Molecular cardiotoxic effects of proteasome inhibitors Carfilzomib and Ixazomib and their combination with dexamethasone involve mitochondrial dysregulation

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dc.authorid0000-0001-6043-7560en_US
dc.authorscopusid6602718563en_US
dc.authorwosidAAD-6135-2020en_US
dc.contributor.authorJannuzzi, Ayşe Tarbin
dc.contributor.authorKorkmaz, Nalan Sümeyra
dc.contributor.authorGünaydın-Akyıldız, Ayşenur
dc.contributor.authorArslan Eseryel, Sema
dc.contributor.authorKarademir Yılmaz, Betül
dc.contributor.authorAlpertunga, Buket
dc.date.accessioned2023-03-01T10:06:41Z
dc.date.available2023-03-01T10:06:41Z
dc.date.issued2023en_US
dc.departmentFakülteler, Eczacılık Fakültesi, Eczacılık Meslek Bilimleri Bölümü, Farmasötik Toksikoloji Ana Bilim Dalıen_US
dc.description.abstractWith the development and approval of new proteasome inhibitors, proteasome inhibition is increasingly recognized in cancer therapy. Besides successful anti-cancer effects in hematological cancers, side effects such as cardiotoxicity are limiting effective treatment. In this study, we used a cardiomyocyte model to investigate the molecular cardiotoxic mechanisms of carfilzomib (CFZ) and ixazomib (IXZ) alone or in combination with the immunomodulatory drug dexamethasone (DEX) which is frequently used in combination therapies in the clinic. According to our findings, CFZ showed a higher cytotoxic effect at lower concentrations than IXZ. DEX combination attenuated the cytotoxicity for both proteasome inhibitors. All drug treatments caused a marked increase in K48 ubiquitination. Both CFZ and IXZ caused an upregulation in cellular and endoplasmic reticulum stress protein (HSP90, HSP70, GRP94, and GRP78) levels and DEX combination attenuated the increased stress protein levels. Importantly, IXZ and IXZ-DEX treatments caused upregulation of mitochondria fission and fusion gene expression levels higher than caused by CFZ and CFZ-DEX combination. The IXZ-DEX combination reduced the levels of OXPHOS proteins (Complex II-V) more than the CFZ-DEX combination. Reduced mitochondrial membrane potential and ATP production were detected with all drug treatments in cardiomyocytes. Our findings suggest that the cardiotoxic effect of proteasome inhibitors may be due to their class effect and stress response and mitochondrial dysfunction may be involved in the cardiotoxicity process.en_US
dc.identifier.citationJannuzzi, A. T., Korkmaz, N. S., Günaydın-Akyıldız, A., Arslan Eseryel, S., Karademir Yılmaz, B., & Alpertunga, B. (2023). Molecular cardiotoxic effects of proteasome inhibitors Carfilzomib and Ixazomib and their combination with dexamethasone involve mitochondrial dysregulation. Cardiovascular Toxicology, 23(3-4), 121-131. https://doi.org/10.1007/s12012-023-09785-7en_US
dc.identifier.doi10.1007/s12012-023-09785-7en_US
dc.identifier.endpage131en_US
dc.identifier.issn1530-7905
dc.identifier.issn1559-0259
dc.identifier.issue3-4en_US
dc.identifier.pmidPMID: 36809482en_US
dc.identifier.scopus2-s2.0-85148501456en_US
dc.identifier.scopusqualityQ2en_US
dc.identifier.startpage121en_US
dc.identifier.urihttps://doi.org/10.1007/s12012-023-09785-7
dc.identifier.urihttps://hdl.handle.net/20.500.13055/403
dc.identifier.volume23en_US
dc.identifier.wosWOS:000936061300001en_US
dc.identifier.wosqualityQ2en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.indekslendigikaynak.otherSCI-E - Science Citation Index Expandeden_US
dc.institutionauthorAlpertunga, Buket
dc.language.isoenen_US
dc.publisherHumana Pressen_US
dc.relation.ispartofCardiovascular Toxicologyen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.subjectCardiotoxicityen_US
dc.subjectMitochondrial Toxicityen_US
dc.subjectProteasome Inhibitorsen_US
dc.subjectStress Responseen_US
dc.titleMolecular cardiotoxic effects of proteasome inhibitors Carfilzomib and Ixazomib and their combination with dexamethasone involve mitochondrial dysregulationen_US
dc.typeArticleen_US
dspace.entity.typePublication

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