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

Adeline Gasser; Yu-Wen Chen; Anais Audebrand; Ayhan Daglayan; Marine Charavin; Brigitte Escoubet; Pavel Karpov; Igor Tetko; Michael W Y Chan; Daniela Cardinale; Laurent Désaubry; Canan G Nebigil

doi:10.1016/j.jaccao.2019.06.003

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

JACC CardioOncol. 2019 Jul 10;1(1):84-102. doi: 10.1016/j.jaccao.2019.06.003. eCollection 2019 Sep.

Authors

Affiliations

¹ Laboratory of Cardio-Oncology and Medicinal Chemistry, CNRS (FRE2033), Illkirch, France.
² Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
³ FRIM UMS37, Hospital Bichat assistance public-Paris Hospital, University of Paris Diderot, PRES Paris Cité, DHU FIRE, Inserm U1138, Paris, France.
⁴ Institute of Structural Biology, Helmholtz Zentrum München-German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
⁵ Department of Biomedical Sciences, National Chung Cheng University, Chiayi, Taiwan.
⁶ Cardioncology Unit, European Institute of Oncology, I.R.C.C.S., Milan Italy.

Abstract

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.

Keywords: DMSO, dimethyl sulfoxide; EC, endothelial cell; EDPC, epicardium-derived progenitor cell; EF, ejection fraction; FS, fractional shortening; GPCR, G-protein–coupled receptor; HAEC, human aortic endothelial cell; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; MAPK, mitogen-activated protein kinase; NRF2, nuclear factor, erythroid 2 like 2 (also known as NFE2L2); PECAM, platelet and endothelial cell adhesion molecule; PKR1, prokineticin receptor-1 (also known as PROKR1); PKR1-KO, prokineticin receptor 1 knockout mice; PROK1, prokineticin 1; PROK2, prokineticin 2; TUNEL, terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling; breast cancer; doxorubicin; endothelial dysfunction; epicardial progenitor cells; heart failure.