Abstract 11067: ABCB10 Overexpression Prevents Acute Doxorubicin-Induced Cardiac Dysfunction

Abstract

Introduction: Doxorubicin (DOX) is a highly effective chemotherapy agent used to treat solid tumor cancers and hematological malignancies. However, DOX treatment can cause adverse cardiac events, which can negatively affect patient outcomes by limiting cancer treatment and reducing overall survival. DOX-induced cardiotoxicity occurs due to its off-target accumulation within cardiomyocytes following administration. Within the heart, DOX predominantly localizes within the mitochondria where it promotes cellular injury via the production of reactive oxygen species (ROS). Currently, there is no clinically approved therapy to prevent this debilitating condition. Therefore, work is needed to identify therapeutic countermeasures to prevent DOX cardiotoxicity. In this regard, ABCB10 is a mitochondria-localized ATP-binding cassette transporter that is hypothesized to play a role in the maintenance of mitochondrial redox balance and iron homeostasis. Hypothesis: We hypothesize that cardiac overexpression of ABCB10 would reduce DOX-induced oxidative damage and preserve cardiac function. Methods: Cause and effect were determined by overexpressing ABCB10 in the heart using an AAV9-MHCK7-ABCB10 construct. Acute effects of DOX (20 mg/kg i.p.) on the heart were assessed by echocardiography. Results: Our findings confirm that DOX treatment results in detriments to both cardiac and mitochondrial function 48-hours following administration. Importantly, cardiac overexpression of ABCB10 was sufficient to prevent the DOX-induced reduction in mitochondrial respiratory control ratio. In addition, both left ventricular fractional shortening percentage and myocardial performance index were preserved in ABCB10 overexpressing animals treated acutely with DOX. Conclusions: ABCB10 overexpression in the heart is an effective intervention to prevent cardiotoxicity and mitochondrial dysfunction acutely following DOX chemotherapy treatment.