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.
Metrics
-
- 780
- views
-
- 161
- downloads
-
- 1
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
EPAC1 inhibition protects the heart from doxorubicin-induced toxicity
eLife 12:e83831.
https://doi.org/10.7554/eLife.83831
Further reading
-
- Cancer Biology
Certain bacteria demonstrate the ability to target and colonize the tumor microenvironment, a characteristic that positions them as innovative carriers for delivering various therapeutic agents in cancer therapy. Nevertheless, our understanding of how bacteria adapt their physiological condition to the tumor microenvironment remains elusive. In this work, we employed liquid chromatography-tandem mass spectrometry to examine the proteome of E. coli colonized in murine tumors. Compared to E. coli cultivated in the rich medium, we found that E. coli colonized in tumors notably upregulated the processes related to ferric ions, including the enterobactin biosynthesis and iron homeostasis. This finding indicated that the tumor is an iron-deficient environment to E. coli. We also found that the colonization of E. coli in the tumor led to an increased expression of lipocalin 2 (LCN2), a host protein that can sequester the enterobactin. We therefore engineered E. coli in order to evade the nutritional immunity provided by LCN2. By introducing the IroA cluster, the E. coli synthesizes the glycosylated enterobactin, which creates steric hindrance to avoid the LCN2 sequestration. The IroA-E. coli showed enhanced resistance to LCN2 and significantly improved the anti-tumor activity in mice. Moreover, the mice cured by the IroA-E. coli treatment became resistant to the tumor re-challenge, indicating the establishment of immunological memory. Overall, our study underscores the crucial role of bacteria’s ability to acquire ferric ions within the tumor microenvironment for effective cancer therapy.
-
- Cancer Biology
- Cell Biology
Mutations in the gene for β-catenin cause liver cancer cells to release fewer exosomes, which reduces the number of immune cells infiltrating the tumor.
