In vitro and in vivo investigation of cardiotoxicity associated with anticancer proteasome inhibitors and their combination with anthracycline
Jazyk angličtina Země Anglie, Velká Británie Médium electronic-print
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
31409729
DOI
10.1042/cs20190139
PII: CS20190139
Knihovny.cz E-zdroje
- 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
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.
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