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

  1. Marianne Mazevet

    University of Paris-Saclay, Orsay, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Anissa Belhadef

    University of Paris-Saclay, Orsay, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Maxance Ribeiro

    University of Paris-Saclay, Orsay, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Delphine Dayde

    University of Paris-Saclay, Orsay, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8543-2352
  5. Anna Llach

    University of Paris-Saclay, Orsay, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Marion Laudette

    Institut des Maladies Metaboliques et Cardiovasculaires - I2MC, INSERM, Université de Toulouse, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Tiphaine Belleville

    Université Paris Descartes, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  8. Philippe Mateo

    University of Paris-Saclay, Orsay, France
    Competing interests
    The authors declare that no competing interests exist.
  9. Mélanie Gressette

    University of Paris-Saclay, Orsay, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Florence Lefebvre

    University of Paris-Saclay, Orday, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Ju Chen

    Department of Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Christilla Bachelot-Loza

    Université Paris Descartes, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  13. Catherine Rucker-Martin

    Faculte de Medecine, University of Paris-Saclay, Le Kremlin Bicêtre, France
    Competing interests
    The authors declare that no competing interests exist.
  14. Frank Lezoualch

    Institut des Maladies Métaboliques et Cardiovasculaires, Université de Toulouse, Toulouse, France
    Competing interests
    The authors declare that no competing interests exist.
  15. Bertrand Crozatier

    University of Paris-Saclay, Orsay, France
    Competing interests
    The authors declare that no competing interests exist.
  16. Jean-Pierre Benitah

    University of Paris-Saclay, Orsay, France
    Competing interests
    The authors declare that no competing interests exist.
  17. Marie-Catherine Vozenin

    Laboratoire de Radio-Oncologie, CHUV, Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2109-8073
  18. Rodolphe Fischmeister

    University of Paris-Saclay, Orsay, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2086-9865
  19. Ana-Maria Gomez

    University of Paris-Saclay, Orsay, France
    Competing interests
    The authors declare that no competing interests exist.
  20. Christophe Lemaire

    University of Paris-Saclay, Orsay, France
    Competing interests
    The authors declare that no competing interests exist.
  21. Eric Morel

    University of Paris-Saclay, Orsay, France
    For correspondence
    eric.morel@universite-paris-saclay.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1960-0121

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

  1. 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

  1. Preprint posted: June 17, 2021 (view preprint)
  2. Received: September 29, 2022
  3. Accepted: August 3, 2023
  4. Accepted Manuscript published: August 8, 2023 (version 1)
  5. Version of Record published: September 7, 2023 (version 2)
  6. 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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  1. Marianne Mazevet
  2. Anissa Belhadef
  3. Maxance Ribeiro
  4. Delphine Dayde
  5. Anna Llach
  6. Marion Laudette
  7. Tiphaine Belleville
  8. Philippe Mateo
  9. Mélanie Gressette
  10. Florence Lefebvre
  11. Ju Chen
  12. Christilla Bachelot-Loza
  13. Catherine Rucker-Martin
  14. Frank Lezoualch
  15. Bertrand Crozatier
  16. Jean-Pierre Benitah
  17. Marie-Catherine Vozenin
  18. Rodolphe Fischmeister
  19. Ana-Maria Gomez
  20. Christophe Lemaire
  21. Eric Morel
(2023)
EPAC1 inhibition protects the heart from doxorubicin-induced toxicity
eLife 12:e83831.
https://doi.org/10.7554/eLife.83831

Share this article

https://doi.org/10.7554/eLife.83831

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