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Molecular effects of the phosphatidylinositol-3-kinase inhibitor NVP-BKM120 on T and B-cell acute lymphoblastic leukaemia

2015; Elsevier BV; Volume: 51; Issue: 14 Linguagem: Inglês

10.1016/j.ejca.2015.07.018

1879-0852

João Kleber Novais Pereira, João Agostinho Machado‐Neto, Matheus Rodrigues Lopes, Beatriz Corey Morini, Fabı́ola Traina, Fernando Ferreira Costa, Sara Teresinha Olalla Saad, Patrícia Favaro,

Biochemical and Molecular Research

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. Conclusion In summary, our present study establishes that NVP-BKM120 presents an effective antitumour activity against T-ALL and BL cell lines.