title: PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia.
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.
authors: Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP, Brazil.
authors: André Bortolini
authors: AB
authors: Silveira
authors: Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP, Brazil.
authors: Angelo Brunelli Albertoni
authors: AB
authors: Laranjeira
authors: Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP, Brazil.
authors: Gisele Olinto Libanio
authors: GO
authors: Rodrigues
authors: Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Paulo César
authors: PC
authors: Leal
authors: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors: Bruno António
authors: BA
authors: Cardoso
authors: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal.
authors: João Taborda
authors: JT
authors: Barata
authors: Departamento de Química, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors: Rosendo Augusto
authors: RA
authors: Yunes
authors: Instituto Carlos Chagas, Fundação Oswaldo Cruz, Curitiba, PR, Brazil.
authors: Nilson Ivo Tonin
authors: NI
authors: Zanchin
authors: Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP, Brazil.
authors: Sílvia Regina
authors: SR
authors: Brandalise
authors: Laboratório de Biologia Molecular, Centro Infantil Boldrini, Campinas, SP, Brazil.|Departamento de Genética Médica, Faculdade de Ciências Médicas, UNICAMP, Campinas, SP, Brazil.
authors: José Andrés
authors: JA
authors: Yunes
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005938:Glucocorticoids / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008727:Methotrexate / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011810:Quinoxalines / Q000008:administration & dosage / Q000494:pharmacology; D011897:Random Allocation; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D005938:Glucocorticoids; D008727:Methotrexate; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011810:Quinoxalines; D045162:Thiazolidinediones; C505144:5-quinoxalin-6-ylmethylenethiazolidine-2,4-dione
keywords: AS605240; PI3K; T-ALL; drug resistance; glucocorticoids