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The AKT inhibitor MK-2206 is cytotoxic in hepatocarcinoma cells displaying hyperphosphorylated AKT-1 and synergizes with conventional chemotherapy.

Simioni C, Martelli AM, Cani A, Cetin-Atalay R, McCubrey JA, Capitani S, Neri LM - Oncotarget (2013)

Bottom Line: The inhibitor decreased cell viability and induced cell cycle arrest in the G0/G1 phase of the cell cycle, with a higher efficacy in cells with hyperphosphorylated Akt-1.MK-2206 synergized with doxorubicin, a chemotherapeutic drug widely used for HCC treatment.Our findings suggest that the use of Akt inhibitors, either alone or in combination with doxorubicin, may be considered as an attractive therapeutic regimen for the treatment of HCC.

View Article: PubMed Central - PubMed

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

ABSTRACT
Hepatocellular carcinoma (HCC) is one of the most common potentially lethal human malignancies worldwide. Advanced or recurrent HCC is frequently resistant to conventional chemotherapeutic agents and radiation. Therefore, targeted agents with tolerable toxicity are mandatory to improve HCC therapy and prognosis. In this neoplasia, the PI3K/Akt signaling network has been frequently shown to be aberrantly up-regulated. To evaluate whether Akt could represent a target for treatment of HCC, we studied the effects of the allosteric Akt inhibitor, MK-2206, on a panel of HCC cell lines characterized by different levels of Akt-1 activation. The inhibitor decreased cell viability and induced cell cycle arrest in the G0/G1 phase of the cell cycle, with a higher efficacy in cells with hyperphosphorylated Akt-1. Moreover, MK-2206 induced apoptosis, as documented by Annexin V labeling, and also caused autophagy, as evidenced by increased levels of the autophagy marker LC3A/B. Autophagy was shown to be a protective mechanism against MK-2206 cytotoxicity. MK-2206 down-regulated, in a concentration-dependent manner, the phosphorylation levels of Akt-1 and its downstream targets, GSK3 α/β and FOXO3A. MK-2206 synergized with doxorubicin, a chemotherapeutic drug widely used for HCC treatment. Our findings suggest that the use of Akt inhibitors, either alone or in combination with doxorubicin, may be considered as an attractive therapeutic regimen for the treatment of HCC.

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MK-2006 displays synergistic cytotoxic effects with doxorubicin in Mahlavu cells(A, B) xCELLigence System analysis showing the synergistic effects of a combined treatment consisting of doxorubicin (DOXO) at a single concentration (0.1 μM) and MK-2206 at two different concentrations (0.5 and 1.5 μM). The CI was monitored after 48h of treatment. In (A) one representative of three different experiments is shown, while in (B) the results are the mean ± s.d. of three different experiments. Asterisks indicate significant differences (p<0.05) in comparison with single treatments.
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Figure 6: MK-2006 displays synergistic cytotoxic effects with doxorubicin in Mahlavu cells(A, B) xCELLigence System analysis showing the synergistic effects of a combined treatment consisting of doxorubicin (DOXO) at a single concentration (0.1 μM) and MK-2206 at two different concentrations (0.5 and 1.5 μM). The CI was monitored after 48h of treatment. In (A) one representative of three different experiments is shown, while in (B) the results are the mean ± s.d. of three different experiments. Asterisks indicate significant differences (p<0.05) in comparison with single treatments.

Mentions: We then examined whether MK-2206 could synergize with the anthracycline antibiotic doxorubicin, since this drug is frequently included in different protocols to treat HCC. Mahlavu cells were treated with doxorubicin at a single concentration (0.1 μM) and with MK-2206 at two different concentrations (0.5 and 1.5 μM) and the synergistic effects of the combination were monitored after 48h or 72h of treatment using the xCELLigence System and by analyzing the Cell Index (Fig.6A and B). We could observe a synergistic effect of the combined drug treatment in suppressing cell proliferation and viability, more evident at the higher (1.5 μM) concentration of MK-2206 (Fig.6A and B).


