Prokineticin Receptor-1 Signaling Inhibits Dose- and Time-Dependent Anthracycline-Induced Cardiovascular Toxicity Via Myocardial and Vascular Protection

Adeline Gasser (1) , Yue-Wen Chen (2) , Anais Audebrand (1) , Ayhan Daglayan (1) , Marine Charavin (1) , Brigitte Escoubet (3) , Pavel Karpov , Igor V Tetko , Michael W.Y. Chan , Daniela Cardinale , Laurent Desaubry (1) , Canan G Nebigil (1)

1 Laboratoire de Cardio-Oncologie et Chimie Médicinale
2 Institute of Biomedical sciences
3 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers

OBJECTIVES This study investigated how different concentrations of doxorubicin (DOX) can affect the function of cardiac cells. This study also examined whether activation of prokineticin receptor (PKR)-1 by a nonpeptide agonist, IS20, prevents DOX-induced cardiovascular toxicity in mouse models. BACKGROUND High prevalence of heart failure during and following cancer treatments remains a subject of intense research and therapeutic interest. METHODS This study used cultured cardiomyocytes, endothelial cells (ECs), and epicardium-derived progenitor cells (EDPCs) for in vitro assays, tumor-bearing models, and acute and chronic toxicity mouse models for in vivo assays. RESULTS Brief exposure to cardiomyocytes with high-dose DOX increased the accumulation of reactive oxygen species (ROS) by inhibiting a detoxification mechanism via stabilization of cytoplasmic nuclear factor, erythroid 2. Prolonged exposure to medium-dose DOX induced apoptosis in cardiomyocytes, ECs, and EDPCs. However, low-dose DOX promoted functional defects without inducing apoptosis in EDPCs and ECs. IS20 alleviated detrimental effects of DOX in cardiac cells by activating the serin threonin protein kinase B (Akt) or mitogen-activated protein kinase pathways. Genetic or pharmacological inactivation of PKR1 subdues these effects of IS20. In a chronic mouse model of DOX cardiotoxicity, IS20 normalized an elevated serum marker of cardiotoxicity and vascular and EDPC deficits, attenuated apoptosis and fibrosis, and improved the survival rate and cardiac function. IS20 did not interfere with the cytotoxicity or antitumor effects of DOX in breast cancer lines or in a mouse model of breast cancer, but it did attenuate the decreases in left ventricular diastolic volume induced by acute DOX treatment. CONCLUSIONS This study identified the molecular and cellular signature of dose-dependent, DOX-mediated cardiotoxicity and provided evidence that PKR-1 is a promising target to combat cardiotoxicity of cancer treatments.

Mots clés: breast cancer; doxorubicin; endothelial dysfunction; epicardial progenitor cells; heart failure

Domaines: Pharmacologie; Cardiologie et système cardiovasculaire

Adeline Gasser, Yue-Wen Chen, Anais Audebrand, Ayhan Daglayan, Marine Charavin, et al.. Prokineticin Receptor-1 Signaling Inhibits Dose- and Time-Dependent Anthracycline-Induced Cardiovascular Toxicity Via Myocardial and Vascular Protection. JACC: CardioOncology, 2019, 1 (1), pp.84-102. ⟨10.1016/j.jaccao.2019.06.003⟩. ⟨hal-03092065⟩