title: Cytotoxic activity of the novel small molecule AKT inhibitor SC66 in hepatocellular carcinoma cells.
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.
authors.affiliation: Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council, Palermo, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Cusimano
authors.affiliation: Istituto Zooprofilattico Sperimentale della Sicilia "A. Mirri", Area Diagnostica Specialistica, Laboratorio di Istopatologia ed Immunoistochimica, Palermo, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Puleio
authors.affiliation: Dipartimento di Scienze per la Promozione della Salute e Materno Infantile "G. D'Alessandro", Università di Palermo, Palermo, Italy.
authors.forename: Natale
authors.initials: N
authors.lastname: D'Alessandro
authors.affiliation: Istituto Zooprofilattico Sperimentale della Sicilia "A. Mirri", Area Diagnostica Specialistica, Laboratorio di Istopatologia ed Immunoistochimica, Palermo, Italy.
authors.forename: Guido R
authors.initials: GR
authors.lastname: Loria
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA.
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
authors.affiliation: Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council, Palermo, Italy.|Biomedical Department of Internal Medicine and Specialties, University of Palermo, Palermo, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Montalto
authors.affiliation: Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council, Palermo, Italy.
authors.forename: Melchiorre
authors.initials: M
authors.lastname: Cervello
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003512:Cyclohexanones / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D003512:Cyclohexanones; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C000598518:SC-66 compound; D051057:Proto-Oncogene Proteins c-akt