title: Molecular effects of the phosphatidylinositol-3-kinase inhibitor NVP-BKM120 on T and B-cell acute lymphoblastic leukaemia.
abstract: BACKGROUND
  Constitutive activation of the PI3K pathway in T cell acute lymphoblastic leukaemia (T-ALL) has been reported and in a mouse model, PI3K activation, together with MYC, cooperates in Burkitt lymphoma (BL) pathogenesis. We investigated the effects of NVP-BKM120, a potent pan-class I PI3K inhibitor, in lymphoblastic leukaemia cell lines.
  
  
  METHODS
  Effects of NVP-BKM120 on cell viability, clonogenicity, apoptosis, cell cycle, cell signalling and autophagy were assessed in vitro on T-ALL (Jurkat and MOLT-4) and BL (Daudi and NAMALWA) cell lines.
  
  
  RESULTS
  NVP-BKM120 treatment decreased cell viability and clonogenic growth in all tested cells. Moreover, the drug arrested cell cycling in association with a decrease in Cyclin B1 protein levels, and increased apoptosis. Immunoblotting analysis of cells treated with the drug revealed decreased phosphorylation, in a dose-dependent manner, of AKT, mTOR, P70S6K and 4EBP1, with stable total protein levels. Additionally, we observed a dose-dependent decrease in BAD phosphorylation, in association with augmented BAX:BCL2 ratio. Quantification of autophagy showed a dose-dependent increase in acidic vesicular organelles in all cells tested.
  
  
  CONCLUSIONS
  In summary, our present study establishes that NVP-BKM120 presents an effective antitumour activity against T-ALL and BL cell lines.
authors.affiliation: Haematology and Hemotherapy Centre-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo 13083-970, Brazil.
authors.forename: João Kleber Novais
authors.initials: JK
authors.lastname: Pereira
authors.affiliation: Haematology and Hemotherapy Centre-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo 13083-970, Brazil.
authors.forename: João Agostinho
authors.initials: JA
authors.lastname: Machado-Neto
authors.affiliation: Haematology and Hemotherapy Centre-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo 13083-970, Brazil.
authors.forename: Matheus Rodrigues
authors.initials: MR
authors.lastname: Lopes
authors.affiliation: Haematology and Hemotherapy Centre-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo 13083-970, Brazil.
authors.forename: Beatriz Corey
authors.initials: BC
authors.lastname: Morini
authors.affiliation: Haematology and Hemotherapy Centre-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo 13083-970, Brazil; Department of Internal Medicine, University of São Paulo at Ribeirão Preto Medical School, Ribeirão Preto, São Paulo, Brazil.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Traina
authors.affiliation: Haematology and Hemotherapy Centre-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo 13083-970, Brazil.
authors.forename: Fernando Ferreira
authors.initials: FF
authors.lastname: Costa
authors.affiliation: Haematology and Hemotherapy Centre-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo 13083-970, Brazil.
authors.forename: Sara Teresinha Olalla
authors.initials: ST
authors.lastname: Saad
authors.affiliation: Haematology and Hemotherapy Centre-University of Campinas/Hemocentro-Unicamp, Instituto Nacional de Ciência e Tecnologia do Sangue, Campinas, São Paulo 13083-970, Brazil; Department of Biological Sciences, Federal University of São Paulo, Diadema, São Paulo 09913-030, Brazil. Electronic address: patricia.favaro@unifesp.br.
authors.forename: Patricia
authors.initials: P
authors.lastname: Favaro
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000631:Aminopyridines; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D058539:Phosphatidylinositol 3-Kinase
keywords: Daudi; Jurkat; Leukaemia; MOLT-4; NAMALWA; NVP-BKM120; PI3K pathway