Beta-blockers disrupt mitochondrial bioenergetics and increase radiotherapy efficacy independently of beta-adrenergic receptors in medulloblastoma - Archive ouverte HAL Access content directly
Journal Articles EBioMedicine Year : 2022

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

Maïlys Rossi
Julie Talbot
  • Function : Author
Patricia Piris
Marion Le Grand
Marie-Pierre Montero
Mélanie Matteudi
  • Function : Author
Emilie Agavnian-Couquiaud
  • Function : Author
Romain Appay
  • Function : Author
Céline Keime
Daniel Williamson
  • Function : Author
Duje Buric
  • Function : Author
Véronique Bourgarel
  • Function : Author
Laetitia Padovani
  • Function : Author
Steven Clifford
  • Function : Author
Olivier Ayrault
  • Function : Author
Eddy Pasquier
  • Function : Author
Nicolas André
  • Function : Author
Manon Carré

Abstract

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.
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Dates and versions

hal-03795367 , version 1 (04-10-2022)

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Maïlys Rossi, Julie Talbot, Patricia Piris, Marion Le Grand, Marie-Pierre Montero, et al.. Beta-blockers disrupt mitochondrial bioenergetics and increase radiotherapy efficacy independently of beta-adrenergic receptors in medulloblastoma. EBioMedicine, 2022, 82 (7), pp.104149. ⟨10.1016/j.ebiom.2022.104149⟩. ⟨hal-03795367⟩
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