title: Triple Akt inhibition as a new therapeutic strategy in T-cell acute lymphoblastic leukemia.
abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder in which chemotherapy resistance and refractory relapses occur, with a poorer prognostic outcome.Constitutively active PI3K/Akt/mTOR pathway is a common feature of T-ALL upregulating cell proliferation, survival and drug resistance. This pathway is currently under clinical trials with small molecules inhibitors (SMI).To verify whether a multi-inhibition treatment against Akt protein could enhance the efficacy of individual drug administration and overcome drug resistance as well as to obtain a decrease in single drug concentration, we tested on T-ALL cell lines the effects of combined treatments with three Akt inhibitors with different mode of action, GSK690693, MK-2206 and Perifosine.In cells with hyperactivated Akt, combined administration of the drugs displayed a significant synergistic and cytotoxic effect and affected PI3K/Akt/mTOR pathway at much lower concentration than single drug use. Highest synergistic effect for full inhibition of Akt was also related to the timing of every drug administration. Furthermore the triple treatment had greater efficacy in inducing cell cycle arrest in G0/G1 phase and both apoptosis and autophagy.Targeting Akt as a key protein of PI3K/Akt/mTOR pathway with multiple drugs might represent a new and promising pharmacological strategy for treatment of T-ALL patients.
authors: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors: Alice
authors: A
authors: Cani
authors: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors: Carolina
authors: C
authors: Simioni
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors: Alberto M
authors: AM
authors: Martelli
authors: Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy.
authors: Giorgio
authors: G
authors: Zauli
authors: Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
authors: Giovanna
authors: G
authors: Tabellini
authors: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors: Simona
authors: S
authors: Ultimo
authors: Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors: James A
authors: JA
authors: McCubrey
authors: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.|LTTA Center, University of Ferrara, Ferrara, Italy.
authors: Silvano
authors: S
authors: Capitani
authors: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.
authors: Luca M
authors: LM
authors: Neri
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004789:Enzyme Activation; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D058990:Molecular Targeted Therapy; D010069:Oxadiazoles / Q000494:pharmacology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C528328:GSK690693; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D010069:Oxadiazoles; D047428:Protein Kinase Inhibitors; D010767:Phosphorylcholine; C105905:perifosine; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Akt; GSK690693; MK-2206; Perifosine; T-acute lymphoblastic leukemia