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PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia

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dc.contributor.authorSilveira, André Bortolini
dc.contributor.authorLaranjeira, Angelo Brunelli Albertoni
dc.contributor.authorRodrigues, Gisele Olinto Libanio
dc.contributor.authorLeal, Paulo César
dc.contributor.authorCardoso, Bruno A.
dc.contributor.authorBarata, João T.
dc.contributor.authorYunes, Rosendo Augusto
dc.contributor.authorZanchin, Nilson Ivo Tonin
dc.contributor.authorBrandalise, Sílvia Regina
dc.contributor.authorYunes, José Andrés
dc.date.accessioned2022-06-17T15:50:33Z
dc.date.available2022-06-17T15:50:33Z
dc.date.issued2015
dc.description© Impact Journals, LLC.pt_PT
dc.description.abstractThe PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K pathway has been suggested as one mechanism of glucocorticoid resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. By gene expression microarray analysis of T-ALL cells treated with the PI3K inhibitor AS605240, we identified Myc as a prominent downstream target of the PI3K pathway. A significant association was found between the AS605240 gene expression signature and that of glucocorticoid resistance and relapse in T-ALL. AS605240 showed anti-leukemic activity and strong synergism with glucocorticoids both in vitro and in a NOD/SCID xenograft model of T-ALL. In contrast, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction, however, could be circumvented by the use of correct drug scheduling schemes. Our data indicate the potential benefits and difficulties for the incorporation of PI3K inhibitors in T-ALL therapy.pt_PT
dc.description.sponsorshipThis work was supported by grants from FAPESP (08/10034–1) to JAY. ABS and ABAL were supported by CNPq and FAPESP fellowships, respectivelypt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationOncotarget. 2015 May 30;6(15):13105-18pt_PT
dc.identifier.doi10.18632/oncotarget.3524pt_PT
dc.identifier.eissn1949-2553
dc.identifier.urihttp://hdl.handle.net/10451/53401
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherImpact Journals, LLCpt_PT
dc.relation.publisherversionhttps://www.oncotarget.com/pt_PT
dc.subjectAS605240pt_PT
dc.subjectPI3Kpt_PT
dc.subjectT-ALLpt_PT
dc.subjectDrug resistancept_PT
dc.subjectGlucocorticoidspt_PT
dc.titlePI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemiapt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.citation.endPage13118pt_PT
oaire.citation.issue15pt_PT
oaire.citation.startPage13105pt_PT
oaire.citation.titleOncotargetpt_PT
oaire.citation.volume6pt_PT
person.familyNameCaetano Cardoso
person.familyNameBarata
person.givenNameBruno António
person.givenNameJoão
person.identifier.ciencia-id0F1A-378B-1157
person.identifier.orcid0000-0002-6521-7257
person.identifier.orcid0000-0002-4826-8976
person.identifier.ridD-9181-2015
person.identifier.scopus-author-id24402845200
person.identifier.scopus-author-id7006937224
rcaap.rightsrestrictedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication5d24249e-4cd5-4ba4-a935-7b8ec493330a
relation.isAuthorOfPublication06f27f7f-1c6c-4c03-a70d-52f8a388bd3b
relation.isAuthorOfPublication.latestForDiscovery06f27f7f-1c6c-4c03-a70d-52f8a388bd3b

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