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The Complex Dynamic of Phase I Drug Metabolism in the Early Stages of Doxorubicin Resistance in Breast Cancer Cells

2022-10-29Artigo científico Acesso aberto
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dc.contributor.authorBarata, Isabel S
dc.contributor.authorGomes, Bruno C
dc.contributor.authorRodrigues, António S
dc.contributor.authorRueff, José
dc.contributor.authorRueff, Jose
dc.contributor.authorKranendonk, Michel
dc.contributor.authorEsteves, Francisco
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutionCentre for Toxicogenomics and Human Health (ToxOmics)
dc.contributor.pblSpringer Science Business Media
dc.date.accessioned2022-11-16T22:10:46Z
dc.date.available2022-11-16T22:10:46Z
dc.date.issued2022-10-29
dc.descriptionFunding: This research was partly funded by the Research Center grant ToxOmics (UIDB/00009/2020 and UIDP/0009/2020), from the Portuguese Fundação para a Ciência e a Tecnologia—FCT
dc.description.abstractThe altered activity of drug metabolism enzymes (DMEs) is a hallmark of chemotherapy resistance. Cytochrome P450s (CYPs), mainly CYP3A4, and several oxidoreductases are responsible for Phase I metabolism of doxorubicin (DOX), an anthracycline widely used in breast cancer (BC) treatment. This study aimed to investigate the role of Phase I DMEs involved in the first stages of acquisition of DOX-resistance in BC cells. For this purpose, the expression of 92 DME genes and specific CYP-complex enzymes activities were assessed in either sensitive (MCF-7 parental cells; MCF-7/DOXS) or DOX-resistant (MCF-7/DOXR) cells. The DMEs genes detected to be significantly differentially expressed in MCF-7/DOXR cells (12 CYPs and eight oxidoreductases) were indicated previously to be involved in tumor progression and/or chemotherapy response. The analysis of CYP-mediated activities suggests a putative enhanced CYP3A4-dependent metabolism in MCF-7/DOXR cells. A discrepancy was observed between CYP-enzyme activities and their corresponding levels of mRNA transcripts. This is indicative that the phenotype of DMEs is not linearly correlated with transcription induction responses, confirming the multifactorial complexity of this mechanism. Our results pinpoint the potential role of specific CYPs and oxidoreductases involved in the metabolism of drugs, retinoic and arachidonic acids, in the mechanisms of chemo-resistance to DOX and carcinogenesis of BC.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent1074963
dc.identifier.doi10.3390/genes13111977
dc.identifier.issn0920-8569
dc.identifier.otherPURE: 47765572
dc.identifier.otherPURE UUID: 16bc20ba-deb3-4145-831a-50290535ced1
dc.identifier.otherPubMed: 36360213
dc.identifier.otherScopus: 85141575095
dc.identifier.otherWOS: 000881135300001
dc.identifier.urihttp://hdl.handle.net/10362/145580
dc.language.isoeng
dc.peerreviewedyes
dc.subjectDrug Resistance, Neoplasm/genetics
dc.subjectCytochrome P-450 CYP3A/genetics
dc.subjectDoxorubicin/pharmacology
dc.subjectAntibiotics, Antineoplastic/pharmacology
dc.subjectNeoplasms
dc.subjectSDG 3 - Good Health and Well-being
dc.titleThe Complex Dynamic of Phase I Drug Metabolism in the Early Stages of Doxorubicin Resistance in Breast Cancer Cellsen
dc.typejournal article
degois.publication.issue11
degois.publication.titleGenes
degois.publication.volume13
dspace.entity.typePublication
person.familyNameRueff
person.givenNameJose
person.identifier793666
person.identifier.ciencia-id0E15-908D-EA21
person.identifier.orcid0000-0002-8456-7295
person.identifier.ridE-6426-2013
person.identifier.scopus-author-id7006536439
rcaap.rightsopenAccess
relation.isAuthorOfPublication91a3b5ac-0328-498d-8cb8-08555b202306
relation.isAuthorOfPublication.latestForDiscovery91a3b5ac-0328-498d-8cb8-08555b202306

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