In vitro and in vivo investigation of cardiotoxicity associated with anticancer proteasome inhibitors and their combination with anthracycline
Language English Country England, Great Britain Media electronic-print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
31409729
DOI
10.1042/cs20190139
PII: CS20190139
Knihovny.cz E-resources
- Keywords
- anthracyclines, bortezomib, cardiotoxicity, carfilzomib, proteasome inhibitors,
- MeSH
- Antineoplastic Agents administration & dosage toxicity MeSH
- Anthracyclines administration & dosage toxicity MeSH
- Bortezomib administration & dosage toxicity MeSH
- Daunorubicin administration & dosage toxicity MeSH
- Proteasome Inhibitors administration & dosage toxicity MeSH
- Myocytes, Cardiac drug effects MeSH
- Cardiotoxicity etiology MeSH
- Rabbits MeSH
- Rats MeSH
- Oligopeptides administration & dosage toxicity MeSH
- Rats, Wistar MeSH
- Proteasome Endopeptidase Complex drug effects metabolism MeSH
- Antineoplastic Combined Chemotherapy Protocols toxicity MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Antineoplastic Agents MeSH
- Anthracyclines MeSH
- Bortezomib MeSH
- carfilzomib MeSH Browser
- Daunorubicin MeSH
- Proteasome Inhibitors MeSH
- Oligopeptides MeSH
- Proteasome Endopeptidase Complex 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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