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In vitro and in vivo investigation of cardiotoxicity associated with anticancer proteasome inhibitors and their combination with anthracycline
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SYSNO ASEP 0517578 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title In vitro and in vivo investigation of cardiotoxicity associated with anticancer proteasome inhibitors and their combination with anthracycline Author(s) Pokorná, Z. (CZ)
Jirkovský, E. (CZ)
Hlaváčková, Markéta (FGU-C) RID, ORCID
Jansová, H. (CZ)
Jirkovská, A. (CZ)
Lencová-Popelová, O. (CZ)
Brázdová, P. (CZ)
Kubeš, J. (CZ)
Sotáková-Kašparová, Dita (FGU-C) RID, ORCID, SAI
Mazurová, Y. (CZ)
Adamcová, M. (CZ)
Vostatková, L. (CZ)
Holzerová, Kristýna (FGU-C) ORCID, RID
Kolář, František (FGU-C) RID, ORCID, SAI
Šimůnek, T. (CZ)
Štěrba, M. (CZ)Source Title Clinical science. - : Portland Press - ISSN 0143-5221
Roč. 133, č. 16 (2019), s. 1827-1844Number of pages 18 s. Language eng - English Country GB - United Kingdom Keywords anthracyclines ; bortezomib ; carfilzomib ; cardiotoxicity ; proteasome inhibitors Subject RIV FR - Pharmacology ; Medidal Chemistry OECD category Pharmacology and pharmacy R&D Projects GA13-15008S GA ČR - Czech Science Foundation (CSF) Method of publishing Limited access Institutional support FGU-C - RVO:67985823 UT WOS 000511195100001 EID SCOPUS 85071685471 DOI https://doi.org/10.1042/CS20190139 Annotation 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. Workplace Institute of Physiology Contact Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Year of Publishing 2020 Electronic address https://doi.org/10.1042/CS20190139
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