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dc.contributor.authorKopecka, Joanna
dc.contributor.authorRankin, Gregory M
dc.contributor.authorSalaroglio, Iris C
dc.contributor.authorPoulsen, Sally-Ann
dc.contributor.authorRiganti, Chiara
dc.date.accessioned2017-11-28T01:47:58Z
dc.date.available2017-11-28T01:47:58Z
dc.date.issued2016
dc.identifier.issn1949-2553
dc.identifier.doi10.18632/oncotarget.13040
dc.identifier.urihttp://hdl.handle.net/10072/100581
dc.description.abstractCarbonic anhydrase XII (CAXII) is a membrane enzyme that maintains pH homeostasis and sustains optimum P-glycoprotein (Pgp) efflux activity in cancer cells. Here, we investigated a panel of eight CAXII inhibitors (compounds 1-8), for their potential to reverse Pgp mediated tumor cell chemoresistance. Inhibitors (5 nM) were screened in human and murine cancer cells (colon, lung, breast, bone) with different expression levels of CAXII and Pgp. We identified three CAXII inhibitors (compounds 1, 2 and 4) that significantly (≥ 2 fold) increased the intracellular retention of the Pgp-substrate and chemotherapeutic doxorubicin, and restored its cytotoxic activity. The inhibitors lowered intracellular pH to indirectly impair Pgp activity. Ca12-knockout assays confirmed that the chemosensitizing property of the compounds was dependent on active CAXII. Furthermore, in a preclinical model of drug-resistant breast tumors compound 1 (1900 ng/kg) restored the efficacy of doxorubicin to the same extent as the direct Pgp inhibitor tariquidar. The expression of carbonic anhydrase IX had no effect on the intracellular doxorubicin accumulation. Our work provides strong evidence that CAXII inhibitors are effective chemosensitizer agents in CAXII-positive and Pgp-positive cancer cells. The use of CAXII inhibitors may represent a turning point in combinatorial chemotherapeutic schemes to treat multidrug-resistant tumors.
dc.description.peerreviewedYes
dc.languageEnglish
dc.publisherImpact Journals LLC
dc.relation.ispartofpagefrom1
dc.relation.ispartofpageto15
dc.relation.ispartofjournalOncotarget
dc.subject.fieldofresearchOncology and Carcinogenesis not elsewhere classified
dc.subject.fieldofresearchOncology and Carcinogenesis
dc.subject.fieldofresearchcode111299
dc.subject.fieldofresearchcode1112
dc.titleP-glycoprotein-mediated chemoresistance is reversed by carbonic anhydrase XII inhibitors
dc.typeJournal article
dc.type.descriptionC1 - Articles
dc.type.codeC - Journal Articles
dcterms.licensehttps://creativecommons.org/licenses/by/3.0/
dc.description.versionPublished
gro.description.notepublicThis publication has been entered into Griffith Research Online as an Advanced Online Version.
gro.rights.copyright© The Author(s) 2016. This is an Open Access article distributed under the terms of the Creative Commons Attribution 3.0 Unported (CC BY 3.0) License (https://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorPoulsen, Sally-Ann
gro.griffith.authorRankin, Gregory


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