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Photosensitization of human skin fibroblasts by vemurafenib promotes pleiotropic effects on membrane-enclosed organelles and apoptosis

2023Journal article Restricted access
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dc.contributor.authorAlpalhão, Miguel
dc.contributor.authorBotequim, David
dc.contributor.authorFerreira, João
dc.contributor.authorSantus, Rene
dc.contributor.authorFilipe, Paulo
dc.date.accessioned2023-01-05T14:40:40Z
dc.date.available2023-01-05T14:40:40Z
dc.date.issued2023
dc.description© 2022 Elsevier B.V. All rights reserved.pt_PT
dc.description.abstractVemurafenib (VB), a BRAF inhibitor and a first-line treatment for unresectable or metastatic melanoma, is strongly phototoxic towards normal skin cells. Herein, we show that in cultured HS 68 human diploid dermal fibroblasts, low concentrations of VB suffice to promote photosensitization to low doses of UVA (∼ 5 J/cm2), as evidenced by a significant decrease in cell viability. In contrast to data obtained in chemico our results support a role for ROS (reactive oxygen species). Indeed, peroxidation of cellular lipids was observed which could be alleviated by the lipophilic antioxidant BHT (2,6-di-tert-butyl-4-methylphenol). Using in vivo confocal laser scanning microscopy and vital fluorescent probes it was shown at the single cell level that the plasma membrane and lipid-rich organelles, namely mitochondria, endoplasmic reticulum, and lysosomes, as well as actin filaments, were severely damaged by the UVA-induced VB-photosensitization. Finally, we showed that mitochondrial impairment was concurrent with caspase 3/7 activation and cell death by apoptosis.pt_PT
dc.description.sponsorshipThis work was supported by AbbVie, Lda., donation FPJ937, and Fundação para a Ciência e Tecnologia/FCT, Portugal (FCT PTDC/MEC-DER/30198/2017 FARM ID).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationJ Photochem Photobiol B. 2023 Jan;238:112600pt_PT
dc.identifier.doi10.1016/j.jphotobiol.2022.112600pt_PT
dc.identifier.eissn1873-2682
dc.identifier.issn1011-1344
dc.identifier.urihttp://hdl.handle.net/10451/55666
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationSerotonergic-based therapies to decrease the impact of moderate to severe psoriasis: translation of fundamental research into industry
dc.relation.publisherversionhttps://www.sciencedirect.com/journal/journal-of-photochemistry-and-photobiology-b-biologypt_PT
dc.subjectApoptosispt_PT
dc.subjectCaspasespt_PT
dc.subjectERpt_PT
dc.subjectMitochondriapt_PT
dc.subjectPhotoperoxidationpt_PT
dc.subjectUVApt_PT
dc.subjectVemurafenibpt_PT
dc.titlePhotosensitization of human skin fibroblasts by vemurafenib promotes pleiotropic effects on membrane-enclosed organelles and apoptosispt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleSerotonergic-based therapies to decrease the impact of moderate to severe psoriasis: translation of fundamental research into industry
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FMEC-DER%2F30198%2F2017/PT
oaire.citation.titleJournal of Photochemistry and Photobiology B: Biologypt_PT
oaire.citation.volume238pt_PT
oaire.fundingStream3599-PPCDT
person.familyNameBotas Alpalhão
person.familyNameBotequim
person.familyNameFerreira
person.familyNamesantus
person.familyNameFilipe
person.givenNameMiguel Duarte
person.givenNameDavid
person.givenNameJoão António Augusto
person.givenNamerene
person.givenNamePaulo
person.identifier.ciencia-id121D-3A5D-E15C
person.identifier.ciencia-id6D1E-4F52-0832
person.identifier.ciencia-idEA1C-91BA-1C8B
person.identifier.ciencia-id171A-309C-C397
person.identifier.orcid0000-0001-7672-0395
person.identifier.orcid0000-0003-0018-0964
person.identifier.orcid0000-0002-9473-8553
person.identifier.orcid0000-0002-7337-6493
person.identifier.scopus-author-id7003448874
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
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