Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia. (Articolo in rivista)

Type
Label
  • Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia. (Articolo in rivista) (literal)
Anno
  • 2009-01-01T00:00:00+01:00 (literal)
Alternative label
  • Chiarini F, Falà F, Tazzari PL, Ricci F, Astolfi A, Pession A, Pagliaro P, McCubrey JA, Martelli AM. (2009)
    Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia.
    in Cancer research (Chic. Ill.)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Chiarini F, Falà F, Tazzari PL, Ricci F, Astolfi A, Pession A, Pagliaro P, McCubrey JA, Martelli AM. (literal)
Pagina inizio
  • 3520 (literal)
Pagina fine
  • 3528 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 69 (literal)
Rivista
Note
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • Department of Human Anatomical Sciences, University of Bologna ; Pediatric Oncology and Haematology Unit, University of Bologna, Immunohaematology and Transfusion Center, Policlinico S.Orsola-Malpighi, IGM-Consiglio Nazionale delle Ricerche, Sezione di Bologna c/o I.O.R., Bologna, Italy; Department of Microbiology and Immunology, School of Medicine, East Carolina University, Greenville, NorthCarolina (literal)
Titolo
  • Dual inhibition of class IA phosphatidylinositol 3-kinase and mammalian target of rapamycin as a new therapeutic option for T-cell acute lymphoblastic leukemia. (literal)
Abstract
  • Recent investigations have documented that constitutively activated phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it strongly influences growth and survival. These findings lend compelling weight for the application of PI3K/Akt/mTOR inhibitors in T-ALL. However, our knowledge of PI3K/Akt/mTOR signaling in T-ALL is limited and it is not clear whether it could be an effective target for innovative therapeutic strategies. Here, we have analyzed the therapeutic potential of the dual PI3K/mTOR inhibitor PI-103, a small synthetic molecule of the pyridofuropyrimidine class, on both T-ALL cell lines and patient samples, which displayed constitutive activation of PI3K/Akt/mTOR signaling. PI-103 inhibited the growth of T-ALL cells, including 170-kDa P-glycoprotein overexpressing cells. PI-103 cytotoxicity was independent of p53 gene status. PI-103 was more potent than inhibitors that are selective only for PI3K (Wortmannin, LY294002) or for mTOR (rapamycin). PI-103 induced G(0)-G(1) phase cell cycle arrest and apoptosis, which was characterized by activation of caspase-3 and caspase-9. PI-103 caused Akt dephosphorylation, accompanied by dephosphorylation of the Akt downstream target, glycogen synthase kinase-3beta. Also, mTOR downstream targets were dephosphorylated in response to PI-103, including p70S6 kinase, ribosomal S6 protein, and 4E-BP1. PI-103 strongly synergized with vincristine. These findings indicate that multitargeted therapy toward PI3K and mTOR alone or with existing drugs may serve as an efficient treatment toward T-ALL cells, which require up-regulation of PI3K/Akt/mTOR signaling for their survival and growth (literal)
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