6533b83afe1ef96bd12a7f2c

RESEARCH PRODUCT

Antitumor activity of the novel small molecule Akt inhibitor SC66 in hepatocellular carcinoma cells.

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Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide characterized by poor and often limited or no response to current drug therapies. The PI3K/Akt/mTOR pathway is a key regulator of cell proliferation and survival. Alterations in this pathway have been reported in many types of human cancer, including HCC. It has become evident that Akt inhibitors have great potential in cancer treatment. SC66 is a new allosteric Akt inhibitor that facilitates ubiquitination of Akt, favoring its degradation via the proteasome, thus inhibiting Akt signaling. In the present study, we investigated the anticancer activity of SC66 in HCC cell lines (HepG2, Huh7, Hep3B, PLC/PRF/5 and HA22T/VGH). Treatment with SC66 reduced cell viability in a dose- and time-dependent manner and inhibited colony formation. At the same time, SC66 induced anoikis, as demonstrated by alterations of cytoskeleton organization and reduction of E-cadherin, -catenin and Snail expression. SC66 induced apoptosis was revealed by flow cytometry analysis, cleavage of PARP, and decreased expression of the anti-apoptotic proteins survivin and Bcl2. In addition, after treatment with SC66 a dose-dependent ROS production was demonstrated by H2DCFDA-based fluorescence staining. Co-treatment with the ROS scavenger NAC prevented the SC66-induced cell growth inhibition and anoikis. In conclusion, our data indicated that the Akt inhibitor SC66 had antitumor effects on HCC cells. This was mediated by ROS production and induction of anoikis-mediated cell death. All together, our results provide a rational basis for the clinical use of SC66 in the treatment of liver cancer.