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

Date
2013
Authors
Simioni, C.
Martelli, A. M.
Cani, A.
Cetin-Atalay, R.
McCubrey, J. A.
Capitani, S.
Neri, L. M.
Advisor
Supervisor
Co-Advisor
Co-Supervisor
Instructor
Source Title
Oncotarget
Print ISSN
1949-2553
Electronic ISSN
Publisher
Impact Group
Volume
4
Issue
9
Pages
1496 - 1506
Language
English
Type
Article
Journal Title
Journal ISSN
Volume Title
Series
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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Keywords
Akt-1, Apoptosis, Autophagy, Hepatocellular carcinoma, MK-2206, Targeted therapy
Citation
Published Version (Please cite this version)