학술논문
EPAC1 inhibition protects the heart from doxorubicin-induced toxicity
Document Type
article
Author
Marianne Mazevet; Anissa Belhadef; Maxance Ribeiro; Delphine Dayde; Anna Llach; Marion Laudette; Tiphaine Belleville; Philippe Mateo; Mélanie Gressette; Florence Lefebvre; Ju Chen; Christilla Bachelot-Loza; Catherine Rucker-Martin; Frank Lezoualch; Bertrand Crozatier; Jean-Pierre Benitah; Marie-Catherine Vozenin; Rodolphe Fischmeister; Ana-Maria Gomez; Christophe Lemaire; Eric Morel
Source
eLife, Vol 12 (2023)
Subject
Language
English
ISSN
2050-084X
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 knock-out (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.