Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach

Heat shock protein (Hsp) synthesis is upregulated in a wide range of cancers to provide the appropriate environment for tumor progression. The Hsp110 and Hsp70 families have been associated to cancer cell survival and resistance to chemotherapy. In this study, we explore the strategy of drug repurpo...

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Authors: Dublang, Leire, Underhaug, Jarl, Flydal, Marte I., Velasco-Carneros, Lorea, Maréchal, Jean Didier, Moro, Fernando, Boyano, María Dolores, Martínez, Aurora, Muga, Arturo
Format: article
Status:Published version
Publication Date:2021
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/311286
Online Access:http://hdl.handle.net/10261/311286
https://api.elsevier.com/content/abstract/scopus_id/85107524303
Access Level:Open access
Keyword:Chaperones
Drug repurposing
Inhibitors
Melanoma
Pinaverium bromide
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spelling Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer ApproachDublang, LeireUnderhaug, JarlFlydal, Marte I.Velasco-Carneros, LoreaMaréchal, Jean DidierMoro, FernandoBoyano, María DoloresMartínez, AuroraMuga, ArturoChaperonesDrug repurposingInhibitorsMelanomaPinaverium bromideHeat shock protein (Hsp) synthesis is upregulated in a wide range of cancers to provide the appropriate environment for tumor progression. The Hsp110 and Hsp70 families have been associated to cancer cell survival and resistance to chemotherapy. In this study, we explore the strategy of drug repurposing to find new Hsp70 and Hsp110 inhibitors that display toxicity against melanoma cancer cells. We found that the hits discovered using Apg2, a human representative of the Hsp110 family, as the initial target bind also to structural regions present in members of the Hsp70 family, and therefore inhibit the remodeling activity of the Hsp70 system. One of these compounds, the spasmolytic agent pinaverium bromide used for functional gastrointestinal disorders, inhibits the intracellular chaperone activity of the Hsp70 system and elicits its cytotoxic activity specifically in two melanoma cell lines by activating apoptosis. Docking and molecular dynamics simulations indicate that this compound interacts with regions located in the nucleotide-binding domain and the linker of the chaperones, modulating their ATPase activity. Thus, repurposing of pinaverium bromide for cancer treatment appears as a promising novel therapeutic approach.This study was funded by grants BFU2016-75983-P and PID2019-111068GB-100 (AEI/FEDER/UE) from MINECO to F.M. and A.M. (Arturo Muga) and IT1201-19 from the Basque Government to F.M. Support from the Research Council of Norway (RCN, Grant FRIMEDBIO 261826/F20), the Western Norway Regional Health Authority (912246 to A.M. (Aurora Martinez) and M.I.F.)Peer reviewedMultidisciplinary Digital Publishing InstituteMinisterio de Economía y Competitividad (España)Ministerio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)European CommissionEusko JaurlaritzaResearch Council of NorwayWestern Norway Regional Health AuthorityConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202320232021info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/311286https://api.elsevier.com/content/abstract/scopus_id/85107524303reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO//BFU2016-75983-Pinfo:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-111068GB-I00https://doi.org/10.3390/cancers13122936Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3112862026-05-22T06:33:51Z
dc.title.none.fl_str_mv Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach
title Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach
spellingShingle Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach
Dublang, Leire
Chaperones
Drug repurposing
Inhibitors
Melanoma
Pinaverium bromide
title_short Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach
title_full Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach
title_fullStr Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach
title_full_unstemmed Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach
title_sort Inhibition of the Human Hsc70 System by Small Ligands as a Potential Anticancer Approach
dc.creator.none.fl_str_mv Dublang, Leire
Underhaug, Jarl
Flydal, Marte I.
Velasco-Carneros, Lorea
Maréchal, Jean Didier
Moro, Fernando
Boyano, María Dolores
Martínez, Aurora
Muga, Arturo
author Dublang, Leire
author_facet Dublang, Leire
Underhaug, Jarl
Flydal, Marte I.
Velasco-Carneros, Lorea
Maréchal, Jean Didier
Moro, Fernando
Boyano, María Dolores
Martínez, Aurora
Muga, Arturo
author_role author
author2 Underhaug, Jarl
Flydal, Marte I.
Velasco-Carneros, Lorea
Maréchal, Jean Didier
Moro, Fernando
Boyano, María Dolores
Martínez, Aurora
Muga, Arturo
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía y Competitividad (España)
Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
European Commission
Eusko Jaurlaritza
Research Council of Norway
Western Norway Regional Health Authority
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Chaperones
Drug repurposing
Inhibitors
Melanoma
Pinaverium bromide
topic Chaperones
Drug repurposing
Inhibitors
Melanoma
Pinaverium bromide
description Heat shock protein (Hsp) synthesis is upregulated in a wide range of cancers to provide the appropriate environment for tumor progression. The Hsp110 and Hsp70 families have been associated to cancer cell survival and resistance to chemotherapy. In this study, we explore the strategy of drug repurposing to find new Hsp70 and Hsp110 inhibitors that display toxicity against melanoma cancer cells. We found that the hits discovered using Apg2, a human representative of the Hsp110 family, as the initial target bind also to structural regions present in members of the Hsp70 family, and therefore inhibit the remodeling activity of the Hsp70 system. One of these compounds, the spasmolytic agent pinaverium bromide used for functional gastrointestinal disorders, inhibits the intracellular chaperone activity of the Hsp70 system and elicits its cytotoxic activity specifically in two melanoma cell lines by activating apoptosis. Docking and molecular dynamics simulations indicate that this compound interacts with regions located in the nucleotide-binding domain and the linker of the chaperones, modulating their ATPase activity. Thus, repurposing of pinaverium bromide for cancer treatment appears as a promising novel therapeutic approach.
publishDate 2021
dc.date.none.fl_str_mv 2021
2023
2023
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/10261/311286
https://api.elsevier.com/content/abstract/scopus_id/85107524303
url http://hdl.handle.net/10261/311286
https://api.elsevier.com/content/abstract/scopus_id/85107524303
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO//BFU2016-75983-P
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-111068GB-I00
https://doi.org/10.3390/cancers13122936
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
publisher.none.fl_str_mv Multidisciplinary Digital Publishing Institute
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 15.812429

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