Triple Akt inhibition as a new therapeutic strategy in T-cell acute lymphoblastic leukemia

Alice Cani, Carolina Simioni, Alberto M. Martelli, Giorgio Zauli, Giovanna Tabellini, Simona Ultimo, James A. McCubrey, Silvano Capitani, Luca M. Neri

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)6597-610
Number of pages14
JournalOncotarget
Volume6
Issue number9
DOIs
Publication statusPublished - Mar 30 2015

Keywords

  • Antineoplastic Combined Chemotherapy Protocols
  • Apoptosis
  • Autophagy
  • Cell Cycle Checkpoints
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Enzyme Activation
  • Heterocyclic Compounds, 3-Ring
  • Humans
  • Jurkat Cells
  • Molecular Targeted Therapy
  • Oxadiazoles
  • Phosphatidylinositol 3-Kinase
  • Phosphorylation
  • Phosphorylcholine
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction
  • TOR Serine-Threonine Kinases
  • Journal Article
  • Research Support, Non-U.S. Gov't

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