title: Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia.
abstract: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder arising from T-cell progenitors. T-ALL accounts for 15% of newly diagnosed ALL cases in children and 25% in adults. Although the prognosis of T-ALL has improved, due to the use of polychemotherapy schemes, the outcome of relapsed/chemoresistant T-ALL cases is still poor. A signaling pathway that is frequently upregulated in T-ALL, is the phosphatidylinositol 3-kinase/Akt/mTOR network. To explore whether Akt could represent a target for therapeutic intervention in T-ALL, we evaluated the effects of the novel allosteric Akt inhibitor, MK-2206, on a panel of human T-ALL cell lines and primary cells from T-ALL patients. MK-2206 decreased T-ALL cell line viability by blocking leukemic cells in the G(0)/G(1) phase of the cell cycle and inducing apoptosis. MK-2206 also induced autophagy, as demonstrated by an increase in the 14-kDa form of LC3A/B. Western blotting analysis documented a concentration-dependent dephosphorylation of Akt and its downstream targets, GSK-3α/β and FOXO3A, in response to MK-2206. MK-2206 was cytotoxic to primary T-ALL cells and induced apoptosis in a T-ALL patient cell subset (CD34(+)/CD4(-)/CD7(-)), which is enriched in leukemia-initiating cells. Taken together, our findings indicate that Akt inhibition may represent a potential therapeutic strategy in T-ALL.
authors.affiliation: Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Simioni
authors.forename: L M
authors.initials: LM
authors.lastname: Neri
authors.forename: G
authors.initials: G
authors.lastname: Tabellini
authors.forename: F
authors.initials: F
authors.lastname: Ricci
authors.forename: D
authors.initials: D
authors.lastname: Bressanin
authors.forename: F
authors.initials: F
authors.lastname: Chiarini
authors.forename: C
authors.initials: C
authors.lastname: Evangelisti
authors.forename: A
authors.initials: A
authors.lastname: Cani
authors.forename: P L
authors.initials: PL
authors.lastname: Tazzari
authors.forename: F
authors.initials: F
authors.lastname: Melchionda
authors.forename: P
authors.initials: P
authors.lastname: Pagliaro
authors.forename: A
authors.initials: A
authors.lastname: Pession
authors.forename: J A
authors.initials: JA
authors.lastname: McCubrey
authors.forename: S
authors.initials: S
authors.lastname: Capitani
authors.forename: A M
authors.initials: AM
authors.lastname: Martelli
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D006801:Humans; D010766:Phosphorylation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D015398:Signal Transduction
chemical_list: D000970:Antineoplastic Agents; D006575:Heterocyclic Compounds, 3-Ring; C548887:MK 2206; D047428:Protein Kinase Inhibitors; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt