Effect of Exercise Preconditioning on Doxorubicin Accumulation in Left Ventricular Tissue

Abstract

Doxorubicin (DOX) is an anthracycline antibiotic that has cytotoxic actions. The therapeutic use of DOX to treat a wide array of cancers is limited by a dose-dependent cardiotoxicity. Although DOX is known to have several adverse side-effects, acute and chronic cardiotoxicity have received the most attention as both may eventually lead to heart failure. While exercise has been shown to protect against DOX cardiotoxicity, a clear and consistent mechanism to explain its cardioprotective effects is lacking. High performance liquid chromatography (HPLC) is a valuable instrument that can be used to evaluate cardiac DOX accumulation. We hypothesized that a reduction in cardiac DOX accumulation may be a mechanism of exercise-induced cardioprotecion. PURPOSE: The purpose of this study was to determine if exercise preconditioning reduces cardiac DOX accumulation, thereby providing a possible mechanism to explain the cardioprotective effects of exercise against DOX toxicity. METHOD: Female Sprague-Dawley rats were randomly assigned to 1 of 2 primary experimental groups: sedentary (SED) or treadmill (TM). Animals in the TM group completed 10 weeks of exercise prior to DOX treatment. DOX was administered 24 hours after the last training session as a bolus i.p. injection at 10 mg/kg. Subgroups of rats from each primary group were sacrificed at 1, 3, and 5 days post exposure and cardiac function was analyzed. Twenty-four hours following sacrifice, cardiac DOX accumulation was analyzed using HPLC. RESULTS: The greatest accumulation of DOX was observed in SED+DOX 1 day post injection. When compared to SED+DOX (1 day), DOX accumulation in TM+DOX (1 day) was significantly reduced (p<0.05). Similarly, DOX accumulation in SED+DOX (3 day) and SED+DOX (5 day) groups was significantly greater than TM+DOX (3 day) and TM+DOX (5 day), respectively (p<0.05). CONCLUSIONS: Exercise preconditioning reduced DOX accumulation in cardiac tissue of female rats. Therefore, it is possible that the cardioprotective effects of exercise against acute DOX-induced injury may be due, in part, to a reduction in myocardial DOX accumulation.