LAUSR

Although proteasome inhibitors (PIs) are modern targeted anticancer drugs, they have been associated with a certain risk of cardiotoxicity and heart failure (HF). Recently, PIs have been combined with anthracyclines to further boost their anticancer efficacy. However, this raised concerns regarding cardiac safety, which were further supported by several in vitro studies on immature cardiomyocytes. In this study, we investigated the toxicity of clinically used PIs alone (bortezomib, carfilzomib) as well as their combinations with an anthracycline (daunorubicin) in both neonatal and adult ventricular cardiomyocytes (NVCMs and AVCMs) and in a chronic rabbit model of daunorubicin-induced HF. Using NVCMs, we found significant cytotoxicity of both PIs around their maximum plasma concentration (cmax) as well as significant augmentation of daunorubicin cytotoxicity. In AVCMs, bortezomib did not induce significant cytotoxicity in therapeutic concentrations, whereas the toxicity of carfilzomib was significant and more profound. Importantly, neither PI significantly augmented the cardiotoxicity of daunorubicin despite even more profound proteasome-inhibitory activity in AVCMs compared to NVCMs. Furthermore, in young adult rabbits, no significant augmentation of chronic ANT cardiotoxicity was noted with respect to any functional, morphological, biochemical or molecular parameter under study, despite significant inhibition of myocardial proteasome activity. Our experimental data show that combination of PIs with anthracyclines is not accompanied by an exaggerated risk of cardiotoxicity and HF in young adult animal cardiomyocytes and hearts.