Activation of the ubiquitin-proteasome system in doxorubicin cardiomyopathy

Doxorubicin (Dox) is a very potent anticancer agent, but its use is limited by its dose-dependent, irreversible cardiotoxicity. Despite intensive research efforts, the mechanism of Dox cardiotoxicity remains poorly understood, so very limited means are available for its prevention or effective management. Recent studies have revealed that a therapeutic dose of Dox can activate proteolysis in cardiomyocytes that is mediated by the ubiquitin-proteasome system (UPS), and that the UPS-mediated degradation of a number of pivotal cardiac transcription factors and/or survival factors is enhanced by Dox treatment. These findings suggest that Dox-induced UPS activation may represent a new mechanism underlying Dox cardiotoxicity. Notably, recent experimental studies suggest that proteasome activation promotes cardiac remodeling during hypertension. This review surveys the current literature on the impact of Dox on the UPS and the potential mechanisms by which UPS activation may compromise the heart during Dox therapy.