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Temozolomide down-regulates P-glycoprotein in human blood-brain barrier cells by disrupting Wnt3 signaling

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dc.creatorRiganti, Chiaraspa
dc.creatorSalaroglio, Iris C.spa
dc.creatorPinzòn-Daza, Martha L.spa
dc.creatorCaldera, Valentinaspa
dc.creatorCampia, Ivanaspa
dc.creatorKopecka, Joannaspa
dc.creatorMellai, Martaspa
dc.creatorAnnovazzi, Lauraspa
dc.creatorCouraud, Pierre-Olivierspa
dc.creatorBosia, Amaliaspa
dc.creatorGhigo, Dariospa
dc.creatorSchiffer, Davidespa
dc.date.accessioned2020-05-26T00:03:58Z
dc.date.available2020-05-26T00:03:58Z
dc.date.created2014spa
dc.description.abstractLow delivery of many anticancer drugs across the blood-brain barrier (BBB) is a limitation to the success of chemotherapy in glioblastoma. This is because of the high levels of ATP-binding cassette transporters like P-glycoprotein (Pgp/ABCB1), which effluxes drugs back to the bloodstream. Temozolomide is one of the few agents able to cross the BBB; its effects on BBB cells permeability and Pgp activity are not known. We found that temozolomide, at therapeutic concentration, increased the transport of Pgp substrates across human brain microvascular endothelial cells and decreased the expression of Pgp. By methylating the promoter of Wnt3 gene, temozolomide lowers the endogenous synthesis of Wnt3 in BBB cells, disrupts the Wnt3/glycogen synthase kinase 3/?-catenin signaling, and reduces the binding of ?-catenin on the promoter of mdr1 gene, which encodes for Pgp. In co-culture models of BBB cells and human glioblastoma cells, pre-treatment with temozolomide increases the delivery, cytotoxicity, and antiproliferative effects of doxorubicin, vinblastine, and topotecan, three substrates of Pgp that are usually poorly delivered across BBB. Our work suggests that temozolomide increases the BBB permeability of drugs that are normally effluxed by Pgp back to the bloodstream. These findings may pave the way to new combinatorial chemotherapy schemes in glioblastoma. © 2013 Springer Basel.eng
dc.format.mimetypeapplication/pdf
dc.identifier.doihttps://doi.org/10.1007/s00018-013-1397-y
dc.identifier.issn1420682X
dc.identifier.issn14209071
dc.identifier.urihttps://repository.urosario.edu.co/handle/10336/23644
dc.language.isoengspa
dc.relation.citationEndPage516
dc.relation.citationIssueNo. 3
dc.relation.citationStartPage499
dc.relation.citationTitleCellular and Molecular Life Sciences
dc.relation.citationVolumeVol. 71
dc.relation.ispartofCellular and Molecular Life Sciences, ISSN:1420682X, 14209071, Vol.71, No.3 (2014); pp. 499-516spa
dc.relation.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-84892814270&doi=10.1007%2fs00018-013-1397-y&partnerID=40&md5=8e2c9c6321ce7d353df3bb3c397e434espa
dc.rights.accesRightsinfo:eu-repo/semantics/openAccess
dc.rights.accesoAbierto (Texto Completo)spa
dc.source.instnameinstname:Universidad del Rosariospa
dc.source.reponamereponame:Repositorio Institucional EdocURspa
dc.subject.keywordABC transporterspa
dc.subject.keywordTumoreng
dc.subject.keywordBeta tubulinspa
dc.subject.keywordCaspase 3spa
dc.subject.keywordClaudin 3spa
dc.subject.keywordClaudin 5spa
dc.subject.keywordDoxorubicinspa
dc.subject.keywordGlycogen synthase kinase 3spa
dc.subject.keywordHoe 33342spa
dc.subject.keywordMultidrug resistance proteinspa
dc.subject.keywordMultidrug resistance protein 1spa
dc.subject.keywordOccludinspa
dc.subject.keywordProtein ZO1spa
dc.subject.keywordRhodamine 123spa
dc.subject.keywordTemozolomidespa
dc.subject.keywordAntineoplastic activityspa
dc.subject.keywordArticlespa
dc.subject.keywordBlood brain barrierspa
dc.subject.keywordCell countspa
dc.subject.keywordCell permeabilizationspa
dc.subject.keywordCell proliferationspa
dc.subject.keywordConcentration (parameters)spa
dc.subject.keywordControlled studyspa
dc.subject.keywordCytotoxicityspa
dc.subject.keywordDown regulationspa
dc.subject.keywordDrug efficacyspa
dc.subject.keywordDrug penetrationspa
dc.subject.keywordGenespa
dc.subject.keywordGenetic transcriptionspa
dc.subject.keywordGlioblastomaspa
dc.subject.keywordHumanspa
dc.subject.keywordHuman cellspa
dc.subject.keywordMDR1 genespa
dc.subject.keywordProtein expressionspa
dc.subject.keywordProtein functionspa
dc.subject.keywordProtein transportspa
dc.subject.keywordWnt signaling pathwayspa
dc.subject.keywordAntineoplastic Agentsspa
dc.subject.keywordBeta Cateninspa
dc.subject.keywordBlood-Brain Barrierspa
dc.subject.keywordCapillary Permeabilityspa
dc.subject.keywordCell Lineeng
dc.subject.keywordDacarbazinespa
dc.subject.keywordDNA Methylationspa
dc.subject.keywordGene Expression Regulationspa
dc.subject.keywordHumansspa
dc.subject.keywordP-Glycoproteinspa
dc.subject.keywordPromoter Regionseng
dc.subject.keywordSignal Transductionspa
dc.subject.keywordWnt3 Proteinspa
dc.subject.keywordBlood-brain barrierspa
dc.subject.keywordGlioblastoma multiformespa
dc.subject.keywordP-glycoproteinspa
dc.subject.keywordTemozolomidespa
dc.subject.keywordWnt3spa
dc.titleTemozolomide down-regulates P-glycoprotein in human blood-brain barrier cells by disrupting Wnt3 signalingspa
dc.typearticleeng
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersion
dc.type.spaArtículospa
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