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: C Simioni, L M Neri, G Tabellini, F Ricci, D Bressanin, F Chiarini, C Evangelisti, A Cani, P L Tazzari, F Melchionda, P Pagliaro, A Pession, J A McCubrey, S Capitani, A M Martelli
• Journal: Leukemia (Leukemia) Vol. 26 Issue 11 Pg. 2336-42 (Nov 2012) ISSN: 1476-5551 [Electronic] England
• PMID: 22614243 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Heterocyclic Compounds, 3-Ring
• MK 2206
• Protein Kinase Inhibitors
• Doxorubicin
• Proto-Oncogene Proteins c-akt

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• Blotting, Western
• Cell Cycle (drug effects)
• Doxorubicin (pharmacology)
• Drug Synergism
• Heterocyclic Compounds, 3-Ring (pharmacology)
• Humans
• Phosphorylation
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (enzymology, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (antagonists & inhibitors)
• Signal Transduction