title: PI3K isoform inhibition associated with anti Bcr-Abl drugs shows in vitro increased anti-leukemic activity in Philadelphia chromosome-positive B-acute lymphoblastic leukemia cell lines.
abstract: B-acute lymphoblastic leukemia (B-ALL) is a malignant disorder characterized by the abnormal proliferation of B-cell progenitors. Philadelphia chromosome-positive (Ph+) B-ALL is a subtype that expresses the Bcr-Abl fusion protein which represents a negative prognostic factor. Constitutive activation of the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) network is a common feature of B-ALL, influencing cell growth and survival. In the present study, we aimed to investigate the efficacy of PI3K isoform inhibition in B-ALL cell lines harboring the Bcr-Abl fusion protein.We studied the effects of anti Bcr-Abl drugs Imatinib, Nilotinib and GZD824 associated with PI3K isoform inhibitors. We used a panel of six compounds which specifically target PI3K isoforms including the pan-PI3K inhibitor ZSTK474, p110α BYL719 inhibitor and the dual p110γ/p110δ inhibitor IPI145. The effects of single drugs and of several drug combinations were analyzed to assess cytotoxicity by MTS assays, apoptosis and autophagy by flow cytometry and Western blot, as well as the phosphorylation status of the pathway.ZSTK474, BYL719 and IPI145 administered in combination with imatinib, nilotinib and GZD824 for 48 h, decreased cell viability, induced apoptosis and autophagy in a marked synergistic manner.These findings suggest that selected PI3K isoform inhibitors used in combination with anti Bcr-Abl drugs may be an attractive novel therapeutic intervention in Ph+ B-ALL.
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Ultimo
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Carolina
authors.initials: C
authors.lastname: Simioni
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Martelli
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Zauli
authors.affiliation: Institute of Molecular Genetics, Rizzoli Orthopedic Institute, National Research Council, Bologna, Italy.
authors.forename: Camilla
authors.initials: C
authors.lastname: Evangelisti
authors.affiliation: Department of Life Sciences, University of Trieste, Trieste, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Celeghini
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Marisi
authors.affiliation: Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ulivi
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.|LTTA Center, University of Ferrara, Ferrara, Italy.
authors.forename: Silvano
authors.initials: S
authors.lastname: Capitani
authors.affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors.forename: Luca M
authors.initials: LM
authors.lastname: Neri
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007546:Isoquinolines / Q000008:administration & dosage / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011687:Purines / Q000008:administration & dosage / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology; D000480:Alkynes; D010880:Piperidines; D011725:Pyridines
chemical_list: D001549:Benzamides; D016044:Fusion Proteins, bcr-abl; D000068877:Imatinib Mesylate; D007527:Isoenzymes; D007546:Isoquinolines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D013844:Thiazoles; D014227:Triazines; C510150:ZSTK474; C585539:Alpelisib; C586691:duvelisib; C498826:nilotinib; C579813:olverembatinib; D000480:Alkynes; D010880:Piperidines; D011725:Pyridines
keywords: Bcr-Abl; PI3K isoforms; Ph+ B-acute lymphoblastic leukemia; autophagy; tyrosine kinase inhibitors