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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

Triple Akt inhibition induces enhanced autophagyA The effect of the three drugs administered alone or in combination on autophagy, after 24 h of treatment, in MOLT-4, JURKAT and CEM-S cell lines, documented by the lipidation of the autophagy marker LC3A/B. The increase in the triple treatment is well evident. Antibody to β-actin served as a loading control. B MTT assays documenting the effects of Bafilomycin A1 and Chloroquine on viability of MOLT-4 and CEM-S cells treated for 24 h with Perifosine, GSK690693 and MK-2206 administered in combination. Results are mean of three different experiments ± SD. Asterisks indicate significant differences (*p < 0.05). One representative experiment of three is shown as well as cell lines are representative also of the others not shown.
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Figure 5: Triple Akt inhibition induces enhanced autophagyA The effect of the three drugs administered alone or in combination on autophagy, after 24 h of treatment, in MOLT-4, JURKAT and CEM-S cell lines, documented by the lipidation of the autophagy marker LC3A/B. The increase in the triple treatment is well evident. Antibody to β-actin served as a loading control. B MTT assays documenting the effects of Bafilomycin A1 and Chloroquine on viability of MOLT-4 and CEM-S cells treated for 24 h with Perifosine, GSK690693 and MK-2206 administered in combination. Results are mean of three different experiments ± SD. Asterisks indicate significant differences (*p < 0.05). One representative experiment of three is shown as well as cell lines are representative also of the others not shown.

Mentions: Therefore, we investigated whether the triple treatment enhanced autophagy in our T-ALL cell panel. The exposure of cells to 24 h of the combined treatment increased the amount of lipidated (14-kDa form) LC3A/B isoform, a well-established autophagy marker, detected by western blot in MOLT-4, JURKAT and CEM-S cells (Fig. 5A).


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)

Triple Akt inhibition induces enhanced autophagyA The effect of the three drugs administered alone or in combination on autophagy, after 24 h of treatment, in MOLT-4, JURKAT and CEM-S cell lines, documented by the lipidation of the autophagy marker LC3A/B. The increase in the triple treatment is well evident. Antibody to β-actin served as a loading control. B MTT assays documenting the effects of Bafilomycin A1 and Chloroquine on viability of MOLT-4 and CEM-S cells treated for 24 h with Perifosine, GSK690693 and MK-2206 administered in combination. Results are mean of three different experiments ± SD. Asterisks indicate significant differences (*p < 0.05). One representative experiment of three is shown as well as cell lines are representative also of the others not shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Triple Akt inhibition induces enhanced autophagyA The effect of the three drugs administered alone or in combination on autophagy, after 24 h of treatment, in MOLT-4, JURKAT and CEM-S cell lines, documented by the lipidation of the autophagy marker LC3A/B. The increase in the triple treatment is well evident. Antibody to β-actin served as a loading control. B MTT assays documenting the effects of Bafilomycin A1 and Chloroquine on viability of MOLT-4 and CEM-S cells treated for 24 h with Perifosine, GSK690693 and MK-2206 administered in combination. Results are mean of three different experiments ± SD. Asterisks indicate significant differences (*p < 0.05). One representative experiment of three is shown as well as cell lines are representative also of the others not shown.
Mentions: Therefore, we investigated whether the triple treatment enhanced autophagy in our T-ALL cell panel. The exposure of cells to 24 h of the combined treatment increased the amount of lipidated (14-kDa form) LC3A/B isoform, a well-established autophagy marker, detected by western blot in MOLT-4, JURKAT and CEM-S cells (Fig. 5A).

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