Location of Repository

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

By Carolina Simioni, Luca Maria Neri, Tabellini G., Ricci F., Bressanin D., Chiarini F., Evangelisti C., Alice Cani, Tazzari P. L., Melchionda F., Pagliaro P., Pession A., Mccubrey J. A., Silvano Capitani and Martelli A. M.

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder arising from T-cell progenitors. T-ALL accounts for\ud 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\ud polychemotherapy schemes, the outcome of relapsed/chemoresistant T-ALL cases is still poor. A signaling pathway that is\ud frequently upregulated in T-ALL, is the phosphatidylinositol 3-kinase/Akt/mTOR network. To explore whether Akt could represent a\ud target for therapeutic intervention in T-ALL, we evaluated the effects of the novel allosteric Akt inhibitor, MK-2206, on a panel of\ud human T-ALL cell lines and primary cells from T-ALL patients. MK-2206 decreased T-ALL cell line viability by blocking leukemic cells\ud in the G0/G1 phase of the cell cycle and inducing apoptosis. MK-2206 also induced autophagy, as demonstrated by an increase in\ud the 14-kDa form of LC3A/B. Western blotting analysis documented a concentration-dependent dephosphorylation of Akt and its\ud downstream targets, GSK-3a/b and FOXO3A, in response to MK-2206. MK-2206 was cytotoxic to primary T-ALL cells and induced\ud apoptosis in a T-ALL patient cell subset (CD34þ/CD4/CD7), which is enriched in leukemia-initiating cells. Taken together, our\ud findings indicate that Akt inhibition may represent a potential therapeutic strategy in T-ALL

Year: 2012
DOI identifier: 10.1038/leu.2012.136
OAI identifier: oai:iris.unife.it:11392/1728532
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://hdl.handle.net/11392/17... (external link)
  • Suggested articles


    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.