title: PI3K pan-inhibition impairs more efficiently proliferation and survival of T-cell acute lymphoblastic leukemia cell lines when compared to isoform-selective PI3K inhibitors.
abstract: Class I phosphatidylinositol 3-kinases (PI3Ks) are frequently activated in T-cell acute lymphoblastic leukemia (T-ALL), mainly due to the loss of PTEN function. Therefore, targeting PI3Ks is a promising innovative approach for T-ALL treatment, however at present no definitive evidence indicated which is the better therapeutic strategy between pan or selective isoform inhibition, as all the four catalytic subunits might participate in leukemogenesis. Here, we demonstrated that in both PTEN deleted and PTEN non deleted T-ALL cell lines, PI3K pan-inhibition exerted the highest cytotoxic effects when compared to both selective isoform inhibition or dual p110γ/δ inhibition. Intriguingly, the dual p110γ/δ inhibitor IPI-145 was effective in Loucy cells, which are representative of early T-precursor (ETP)-ALL, a T-ALL subtype associated with a poor outcome. PTEN gene deletion did not confer a peculiar reliance of T-ALL cells on PI3K activity for their proliferation/survival, as PTEN was inactivated in PTEN non deleted cells, due to posttranslational mechanisms. PI3K pan-inhibition suppressed Akt activation and induced caspase-independent apoptosis. We further demonstrated that in some T-ALL cell lines, autophagy could exert a protective role against PI3K inhibition. Our findings strongly support clinical application of class I PI3K pan-inhibitors in T-ALL treatment, with the possible exception of ETP-ALL cases.
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors: Annalisa
authors: A
authors: Lonetti
authors: Department of Human, Social and Health Sciences, University of Cassino, Cassino, Italy.
authors: Alessandra
authors: A
authors: Cappellini
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors: Antonino Maria
authors: AM
authors: Spartà
authors: Muscoloskeletal Cell Biology Laboratory, IOR, Bologna, Italy.|Institute of Molecular Genetics, National Research Council-Rizzoli Orthopedic Institute, Bologna, Italy.
authors: Francesca
authors: F
authors: Chiarini
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors: Francesca
authors: F
authors: Buontempo
authors: Muscoloskeletal Cell Biology Laboratory, IOR, Bologna, Italy.|Institute of Molecular Genetics, National Research Council-Rizzoli Orthopedic Institute, Bologna, Italy.
authors: Camilla
authors: C
authors: Evangelisti
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors: Cecilia
authors: C
authors: Evangelisti
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors: Ester
authors: E
authors: Orsini
authors: Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors: James A
authors: JA
authors: McCubrey
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors: Alberto Maria
authors: AM
authors: Martelli
mesh_terms: D001343:Autophagy / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006801:Humans; D007527:Isoenzymes; D019169:Jurkat Cells; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016019:Survival Analysis
chemical_list: D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors
keywords: PI3K isoforms; PTEN; T-ALL; autophagy; targeted therapy