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 (ANTs) 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 the present study, we investigated the toxicity of clinically used PIs alone (bortezomib (BTZ), carfilzomib (CFZ)) as well as their combinations with an ANT (daunorubicin (DAU)) in both neonatal and adult ventricular cardiomyocytes (NVCMs and AVCMs) and in a chronic rabbit model of DAU-induced HF. Using NVCMs, we found significant cytotoxicity of both PIs around their maximum plasma concentration (cmax) as well as significant augmentation of DAU cytotoxicity. In AVCMs, BTZ did not induce significant cytotoxicity in therapeutic concentrations, whereas the toxicity of CFZ was significant and more profound. Importantly, neither PI significantly augmented the cardiotoxicity of DAU despite even more profound proteasome-inhibitory activity in AVCMs compared with 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 ANTs is not accompanied by an exaggerated risk of cardiotoxicity and HF in young adult animal cardiomyocytes and hearts.

• Klíčová slova
• anthracyclines, bortezomib, cardiotoxicity, carfilzomib, proteasome inhibitors,
• MeSH
• antitumorózní látky aplikace a dávkování   toxicita   MeSH
• antracykliny aplikace a dávkování   toxicita   MeSH
• bortezomib aplikace a dávkování   toxicita   MeSH
• daunomycin aplikace a dávkování   toxicita   MeSH
• inhibitory proteasomu aplikace a dávkování   toxicita   MeSH
• kardiomyocyty účinky léků   MeSH
• kardiotoxicita etiologie   MeSH
• králíci MeSH
• krysa rodu Rattus MeSH
• oligopeptidy aplikace a dávkování   toxicita   MeSH
• potkani Wistar MeSH
• proteasomový endopeptidasový komplex účinky léků   metabolismus   MeSH
• protokoly antitumorózní kombinované chemoterapie toxicita   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• králíci MeSH
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antitumorózní látky MeSH
• antracykliny MeSH
• bortezomib MeSH
• carfilzomib MeSH Prohlížeč
• daunomycin MeSH
• inhibitory proteasomu MeSH
• oligopeptidy MeSH
• proteasomový endopeptidasový komplex MeSH