title: Inhibition of chymotryptic-like standard proteasome activity exacerbates doxorubicin-induced cytotoxicity in primary cardiomyocytes.
abstract: The anthracycline doxorubicin (DOX) is a potent anticancer agent for multiple myeloma (MM). A major limitation of this drug is the induction of death in cardiomyocytes leading to heart failure. Here we report on the role of the ubiquitin-proteasome system (UPS) as a critical surveillance pathway for preservation of cell vitality counteracting DOX treatment. Since in addition to DOX also suppression of proteasome activity is a rational therapeutic strategy for MM, we examined how small molecular compounds with clinically relevant proteasome subunit specificity affect DOX cytotoxicity. We found that during DOX-treatment, the activity of the β5 standard proteasome subunit is crucial for limiting off-target cytotoxicity in primary cardiomyocytes. In contrast, we demonstrate that the β5 equivalent LMP7 of the immunoproteasome represents a safe target for subunit-specific inhibitors in DOX-exposed cardiomyocytes. Neither inhibition of LMP7 in primary cardiomyocytes nor genetic ablation of LMP7 in heart tissue influenced the development of DOX cardiotoxicity. Our results indicate that as compared to compounds like carfilzomib, which target both the β5 standard proteasome and the LMP7 immunoproteasome subunit, immunoproteasome-specific inhibitors with known anti-tumor capacity for MM cells might be advantageous for reducing cardiomyocyte death, when a combination therapy with DOX is envisaged.
authors.affiliation: Institute for Biochemistry, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; DZHK (German Centre for Cardiovascular Research), partner side, Berlin, Germany.
authors.forename: Eva-Margarete
authors.initials: EM
authors.lastname: Spur
authors.affiliation: Institute for Biochemistry, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; DZHK (German Centre for Cardiovascular Research), partner side, Berlin, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Althof
authors.affiliation: Institute for Biochemistry, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; DZHK (German Centre for Cardiovascular Research), partner side, Berlin, Germany.
authors.forename: Dorota
authors.initials: D
authors.lastname: Respondek
authors.affiliation: Institute for Molecular Pathology, Universitätsklinikum Tübingen, Liebermeisterstr. 8, 72076 Tübingen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Klingel
authors.affiliation: Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany.
authors.forename: Arnd
authors.initials: A
authors.lastname: Heuser
authors.affiliation: Leiden Institute of Chemistry, Faculty of Science, Einsteinweg 55, 2333CC Leiden, Netherlands.
authors.forename: Hermen S
authors.initials: HS
authors.lastname: Overkleeft
authors.affiliation: Institute for Biochemistry, Charité Universitätsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany; DZHK (German Centre for Cardiovascular Research), partner side, Berlin, Germany. Electronic address: antje.voigt@charite.de.
authors.forename: Antje
authors.initials: A
authors.lastname: Voigt
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D004317:Doxorubicin / Q000633:toxicity*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D009842:Oligopeptides / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D009842:Oligopeptides; D025801:Ubiquitin; C524865:carfilzomib; D004317:Doxorubicin; C077436:LMP7 protein; D046988:Proteasome Endopeptidase Complex
keywords: Anthracycline cardiotoxicity; Proteasome; Proteostasis; Subunit-specific proteasome inhibitors; Toxicology