Cytotoxic activity of the novel small molecule AKT inhibitor SC66 in hepatocellular carcinoma cells

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)
Antonella,Puleio,Roberto,D'Alessandro,Natale,Loria R.,McCubrey,James A.,Montalto,Giuseppe,Cervello,Me Cusimano (Creator)
East Carolina University (ECU )
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Abstract: Hepatocellular carcinoma (HCC) is characterized by limited response to currentdrug therapies. Here, we report that SC66, a novel AKT inhibitor, reduced cell viabilityin a dose- and time-dependent manner, inhibited colony formation and inducedapoptosis in HCC cells. SC66 treatment led to a reduction in total and phosphoAKT levels. This was associated with alterations in cytoskeleton organization, areduction in expression levels of E-cadherin, β-catenin and phospho-FAK, togetherwith up-regulation of Snail protein levels. All these alterations were coupled withanoikis cell death induction. In addition, SC66 induced the production of reactiveoxygen species (ROS) and DNA damage. Pre-treatment with the ROS scavengerN-Acetyl-cysteine (NAC) prevented SC66-induced cell growth inhibition and anoikis.SC66 significantly potentiated the effects of both conventional chemotherapeutic andtargeted agents, doxorubicin and everolimus, respectively. In vivo, SC66 inhibitedtumor growth of Hep3B cells in xenograft models, with a similar mechanism observedin the in vitro model. Taken together, these data indicate that the AKT inhibitor SC66had antitumor effects on HCC cells. This was mediated by ROS production, inductionof anoikis-mediated cell death and inhibition of the AKT cell survival pathway. Ourresults provide a rational basis for the use of SC66 in HCC treatment.

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Language: English
Date: 2014
HCC, AKT, mTOR, SC66, anoikis

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