Abstract | BACKGROUND: METHODS:
Medulloblastoma cell lines, patient-derived xenograft cells, 3D spheroids and an innovative cerebellar organotypic model were used to identify synergistic interactions between β-blockers and ionising radiations. Gene expression profiles of β- adrenergic receptors were analysed in medulloblastoma samples from 240 patients. Signaling pathways were explored by RT-qPCR, RNA interference, western blotting and RNA sequencing. Medulloblastoma cell bioenergetics were evaluated by measuring the oxygen consumption rate, the extracellular acidification rate and superoxide production. FINDINGS: Low concentrations of β-blockers significantly potentiated clinically relevant radiation protocols. Although patient biopsies showed detectable expression of β- adrenergic receptors, the ability of the repurposed drugs to potentiate ionising radiations did not result from the inhibition of the canonical signaling pathway. We highlighted that the efficacy of the combinatorial treatment relied on a metabolic catastrophe that deprives medulloblastoma cells of their adaptive bioenergetics capacities. This led to an overproduction of superoxide radicals and ultimately to an increase in ionising radiations-mediated DNA damages. INTERPRETATION: These data provide the evidence of the efficacy of β-blockers as potentiators of radiotherapy in medulloblastoma, which may help improve the treatment and quality of life of children with high-risk brain tumours. FUNDING: This study was funded by institutional grants and charities.
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Authors | Maïlys Rossi, Julie Talbot, Patricia Piris, Marion Le Grand, Marie-Pierre Montero, Mélanie Matteudi, Emilie Agavnian-Couquiaud, Romain Appay, Céline Keime, Daniel Williamson, Duje Buric, Véronique Bourgarel, Laetitia Padovani, Steven C Clifford, Olivier Ayrault, Eddy Pasquier, Nicolas André, Manon Carré |
Journal | EBioMedicine
(EBioMedicine)
Vol. 82
Pg. 104149
(Aug 2022)
ISSN: 2352-3964 [Electronic] Netherlands |
PMID | 35816899
(Publication Type: Journal Article)
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Copyright | Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved. |
Chemical References |
- Receptors, Adrenergic, beta
- Superoxides
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Topics |
- Cerebellar Neoplasms
- Child
- Energy Metabolism
- Humans
- Medulloblastoma
(drug therapy, genetics, radiotherapy)
- Quality of Life
- Receptors, Adrenergic, beta
(metabolism, therapeutic use)
- Superoxides
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