Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2336-2342
Number of pages7
JournalLeukemia
Volume26
Issue number11
DOIs
Publication statusPublished - Nov 2012

Keywords

  • Akt
  • Autophagy
  • Chemotherapy
  • T-cell acute lymphoblastic leukemia
  • Targeted therapy

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

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    Simioni, C., Neri, L. M., Tabellini, G., Ricci, F., Bressanin, D., Chiarini, F., Evangelisti, C., Cani, A., Tazzari, P. L., Melchionda, F., Pagliaro, P., Pession, A., McCubrey, J. A., Capitani, S., & Martelli, A. M. (2012). Cytotoxic activity of the novel Akt inhibitor, MK-2206, in T-cell acute lymphoblastic leukemia. Leukemia, 26(11), 2336-2342. https://doi.org/10.1038/leu.2012.136