EPAC1 inhibition protects the heart from doxorubicin-induced toxicity
- University of Paris-Saclay, France
- Université de Toulouse, France
- Université Paris Descartes, France
- University of California, San Diego, United States
- CHUV, Switzerland
Abstract
Anthracyclines, such as doxorubicin (Dox), are widely used chemotherapeutic agents for the treatment of solid tumors and hematologic malignancies. However, they frequently induce cardiotoxicity leading to dilated cardiomyopathy and heart failure. This study sought to investigate the role of the Exchange Protein directly Activated by cAMP (EPAC) in Dox-induced cardiotoxicity and the potential cardioprotective effects of EPAC inhibition. We show that Dox induces DNA damage and cardiomyocyte cell death with apoptotic features. Dox also led to an increase in both cAMP concentration and EPAC1 activity. The pharmacological inhibition of EPAC1 (with CE3F4) but not EPAC2 alleviated the whole Dox-induced pattern of alterations. When administered in vivo, Dox-treated WT mice developed a dilated cardiomyopathy which was totally prevented in EPAC1 KO mice. Moreover, EPAC1 inhibition potentiated Dox-induced cell death in several human cancer cell lines. Thus, EPAC1 inhibition appears as a potential therapeutic strategy to limit Dox-induced cardiomyopathy without interfering with its antitumoral activity.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1 to 7 and supplementary Figure.
Article and author information
Author details
Marie-Catherine Vozenin
Rodolphe Fischmeister
Funding
Agence Nationale de la Recherche (ANR-13-BSV1-0023)
- Ana-Maria Gomez
Agence Nationale de la Recherche (ANR-15-CE14-0005)
- Jean-Pierre Benitah
- Ana-Maria Gomez
LabEx LERMIT (ANR-10-LABX-0033)
- Marianne Mazevet
- Rodolphe Fischmeister
- Eric Morel
DHU TORINO
- Marie-Catherine Vozenin
- Rodolphe Fischmeister
- Ana-Maria Gomez
- Eric Morel
Leducq Foundation for Cardiovascular Research (19CVD02)
- Delphine Dayde
- Rodolphe Fischmeister
- Eric Morel
EU MILEAGE (project #734931)
- Jean-Pierre Benitah
- Rodolphe Fischmeister
- Ana-Maria Gomez
Lefoulon Delalande fellowship (Graduate Student Fellowship)
- Anna Llach
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Arduino A Mangoni, Flinders Medical Centre, Australia
Ethics
Animal experimentation: All animal experiments were conducted in line with the French/European Union Council Directives for the laboratory animals care 86/609/EEC, (MESRI 18927 authorization).
Version history
- Preprint posted: June 17, 2021 (view preprint)
- Received: September 29, 2022
- Accepted: August 3, 2023
- Accepted Manuscript published: August 8, 2023 (version 1)
- Version of Record published: September 7, 2023 (version 2)
- Version of Record updated: October 16, 2023 (version 3)
Copyright
© 2023, Mazevet et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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EPAC1 inhibition protects the heart from doxorubicin-induced toxicity
eLife 12:e83831.
https://doi.org/10.7554/eLife.83831
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