Abstract 9450: Exercise Reduces Myocardial Doxorubicin Accumulation by Upregulating Multidrug Resistance Protein Expression

Abstract

Background: The anthracycline antibiotic doxorubicin (DOX) is an effective antineoplastic agent. However, treatment with DOX is associated with a dose-dependent cardiotoxicity that can lead to dilated cardiomyopathy and congestive heart failure. While previous studies have reported that exercise preconditioning can reduce DOX accumulation within the myocardium, the mechanisms are unknown. Members of the ATP binding cassette transporter superfamily, multidrug resistance proteins 1, 2 and 7 (MRP-1. -2, -7) are known to extrude DOX from cells and their expression may factor into the degree of cardiac DOX accumulation and therefore the severity of cardiac dysfunction. We hypothesized that exercise elicits an upregulation of MRP expression, which leads to a reduction in DOX accumulation. Methods and Results: Male Sprague-Dawley rats were randomly assigned to undergo 10-weeks of voluntary wheel running (WR: n=15) or remain sedentary (SED: n=15). Upon completion of 10-weeks, rats were further randomized to receive a 15mg/kg body weight bolus i.p. injection of DOX (WR-DOX: n=8, SED-DOX: n=7) or equivalent volume of saline (WR-SAL: n=8, SED-SAL: n=7). Animals were sacrificed 24-hours following injection and hearts were excised, flushed of blood, and left ventricles were isolated. High performance liquid chromatography was utilized to quantify myocardial DOX accumulation and Western blotting to analyze MRP expression. A significant reduction in DOX accumulation was observed in WR animals when compared to SED (1055±189 ng/g vs. 1284±151 ng/g). When compared to SED-SAL, all groups exhibited an increase in MRP-2 and MRP-7 expression (WR-DOX: MRP-2, 83% increase; MRP-7, 337% increase. SED-DOX: MRP-2, 107% increase; MRP-7, 193% increase. WR-SAL: MRP-2, 99% increase; MRP-7, 179% increase). In addition, MRP-1 was significantly increased in DOX treated groups (WR-DOX: 136% increase. SED-DOX: 79% increase), however, no significant differences were observed with exercise (WR-SAL: 56% increase). Conclusion: An upregulation of myocardial MRP-2 and MRP-7 expression with exercise contributes to a decrease in myocardial DOX accumulation and may result in a subsequent cardioprotective effect. DOX exposure alone also induces an upregluation of MRPs.