Dataset Information

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%, 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.

INSTRUMENT(S): Liquid Chromatography MS - Alternating (LC-MS (Alternating))

SUBMITTER: Isabel Vincent

PROVIDER: MTBLS858 | MetaboLights | 2022-11-30

REPOSITORIES: MetaboLights

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

Nile Donna L DL Rae Colin C Walker David J DJ Waddington Joe Canning JC Vincent Isabel I Burgess Karl K Gaze Mark N MN Mairs Robert J RJ Chalmers Anthony J AJ

Cancer & metabolism 20210519 1

<h4>Background</h4>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 ...[more]

PMID: 34011385

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	MTBLS858	Other
	FILES	Other
	a_MTBLS858_NEG_mass_spectrometry.txt	Txt
	a_MTBLS858_POS_mass_spectrometry.txt	Txt
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