Abstract P2182: Cardioprotective Effect Of APE1/Ref-1 In Doxorubicin-induced Cardiotoxicity

Abstract

Doxorubicin is a potent anthracycline anticancer drug widely used to treat various malignancies. Unfortunately, it can cause negative side effects such as cardiomyopathy. Apurinic apyrimidinic endonuclease 1/Redox factor-1 (APE1/Ref-1) is a versatile protein capable of being secreted from cells, but the role of secreted APE1/Ref-1 in doxorubicin-induced cardiomyopathy remains unknown. In this study, we used Adenoviral preprotrypsin leading sequence APE1/Ref-1 (Ad-PPTLS-APE1/Ref-1) to overexpress secreted APE1/Ref-1 in cells and mice through transfection. We aimed to investigate the potential role of secreted APE1/Ref-1 in preventing doxorubicin-induced cardiomyopathy, a serious side effect associated with the use of this widely used anticancer drug. Our findings reveal that exposure to secreted APE1/Ref-1 significantly decreases NT-proBNP levels, a known marker for cardiomyocyte injury, in doxorubicin-treated H9C2 cells. Furthermore, secreted APE1/Ref-1 was found to reduce the severity of cardiomyocyte injury and apoptosis both in vitro and in vivo models of doxorubicin cardiotoxicity. These cardioprotective effects were mediated through the inhibition of the p53 signaling pathway and the enhancement of cell viability in doxorubicin-treated cardiomyocytes.Our study provides evidence that secreted APE1/Ref-1 has the potential to attenuate oxidative stress and inhibit doxorubicin-induced apoptosis both in vitro and in vivo. Based on our results, supplementing secreted APE1/Ref-1 to patients at high risk of doxorubicin-induced cardiotoxicity could be a promising strategy for reducing the harmful effects of doxorubicin. Further studies are needed to fully understand the mechanism by which APE1/Ref-1 protects against doxorubicin-induced cardiotoxicity and to determine if this finding can be translated to human patients.