The AKT inhibitor MK-2206 is cytotoxic in hepatocarcinoma cells displaying hyperphosphorylated AKT-1 and synergizes with conventional chemotherapy.

Simioni C, Martelli AM, Cani A, Cetin-Atalay R, McCubrey JA, Capitani S, Neri LM - Oncotarget (2013)

MK-2006 displays synergistic cytotoxic effects with doxorubicin in Mahlavu cells(A, B) xCELLigence System analysis showing the synergistic effects of a combined treatment consisting of doxorubicin (DOXO) at a single concentration (0.1 μM) and MK-2206 at two different concentrations (0.5 and 1.5 μM). The CI was monitored after 48h of treatment. In (A) one representative of three different experiments is shown, while in (B) the results are the mean ± s.d. of three different experiments. Asterisks indicate significant differences (p<0.05) in comparison with single treatments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824526&req=5

Figure 6: MK-2006 displays synergistic cytotoxic effects with doxorubicin in Mahlavu cells(A, B) xCELLigence System analysis showing the synergistic effects of a combined treatment consisting of doxorubicin (DOXO) at a single concentration (0.1 μM) and MK-2206 at two different concentrations (0.5 and 1.5 μM). The CI was monitored after 48h of treatment. In (A) one representative of three different experiments is shown, while in (B) the results are the mean ± s.d. of three different experiments. Asterisks indicate significant differences (p<0.05) in comparison with single treatments.
Mentions: We then examined whether MK-2206 could synergize with the anthracycline antibiotic doxorubicin, since this drug is frequently included in different protocols to treat HCC. Mahlavu cells were treated with doxorubicin at a single concentration (0.1 μM) and with MK-2206 at two different concentrations (0.5 and 1.5 μM) and the synergistic effects of the combination were monitored after 48h or 72h of treatment using the xCELLigence System and by analyzing the Cell Index (Fig.6A and B). We could observe a synergistic effect of the combined drug treatment in suppressing cell proliferation and viability, more evident at the higher (1.5 μM) concentration of MK-2206 (Fig.6A and B).

Bottom Line: The inhibitor decreased cell viability and induced cell cycle arrest in the G0/G1 phase of the cell cycle, with a higher efficacy in cells with hyperphosphorylated Akt-1.MK-2206 synergized with doxorubicin, a chemotherapeutic drug widely used for HCC treatment.Our findings suggest that the use of Akt inhibitors, either alone or in combination with doxorubicin, may be considered as an attractive therapeutic regimen for the treatment of HCC.

View Article: PubMed Central - PubMed

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

ABSTRACT
Hepatocellular carcinoma (HCC) is one of the most common potentially lethal human malignancies worldwide. Advanced or recurrent HCC is frequently resistant to conventional chemotherapeutic agents and radiation. Therefore, targeted agents with tolerable toxicity are mandatory to improve HCC therapy and prognosis. In this neoplasia, the PI3K/Akt signaling network has been frequently shown to be aberrantly up-regulated. To evaluate whether Akt could represent a target for treatment of HCC, we studied the effects of the allosteric Akt inhibitor, MK-2206, on a panel of HCC cell lines characterized by different levels of Akt-1 activation. The inhibitor decreased cell viability and induced cell cycle arrest in the G0/G1 phase of the cell cycle, with a higher efficacy in cells with hyperphosphorylated Akt-1. Moreover, MK-2206 induced apoptosis, as documented by Annexin V labeling, and also caused autophagy, as evidenced by increased levels of the autophagy marker LC3A/B. Autophagy was shown to be a protective mechanism against MK-2206 cytotoxicity. MK-2206 down-regulated, in a concentration-dependent manner, the phosphorylation levels of Akt-1 and its downstream targets, GSK3 α/β and FOXO3A. MK-2206 synergized with doxorubicin, a chemotherapeutic drug widely used for HCC treatment. Our findings suggest that the use of Akt inhibitors, either alone or in combination with doxorubicin, may be considered as an attractive therapeutic regimen for the treatment of HCC.

Show MeSH
Related in: MedlinePlus