title: Activity of the pan-class I phosphoinositide 3-kinase inhibitor NVP-BKM120 in T-cell acute lymphoblastic leukemia.
abstract: Constitutively active phosphoinositide 3-kinase (PI3K) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), where it upregulates cell proliferation, survival and drug resistance. These observations lend compelling weight to the application of PI3K inhibitors in the therapy of T-ALL. Here, we have analyzed the therapeutic potential of the pan-PI3K inhibitor NVP-BKM120 (BKM120), an orally bioavailable 2,6-dimorpholino pyrimidine derivative, which has entered clinical trials for solid tumors, on both T-ALL cell lines and patient samples. BKM120 treatment resulted in G2/M phase cell cycle arrest and apoptosis, being cytotoxic to a panel of T-ALL cell lines and patient T lymphoblasts, and promoting a dose- and time-dependent dephosphorylation of Akt and S6RP. BKM120 maintained its pro-apoptotic activity against Jurkat cells even when cocultured with MS-5 stromal cells, which mimic the bone marrow microenvironment. Remarkably, BKM120 synergized with chemotherapeutic agents currently used for treating T-ALL patients. Moreover, in vivo administration of BKM120 to a subcutaneous xenotransplant model of human T-ALL significantly delayed tumor growth, thus prolonging survival time. Taken together, our findings indicate that BKM120, either alone or in combination with chemotherapeutic drugs, may be an efficient treatment for T-ALLs that have aberrant upregulation of the PI3K signaling pathway.
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors: A
authors: A
authors: Lonetti
authors: Cancer Biology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
authors: I L
authors: IL
authors: Antunes
authors: 1] Institute of Molecular Genetics, National Research Council, Pavia, Italy [2] Muscoloskeletal Cell Biology Laboratory, IOR, Bologna, Italy.
authors: F
authors: F
authors: Chiarini
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors: E
authors: E
authors: Orsini
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors: F
authors: F
authors: Buontempo
authors: Immunohematology and Transfusion Center, Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors: F
authors: F
authors: Ricci
authors: Immunohematology and Transfusion Center, Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors: P L
authors: PL
authors: Tazzari
authors: Immunohematology and Transfusion Center, Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors: P
authors: P
authors: Pagliaro
authors: Clinica Pediatrica, University of Bologna, Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors: F
authors: F
authors: Melchionda
authors: Clinica Pediatrica, University of Bologna, Policlinico S.Orsola-Malpighi, Bologna, Italy.
authors: A
authors: A
authors: Pession
authors: Oncoematologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors: A
authors: A
authors: Bertaina
authors: Oncoematologia Pediatrica, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
authors: F
authors: F
authors: Locatelli
authors: Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors: J A
authors: JA
authors: McCubrey
authors: Cancer Biology Unit, Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
authors: J T
authors: JT
authors: Barata
authors: 1] Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy [2] Institute of Molecular Genetics, National Research Council, Pavia, Italy [3] Muscoloskeletal Cell Biology Laboratory, IOR, Bologna, Italy.
authors: A M
authors: AM
authors: Martelli
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009025:Morpholines / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000631:Aminopyridines; D009025:Morpholines; C571178:NVP-BKM120; D000081082:Phosphoinositide-3 Kinase Inhibitors