Anti-cancer agent Olaparib ameliorates doxorubicin-induced cardiotoxicity in vitro and in vivo

Abstract

Inhibition of poly (ADP-ribose) polymerase (PARP) has shown cardioprotective effects in myocardial injury, and PARP activation has been implicated in Doxorubicin-induced cardiotoxicity (DIC). Thus, PARP inhibition may be a potential preventive therapy for DIC. The present study aims to determine the cardioprotective effects of Olaparib in preventing DIC in in vitro and in vivo models. In vitro: Human cardiomyocytes (HCM) were treated with Doxorubicin at 1 μM (EC50) +/− 80 μM of Olaparib for 48 and 72 h, assessing cell viability (CellTiter-Glo®) and conducted gene expression analysis; Concomitant Olaparib treatment prevented Doxorubicin-induced impairment of HCM viability. Doxorubicin induced upregulation of mRNA expressions of genes involved in apoptosis: CASP3; DNA damage: BBC3; and cardiac remodeling: TGF-β; −all were reversed by Olaparib. In vivo: Female C57BL/6 mice were administered intraperitoneally either: A) vehicle of 0.9 % saline and 8 % DMSO in PBS; B) Doxorubicin at 5 mg/kg/wk. for 5 weeks; C) Olaparib at a dose of 50 mg/kg in 8 % DMSO, administered 3 times/week; D) Olaparib at 50 mg/kg, administered 3 times/week, started one week prior to commencement of Doxorubicin treatments at 5 mg/kg/week. Serial echocardiography was performed. mRNA, protein expressions and RNA sequencing were performed in the cardiac tissues; Doxorubicin induced significant LV dysfunction after 6 weeks of treatment; whereas the mice treated with Olaparib in combination with Doxorubicin showed preservation of cardiac function. Analysis of RNA-seq and Western blot data suggested that Olaparib's cardioprotective effects in DIC may involve regulating innate immune responses by lowering cGAS-STING levels, elevated by Doxorubicin. Olaparib protects HCM against DIC both in vitro and in vivo. This is mediated in part via cGAS-STING pathway.