Abstract
Hepatocellular carcinoma (HCC) is characterized by limited response to current drug therapies. Here, we report that SC66, a novel AKT inhibitor, reduced cell viability in a dose- and time-dependent manner, inhibited colony formation and induced apoptosis in HCC cells. SC66 treatment led to a reduction in total and phospho-AKT levels. This was associated with alterations in cytoskeleton organization, a reduction in expression levels of E-cadherin, β-catenin and phospho-FAK, together with up-regulation of Snail protein levels. All these alterations were coupled with anoikis cell death induction. In addition, SC66 induced the production of reactive oxygen species (ROS) and DNA damage. Pre-treatment with the ROS scavenger N-Acetyl-cysteine (NAC) prevented SC66-induced cell growth inhibition and anoikis. SC66 significantly potentiated the effects of both conventional chemotherapeutic and targeted agents, doxorubicin and everolimus, respectively. In vivo, SC66 inhibited tumor growth of Hep3B cells in xenograft models, with a similar mechanism observed in the in vitro model. Taken together, these data indicate that the AKT inhibitor SC66 had antitumor effects on HCC cells. This was mediated by ROS production, induction of anoikis-mediated cell death and inhibition of the AKT cell survival pathway. Our results provide a rational basis for the use of SC66 in HCC treatment.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, characterized by an increasing incidence and a poor prognosis [1,2,3,4,5]
To investigate the effects of SC66 on HCC cell viability, HepG2, Huh7, Hep3B, PLC/PRF/5 and HA22T/VGH cell lines were incubated with increasing concentrations of SC66 and cell viability was analyzed after 24, 48 and 72 hours
Considering that the PI3K/ AKT/mammalian target of rapamycin (mTOR) pathway is a key pathway in HCC, as its activation induces cell proliferation and increases survival and therapy resistance, in the present study we investigated the potential antitumor activity of SC66, a novel allosteric inhibitor of AKT activity, on HCC cell lines
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, characterized by an increasing incidence and a poor prognosis [1,2,3,4,5]. The standard treatments are surgical resection and liver transplantation, but they are indicated only in specific conditions, both are rarely successful. Other treatments, such as chemoablation, focused ultrasound and radiation rarely lead to complete recovery [5]. Standard cancer drugs such as doxorubicin, cisplatin, and 5-fluorouracil have very limited efficacy [5]. Sorafenib improves prognosis in advanced HCC, response to sorafenib remains low and the median overall survival is only extended by a few months [6,7,8,9,10]
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