Limits...
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.

Show MeSH

Related in: MedlinePlus

Dynamic monitoring of cell growth in HCC cells with the xCELLigence System(A) Concentration- and time- dependent cytotoxic effects of MK-2206 in PLC and Mahlavu cells after MK-2206 treatment, analyzed using the xCELLigence System. (B) IC50 values of MK-2206 at 24h of treatment in PLC, SNU387, Mahlavu and SNU475 cell lines. (C) CI values in PLC, SNU387, Mahlavu and SNU475 cell lines after 24h of treatment with MK-2206. One representative of three different experiments is shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3824526&req=5

Figure 2: Dynamic monitoring of cell growth in HCC cells with the xCELLigence System(A) Concentration- and time- dependent cytotoxic effects of MK-2206 in PLC and Mahlavu cells after MK-2206 treatment, analyzed using the xCELLigence System. (B) IC50 values of MK-2206 at 24h of treatment in PLC, SNU387, Mahlavu and SNU475 cell lines. (C) CI values in PLC, SNU387, Mahlavu and SNU475 cell lines after 24h of treatment with MK-2206. One representative of three different experiments is shown.

Mentions: To further analyze the activity of MK-2206 in HCC cells, we used a novel cell surveillance system to monitor the dynamic changes in cell growth based on the electrical impedance measurement technique (xCELLigence System). The xCELLigence System allowed us to study the effects of MK-2206 on HCC cells by a label-free and a real-time native approach. After the setting of the proliferation standards of PLC, SNU387, Mahlavu and SNU475 cells, we studied the cytotoxicity of the inhibitor at increasing concentrations. The plots demonstrated the concentration- and time-dependent cytotoxic effect of MK-2206 on PLC and Mahlavu cells (Fig. 2A) and the IC50 values of the drug at 24h of treatment was obtained by this technique: 18 μM for PLC, 16 μM for SNU387, 6.4 μM for Mahlavu and 6.7 μM for SNU475 cells, respectively (Fig. 2B).


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)

Dynamic monitoring of cell growth in HCC cells with the xCELLigence System(A) Concentration- and time- dependent cytotoxic effects of MK-2206 in PLC and Mahlavu cells after MK-2206 treatment, analyzed using the xCELLigence System. (B) IC50 values of MK-2206 at 24h of treatment in PLC, SNU387, Mahlavu and SNU475 cell lines. (C) CI values in PLC, SNU387, Mahlavu and SNU475 cell lines after 24h of treatment with MK-2206. One representative of three different experiments is shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Dynamic monitoring of cell growth in HCC cells with the xCELLigence System(A) Concentration- and time- dependent cytotoxic effects of MK-2206 in PLC and Mahlavu cells after MK-2206 treatment, analyzed using the xCELLigence System. (B) IC50 values of MK-2206 at 24h of treatment in PLC, SNU387, Mahlavu and SNU475 cell lines. (C) CI values in PLC, SNU387, Mahlavu and SNU475 cell lines after 24h of treatment with MK-2206. One representative of three different experiments is shown.
Mentions: To further analyze the activity of MK-2206 in HCC cells, we used a novel cell surveillance system to monitor the dynamic changes in cell growth based on the electrical impedance measurement technique (xCELLigence System). The xCELLigence System allowed us to study the effects of MK-2206 on HCC cells by a label-free and a real-time native approach. After the setting of the proliferation standards of PLC, SNU387, Mahlavu and SNU475 cells, we studied the cytotoxicity of the inhibitor at increasing concentrations. The plots demonstrated the concentration- and time-dependent cytotoxic effect of MK-2206 on PLC and Mahlavu cells (Fig. 2A) and the IC50 values of the drug at 24h of treatment was obtained by this technique: 18 μM for PLC, 16 μM for SNU387, 6.4 μM for Mahlavu and 6.7 μM for SNU475 cells, respectively (Fig. 2B).

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