Abstract 321: Exercise Preconditioning Diminishes Solute Carrier Protein Expression and Cardiac Doxorubicin Accumulation Academic Article uri icon

abstract

  • Doxorubicin (DOX) is an anthracycline antibiotic used in cancer treatment. Unfortunately, the clinical use of this highly efficacious anticancer drug is limited due to the development of irreversible and dose-dependent cardiomyopathy. While the mechanisms responsible for DOX-induced cardiotoxicity remain unclear, previous work demonstrates that the incidence of cardiac dysfunction greatly correlates to the concentration of DOX transported into the cardiomyocytes. In this regard, we recently demonstrated that endurance exercise performed prior to DOX administration is sufficient to reduce the accumulation of DOX within the heart and prevent left ventricular dysfunction. While the mechanisms for the exercise-induced reduction in cardiac DOX levels are unknown, we hypothesize that endurance exercise alters the expression of solute carrier proteins (SLCs) required for the influx of DOX into the heart. To determine if exercise training can alter SLC protein expression in the heart, animals underwent two weeks of treadmill running (5 days/week; 60 min/day; 30m/min). Twenty-four hours following completion of the exercise training period, animals received either saline or DOX (20mg/kg i.p.) treatment. DOX is a slightly basic cationic compound that is thought to be transported into cells by organic cation transporters. Analysis of the expression of the high affinity organic cation transporters SLC22A4 and SLC22A5 revealed a significant increase in their expression in DOX treated animals, which was mitigated by exercise preconditioning. In addition, the low affinity organic cation transporter SLC22A1 was also increased in DOX treated animals compared to exercise trained animals, while SLC22A3 expression did not differ between groups. Finally, exercise training also reduced the DOX-induced increase in the expression of the mitochondria-localized SLC transporter SLC25A1. These data demonstrate that DOX enhances the expression of several SLCs in the heart, and that exercise may ameliorate cardiac DOX accumulation by preventing the upregulation of proteins with the potential to promote DOX cellular influx.

published proceedings

  • Circulation Research

author list (cited authors)

  • Smuder, A. J., Mor Huertas, A., & Morton, A. B.

citation count

  • 0

complete list of authors

  • Smuder, Ashley J||Mor Huertas, Andres||Morton, Aaron B

publication date

  • January 2020