title: Preclinical model in HCC: the SGK1 kinase inhibitor SI113 blocks tumor progression in vitro and in vivo and synergizes with radiotherapy.
abstract: The SGK1 kinase is pivotal in signal transduction pathways operating in cell transformation and tumor progression. Here, we characterize in depth a novel potent and selective pyrazolo[3,4-d]pyrimidine-based SGK1 inhibitor. This compound, named SI113, active in vitro in the sub-micromolar range, inhibits SGK1-dependent signaling in cell lines in a dose- and time-dependent manner. We recently showed that SI113 slows down tumor growth and induces cell death in colon carcinoma cells, when used in monotherapy or in combination with paclitaxel. We now demonstrate for the first time that SI113 inhibits tumour growth in hepatocarcinoma models in vitro and in vivo. SI113-dependent tumor inhibition is dose- and time-dependent. In vitro and in vivo SI113-dependent SGK1 inhibition determined a dramatic increase in apoptosis/necrosis, inhibited cell proliferation and altered the cell cycle profile of treated cells. Proteome-wide biochemical studies confirmed that SI113 down-regulates the abundance of proteins downstream of SGK1 with established roles in neoplastic transformation, e.g. MDM2, NDRG1 and RAN network members. Consistent with knock-down and over-expressing cellular models for SGK1, SI113 potentiated and synergized with radiotherapy in tumor killing. No short-term toxicity was observed in treated animals during in vivo SI113 administration. These data show that direct SGK1 inhibition can be effective in hepatic cancer therapy, either alone or in combination with radiotherapy.
authors.affiliation: Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, Viale Europa, Catanzaro, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Talarico
authors.affiliation: Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, Viale Europa, Catanzaro, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: D'Antona
authors.affiliation: Department of "Medicina Sperimentale e Clinica", University "Magna Graecia" of Catanzaro, Viale Europa, Catanzaro, Italy.
authors.forename: Domenica
authors.initials: D
authors.lastname: Scumaci
authors.affiliation: Department of "Medicina Sperimentale e Clinica", University "Magna Graecia" of Catanzaro, Viale Europa, Catanzaro, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Barone
authors.affiliation: Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, Viale Europa, Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Gigliotti
authors.affiliation: Department of "Medicina Sperimentale e Clinica", University "Magna Graecia" of Catanzaro, Viale Europa, Catanzaro, Italy.
authors.forename: Claudia Vincenza
authors.initials: CV
authors.lastname: Fiumara
authors.affiliation: Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, Viale Europa, Catanzaro, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Dattilo
authors.affiliation: Section of Pathology, Regina Elena National Cancer Institute, IRCCS, Rome, Italy.
authors.forename: Enzo
authors.initials: E
authors.lastname: Gallo
authors.affiliation: Section of Pathology, Regina Elena National Cancer Institute, IRCCS, Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Visca
authors.affiliation: Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, Viale Europa, Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.affiliation: Experimental Oncology, Regina Elena National Cancer Institute, IRCCS, Rome, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Abbruzzese
authors.affiliation: Department of Biotecnologie, Chimica e Farmacia, University of Siena, Siena, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Botta
authors.affiliation: Department of Farmacia, University of Genova, Genova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.affiliation: Department of "Medicina Sperimentale e Clinica", University "Magna Graecia" of Catanzaro, Viale Europa, Catanzaro, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cuda
authors.affiliation: Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, Viale Europa, Catanzaro, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.affiliation: Department of "Medicina Sperimentale e Clinica", University "Magna Graecia" of Catanzaro, Viale Europa, Catanzaro, Italy.
authors.forename: Cataldo
authors.initials: C
authors.lastname: Bianco
authors.affiliation: Institute of Molecular Biology and Pathology (IBPM), National Research Council of Italy (CNR), c/o University "La Sapienza", Rome, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Lavia
authors.affiliation: Experimental Oncology, Regina Elena National Cancer Institute, IRCCS, Rome, Italy.
authors.forename: Marco G
authors.initials: MG
authors.lastname: Paggi
authors.affiliation: Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, Viale Europa, Catanzaro, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Perrotti
authors.affiliation: Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, Viale Europa, Catanzaro, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Amato
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D005720:Gamma Rays; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000528:radiation effects; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology / Q000532:radiotherapy; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020543:Proteome / Q000032:analysis; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011836:Radiation Tolerance / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D020543:Proteome; D011720:Pyrazoles; D011743:Pyrimidines; D000099184:Serum-Glucocorticoid Regulated Kinases; C000603764:SI113 compound
keywords: HCC; SGK1; apoptosis; kinase inhibitor; radiotherapy