The AKT Inhibitor MK-2206 is Cytotoxic in Hepatocarcinoma Cells Displaying Hyperphosphorylated AKT-1 and Synergizes with Conventional Chemotherapy
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Carolina Simioni1, Alberto M. Martelli2,3,4, Alice Cani1, Rengul Cetin-Atalay5, James A. McCubrey6, Silvano Capitani1, Luca M. Neri1
1 Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy,
2 Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy;
3 Institute of Molecular Genetics, National Research Council, Pavia, Italy;
4 Muscoloskeletal Cell Biology Laboratory, IOR, Bologna, Italy
5 Department of Molecular Biology and Genetics, Bilkent University, Ankara, Turkey
6 Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
Luca M. Neri, email:
Keywords: Hepatocellular carcinoma, MK-2206, Akt-1, targeted therapy, apoptosis, autophagy
Received: August 1, 2013 Accepted: August 22, 2013 Published: August 24, 2013
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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