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

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dc.citation.epage1506en_US
dc.citation.issueNumber9en_US
dc.citation.spage1496en_US
dc.citation.volumeNumber4en_US
dc.contributor.authorSimioni, C.en_US
dc.contributor.authorMartelli, A. M.en_US
dc.contributor.authorCani, A.en_US
dc.contributor.authorCetin-Atalay, R.en_US
dc.contributor.authorMcCubrey, J. A.en_US
dc.contributor.authorCapitani, S.en_US
dc.contributor.authorNeri, L. M.en_US
dc.date.accessioned2016-02-08T09:34:55Z
dc.date.available2016-02-08T09:34:55Z
dc.date.issued2013en_US
dc.departmentDepartment of Molecular Biology and Geneticsen_US
dc.description.abstractHepatocellular 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.en_US
dc.identifier.issn1949-2553
dc.identifier.urihttp://hdl.handle.net/11693/20771
dc.language.isoEnglishen_US
dc.publisherImpact Groupen_US
dc.source.titleOncotargeten_US
dc.subjectAkt-1en_US
dc.subjectApoptosisen_US
dc.subjectAutophagyen_US
dc.subjectHepatocellular carcinomaen_US
dc.subjectMK-2206en_US
dc.subjectTargeted therapyen_US
dc.titleThe AKT inhibitor MK-2206 is cytotoxic in hepatocarcinoma cells displaying hyperphosphorylated AKT-1 and synergizes with conventional chemotherapyen_US
dc.typeArticleen_US
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