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Higher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomib

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dc.contributor.authorYILMAZ GÖLER, AYŞE MİNE
dc.contributor.authorsJannuzzi, Ayse Tarbin; Arslan, Sema; Yilmaz, Ayse Mine; Sari, Gulce; Beklen, Hande; Mendez, Lucia; Fedorova, Maria; Arga, Kazim Yalcin; Yilmaz, Betul Karademir; Alpertunga, Buket
dc.date.accessioned2022-03-14T09:24:48Z
dc.date.available2022-03-14T09:24:48Z
dc.date.issued2020-05
dc.description.abstractProteasome inhibitors have great success for their therapeutic potential against hematologic malignancies. First generation proteasome inhibitor bortezomib induced peripheral neuropathy is considered as a limiting factor in chemotherapy and its second-generation counterpart carfilzomib is associated with lower rates of neurotoxicity. The mitochondrial toxicity (mitotoxicity) hypothesis arises from studies with animal models of bortezomib induced peripheral neuropathy. However, molecular mechanisms are not fully elucidated and the role of mitotoxicity in bortezomib and carfilzomib induced neurotoxicity has not been investigated comparatively. Herein, we characterized the neurotoxic effects of bortezomib and carfilzomib at the molecular level in human neuronal cells using LC-MS/MS analysis, flow cytometry, RT-qPCR, confocal microscopy and western blotting. We showed that bortezomib and carfilzomib affected the human neuronal proteome differently, and bortezomib caused higher proteotoxic stress via protein oxidation, protein K48-ubiquitination, heat shock protein expression up-regulation and reduction of mitochondria membrane potential. Bortezomib and carfilzomib did not affect the gene expression levels related to mitochondrial dynamics (optic atrophy 1; OPA1, mitofusin 1; MFN1, mitofusin 2; MFN2, fission 1; FIS1, dynamin-related protein 1; DRP1) and overall mitophagy rate whereas, PINK1/Parkin mediated mitophagy gene expressions were altered with both drugs. Bortezomib and carfilzomib caused downregulation of the contents of mitochondrial oxidative phosphorylation complexes, voltage-dependent anion channel 1 (VDAC1) and uncoupling protein 2 (UCP2) similarly. Our findings suggest that, both drugs induce mitotoxicity besides proteotoxic stress in human neuronal cells and the higher incidence of neurotoxicity with bortezomib than carfilzomib is not directly related to mitochondrial pathways.
dc.identifier.doi10.1016/j.redox.2020.101502
dc.identifier.issn2213-2317
dc.identifier.pubmed32244176
dc.identifier.urihttps://hdl.handle.net/11424/243088
dc.identifier.wosWOS:000537459900037
dc.language.isoeng
dc.publisherELSEVIER
dc.relation.ispartofREDOX BIOLOGY
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectBortezomib
dc.subjectCarfilzomib
dc.subjectMitotoxicity
dc.subjectNeurotoxicity
dc.subjectPeripheral neuropathy
dc.subjectUBIQUITIN-PROTEASOME SYSTEM
dc.subjectINDUCED PERIPHERAL NEUROPATHY
dc.subjectPREVENTS NEURONAL DEATH
dc.subjectHEAT-SHOCK PROTEINS
dc.subjectOXIDATIVE STRESS
dc.subject26S PROTEASOME
dc.subjectDEGRADATION
dc.subjectMITOTOXICITY
dc.subjectINHIBITORS
dc.subjectMITOPHAGY
dc.titleHigher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomib
dc.typearticle
dspace.entity.typePublication
local.avesis.idb7383e8f-91b5-479a-be10-3ffb62be8532
local.import.packageSS16
local.indexed.atWOS
local.indexed.atSCOPUS
local.indexed.atPUBMED
local.journal.articlenumber101502
local.journal.numberofpages12
local.journal.quartileQ1
oaire.citation.titleREDOX BIOLOGY
oaire.citation.volume32
relation.isAuthorOfPublication8a72311b-9078-47c0-9fd8-bd73292b7739
relation.isAuthorOfPublication.latestForDiscovery8a72311b-9078-47c0-9fd8-bd73292b7739

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