma cells |
title_full_unstemmed |
Inhibition of glycolysis and mitochondrial respiration promotes radiosensitisation of neuroblastoma and glioma cells |
title_sort |
inhibition of glycolysis and mitochondrial respiration promotes radiosensitisation of neuroblastoma and glioma cells |
publisher |
BMC |
series |
Cancer & Metabolism |
issn |
2049-3002 |
publishDate |
2021-05-01 |
description |
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. |
topic |
Neuroblastoma Radiation Metabolism 2-DG Metformin 131I-MIBG |
url |
https://doi.org/10.1186/s40170-021-00258-5 |
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