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

12 pages, 6 figures, 1 table.-- This is an open access article under the CC BY-NC-ND license

Detalles Bibliográficos
Autores: Jannuzzi, Ayse Tarbin, Arslan, Sema, Yilmaz, Ayse Mine, Sari, Gulce, Beklen, Hande, Méndez, Lucía, Fedorova, Maria, Arga, Kazim Yalcin, Yilmaz, Betul Karademir
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2020
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/206090
Acceso en línea:http://hdl.handle.net/10261/206090
Access Level:acceso abierto
Palabra clave:Bortezomib
Carfilzomib
Mitotoxicity
Neurotoxicity
Peripheral neuropathy
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spelling Higher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomibJannuzzi, Ayse TarbinArslan, SemaYilmaz, Ayse MineSari, GulceBeklen, HandeMéndez, LucíaFedorova, MariaArga, Kazim YalcinYilmaz, Betul KarademirBortezomibCarfilzomibMitotoxicityNeurotoxicityPeripheral neuropathy12 pages, 6 figures, 1 table.-- This is an open access article under the CC BY-NC-ND licenseProteasome 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 upregulation 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 pathwaysThis study was supported by The Scientific and Technological Research Council of Turkey - TUBITAK (216S838) and Istanbul University Research Fund (TDK-2017-24221 and TSA-2017-25380). Financial support from the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept for SysMedOS project is gratefully acknowledged. Xunta de Galicia is thankfully acknowledged for the postdoctoral scholarship provided L.MPeer reviewedElsevierThe Scientific and Technological Research Council of TürkiyeIstanbul UniversityFederal Ministry of Education and Research (Germany)Xunta de GaliciaConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202020202020info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/206090reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésThe underlying dataset has been published as supplementary material of the article in the publishers platform at DOI https://doi.org/10.1016/j.redox.2020.101502https://doi.org/10.1016/j.redox.2020.101502Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/2060902026-05-22T06:33:51Z
dc.title.none.fl_str_mv Higher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomib
title Higher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomib
spellingShingle Higher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomib
Jannuzzi, Ayse Tarbin
Bortezomib
Carfilzomib
Mitotoxicity
Neurotoxicity
Peripheral neuropathy
title_short Higher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomib
title_full Higher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomib
title_fullStr Higher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomib
title_full_unstemmed Higher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomib
title_sort Higher proteotoxic stress rather than mitochondrial damage is involved in higher neurotoxicity of bortezomib compared to carfilzomib
dc.creator.none.fl_str_mv Jannuzzi, Ayse Tarbin
Arslan, Sema
Yilmaz, Ayse Mine
Sari, Gulce
Beklen, Hande
Méndez, Lucía
Fedorova, Maria
Arga, Kazim Yalcin
Yilmaz, Betul Karademir
author Jannuzzi, Ayse Tarbin
author_facet Jannuzzi, Ayse Tarbin
Arslan, Sema
Yilmaz, Ayse Mine
Sari, Gulce
Beklen, Hande
Méndez, Lucía
Fedorova, Maria
Arga, Kazim Yalcin
Yilmaz, Betul Karademir
author_role author
author2 Arslan, Sema
Yilmaz, Ayse Mine
Sari, Gulce
Beklen, Hande
Méndez, Lucía
Fedorova, Maria
Arga, Kazim Yalcin
Yilmaz, Betul Karademir
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv The Scientific and Technological Research Council of Türkiye
Istanbul University
Federal Ministry of Education and Research (Germany)
Xunta de Galicia
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Bortezomib
Carfilzomib
Mitotoxicity
Neurotoxicity
Peripheral neuropathy
topic Bortezomib
Carfilzomib
Mitotoxicity
Neurotoxicity
Peripheral neuropathy
description 12 pages, 6 figures, 1 table.-- This is an open access article under the CC BY-NC-ND license
publishDate 2020
dc.date.none.fl_str_mv 2020
2020
2020
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/206090
url http://hdl.handle.net/10261/206090
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv The underlying dataset has been published as supplementary material of the article in the publishers platform at DOI https://doi.org/10.1016/j.redox.2020.101502
https://doi.org/10.1016/j.redox.2020.101502
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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