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Multidrug resistance reversal effects of aminated thioxanthones and interaction with cytochrome P450 3A4

2011Journal article Open access
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dc.contributor.authorPalmeira, Andreia
dc.contributor.authorSousa, Maria Emília
dc.contributor.authorFernandes, Miguel X.
dc.contributor.authorPinto, Madalena M.
dc.contributor.authorVasconcelos, M. Helena
dc.date.accessioned2023-02-08T15:37:28Z
dc.date.available2023-02-08T15:37:28Z
dc.date.issued2011
dc.description.abstractAminated thioxanthones have recently been described as dual-acting agents: growth inhibitors of leukemia cell lines and P-glycoprotein (P-gp) inhibitors. To evaluate the selectivity profile of thioxanthones as inhibitors of multidrug resistance (MDR), their interaction with other ABC transporters, which were found to have a strong correlation with multidrug resistance, such as multidrug resistant proteins 1 (MRP1), 2 (MRP2) and 3 (MRP3) and breast cancer resistance protein (BCRP) was also evaluated. The interaction of thioxanthones with cytochrome P450 3A4 (CYP3A4) together with the prediction of their binding conformations and metabolism sites was also investigated. Methods. The UIC2 monoclonal antibody-labelling assay was performed using P-gp overexpressing leukemia cells, K562Dox, incubated with eight thioxanthonic derivatives, in order to confirm their P-gp inhibitory activity. A colorimetric-based ATPase assay using membrane vesicles from mammalian cells overexpressing a selected human ABC transporter protein (P-gp, MRP1, MRP2, MRP3, or BCRP) was performed. To verify if some of the thioxanthonic derivatives were substrates or inhibitors of CYP3A4, a luciferin-based luminescence assay was performed. Finally, the in silico prediction of the most probable metabolism sites and docking studies of thioxanthones on CYP3A4 binding site were investigated. Results. Thioxanthones interacted not only with P-gp but also with MRP and BCRP transporters. These compounds also interfere with CYP3A4 activity in vitro, in accordance with the in silico prediction. Conclusion. Thioxanthonic derivatives are multi-target compounds. A better characterization of the interactions of these compounds with classical resistance mechanisms may possibly identify improved treatment applications.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationPalmeira, A., Sousa, M. E., Fernandes, M. X., Pinto, M. M., & Vasconcelos, M. H. (2011). Multidrug resistance reversal effects of aminated thioxanthones and interaction with cytochrome P450 3A4. Journal of Pharmacy & Pharmaceutical Sciences, 15(1), 31–45. https://doi.org/10.18433/J3BG65pt_PT
dc.identifier.doi10.18433/J3BG65pt_PT
dc.identifier.urihttp://hdl.handle.net/10400.13/5017
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherFrontiers Mediapt_PT
dc.relationStrategic Project - UI 4040 - 2011-2012
dc.relation.publisherversionhttps://journals.library.ualberta.ca/jpps/index.php/JPPS/article/view/11714/9487pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAminated Thioxanthonespt_PT
dc.subjectMultidrug resistancept_PT
dc.subjectCytochrome P450 3A4pt_PT
dc.subject.pt_PT
dc.subjectFaculdade de Ciências Exatas e da Engenhariapt_PT
dc.titleMultidrug resistance reversal effects of aminated thioxanthones and interaction with cytochrome P450 3A4pt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleStrategic Project - UI 4040 - 2011-2012
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/PEst-OE%2FSAU%2FUI4040%2F2011/PT
oaire.citation.endPage45pt_PT
oaire.citation.issue1pt_PT
oaire.citation.startPage31pt_PT
oaire.citation.titleJournal of Pharmacy & Pharmaceutical Sciencespt_PT
oaire.citation.volume15pt_PT
oaire.fundingStream6817 - DCRRNI ID
person.familyNameFernandes
person.givenNameMiguel Xavier
person.identifier.ciencia-idED1D-3C7A-467C
person.identifier.orcid0000-0002-1840-616X
person.identifier.ridA-4373-2013
person.identifier.scopus-author-id35466972500
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
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relation.isAuthorOfPublication.latestForDiscovery8dab9a0d-f44a-4d2d-b9b1-7b3145162ca3
relation.isProjectOfPublication85f8b1e6-0236-47a6-b77b-6d8826f36004
relation.isProjectOfPublication.latestForDiscovery85f8b1e6-0236-47a6-b77b-6d8826f36004

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