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Beta-blockers disrupt mitochondrial bioenergetics and increase radiotherapy efficacy independently of beta-adrenergic receptors in medulloblastoma

Lookup NU author(s): Dr Daniel Williamson, Professor Steven CliffordORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2022 The Author(s)Background: Medulloblastoma is the most frequent brain malignancy of childhood. The current multimodal treatment comes at the expense of serious and often long-lasting side effects. Drug repurposing is a strategy to fast-track anti-cancer therapy with low toxicity. Here, we showed the ability of β-blockers to potentiate radiotherapy in medulloblastoma with bad prognosis. 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.

Publication metadata

Author(s): Rossi M, Talbot J, Piris P, Grand ML, Montero M-P, Matteudi M, Agavnian-Couquiaud E, Appay R, Keime C, Williamson D, Buric D, Bourgarel V, Padovani L, Clifford SC, Ayrault O, Pasquier E, Andre N, Carre M

Publication type: Article

Publication status: Published

Journal: eBioMedicine

Year: 2022

Volume: 82

Online publication date: 08/07/2022

Acceptance date: 02/04/2018

Date deposited: 23/06/2023

ISSN (electronic): 2352-3964

Publisher: Elsevier B.V.


DOI: 10.1016/j.ebiom.2022.104149

PubMed id: 35816899


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Funder referenceFunder name
Canceropole PACA
Cancer Research UK
Courir pour la Vie - Courir pour Curie, Ligue Contre le Cancer - Corse Sud
La Compagnie Apres la Pluie
Institut National du Cancer and Region Sud
La Marie-Do
Societe Francaise des Cancers de l'Enfant