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dc.contributor.authorSalaroglio, IC
dc.contributor.authorMujumdar, P
dc.contributor.authorAnnovazzi, L
dc.contributor.authorKopecka, J
dc.contributor.authorMellai, M
dc.contributor.authorSchiffer, D
dc.contributor.authorPoulsen, SA
dc.contributor.authorRiganti, C
dc.date.accessioned2021-02-25T04:13:20Z
dc.date.available2021-02-25T04:13:20Z
dc.date.issued2018
dc.identifier.issn1535-7163
dc.identifier.doi10.1158/1535-7163.MCT-18-0533
dc.identifier.urihttp://hdl.handle.net/10072/383570
dc.description.abstractThe role of carbonic anhydrase XII (CAXII) in the chemoresistance of glioblastoma is unexplored. We found CAXII and P-glycoprotein (Pgp) coexpressed in neurospheres derived from 3 of 3 patients with different genetic backgrounds and low response to temozolomide (time to recurrence: 6–9 months). CAXII was necessary for the Pgp efflux of temozolomide and second-line chemotherapeutic drugs, determining chemoresistance in neurospheres. Psammaplin C, a potent inhibitor of CAXII, resensitized primary neurospheres to temozolomide by reducing temozolomide efflux via Pgp. This effect was independent of other known temozolomide resistance factors present in the patients. The overall survival in orthotopic patient-derived xenografts of temozolomide-resistant neurospheres, codosed with Psammaplin C and temozolomide, was significantly increased over temozolomide-treated (P < 0.05) and untreated animals (P < 0.02), without detectable signs of systemic toxicity. We propose that a CAXII inhibitor in combination with temozolomide may provide a new and effective approach to reverse chemoresistance in glioblastoma stem cells. This novel mechanism of action, via the interaction of CAXII and Pgp, ultimately blocks the efflux function of Pgp to improve glioblastoma patient outcomes.
dc.description.peerreviewedYes
dc.languageEnglish
dc.language.isoeng
dc.publisherAmerican Association for Cancer Research
dc.relation.ispartofpagefrom2598
dc.relation.ispartofpageto2609
dc.relation.ispartofissue12
dc.relation.ispartofjournalMolecular Cancer Therapeutics
dc.relation.ispartofvolume17
dc.subject.fieldofresearchOncology and Carcinogenesis
dc.subject.fieldofresearchPharmacology and Pharmaceutical Sciences
dc.subject.fieldofresearchcode1112
dc.subject.fieldofresearchcode1115
dc.titleCarbonic anhydrase XII inhibitors overcome P-glycoprotein–mediated resistance to temozolomide in glioblastoma
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dc.description.versionAccepted Manuscript (AM)
gro.rights.copyright© 2018 AACR. This is the author-manuscript version of the paper. Reproduced in accordance with the copyright policy of the publisher. Please refer to the journal link for access to the definitive, published version.
gro.hasfulltextFull Text
gro.griffith.authorPoulsen, Sally-Ann
gro.griffith.authorMujumdar, Prashant


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