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

Cani A, Simioni C, Martelli AM, Zauli G, Tabellini G, Ultimo S, McCubrey JA, Capitani S, Neri LM - Oncotarget (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.

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.

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Related in: MedlinePlus

Expression and phosphorylation status of Akt, PTEN and mTOR in T- ALL cell linesWestern blot analysis of T-ALL cell lines to detect the expression and phosphorylation levels of Akt, PTEN and mTOR. Twenty-five μg of protein was blotted to each lane. Antibody to β-actin served as a loading control.
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Figure 1: Expression and phosphorylation status of Akt, PTEN and mTOR in T- ALL cell linesWestern blot analysis of T-ALL cell lines to detect the expression and phosphorylation levels of Akt, PTEN and mTOR. Twenty-five μg of protein was blotted to each lane. Antibody to β-actin served as a loading control.

Mentions: Whereas PEER and BE-13 cells did not displayed phosphorylated Akt, the other four cell lines displayed an hyperphosphorylated form, which is indicative of constitutive activation of PI3K signaling pathway (Fig. 1).


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

Cani A, Simioni C, Martelli AM, Zauli G, Tabellini G, Ultimo S, McCubrey JA, Capitani S, Neri LM - Oncotarget (2015)

Expression and phosphorylation status of Akt, PTEN and mTOR in T- ALL cell linesWestern blot analysis of T-ALL cell lines to detect the expression and phosphorylation levels of Akt, PTEN and mTOR. Twenty-five μg of protein was blotted to each lane. Antibody to β-actin served as a loading control.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4466637&req=5

Figure 1: Expression and phosphorylation status of Akt, PTEN and mTOR in T- ALL cell linesWestern blot analysis of T-ALL cell lines to detect the expression and phosphorylation levels of Akt, PTEN and mTOR. Twenty-five μg of protein was blotted to each lane. Antibody to β-actin served as a loading control.
Mentions: Whereas PEER and BE-13 cells did not displayed phosphorylated Akt, the other four cell lines displayed an hyperphosphorylated form, which is indicative of constitutive activation of PI3K signaling pathway (Fig. 1).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy.

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.

Show MeSH
Related in: MedlinePlus