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Type: Artigo
Title: PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia
Author: Silveira, André Bortolini
Laranjeira, Angelo Brunelli Albertoni
Rodrigues, Gisele Olinto Libanio
Leal, Paulo César
Cardoso, Bruno António
Barata, João Taborda
Yunes, Rosendo Augusto
Zanchin, Nilson Ivo Tonin
Brandalise, Sílvia Regina
Yunes, José Andrés
Abstract: The 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
Subject: Glicocorticoides
Country: Estados Unidos
Editor: Impact Journals
Rights: Fechado
Identifier DOI: 10.18632/oncotarget.3524
Date Issue: 2015
Appears in Collections:FCM - Artigos e Outros Documentos

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