title: SI113, a SGK1 inhibitor, potentiates the effects of radiotherapy, modulates the response to oxidative stress and induces cytotoxic autophagy in human glioblastoma multiforme cells.
abstract: Glioblastoma multiforme (GBM) is the most aggressive CNS tumor and is characterized by a very high frequency of clinical relapse after therapy and thus by a dismal prognosis, which strongly compromises patients survival. We have recently identified the small molecule SI113, as a potent and selective inhibitor of SGK1, a serine/threonine protein kinase, that modulates several oncogenic signaling cascades. The SI113-dependent SGK1 inhibition induces cell death, blocks proliferation and perturbs cell cycle progression by modulating SGK1-related substrates. SI113 is also able to strongly and consistently block, in vitro and in vivo, growth and survival of human hepatocellular-carcinomas, either used as a single agent or in combination with ionizing radiations. In the present paper we aim to study the effect of SI113 on human GBM cell lines with variable p53 expression. Cell viability, cell death, caspase activation and cell cycle progression were then analyzed by FACS and WB-based assays, after exposure to SI113, with or without oxidative stress and ionizing radiations. Moreover, autophagy and related reticulum stress response were evaluated. We show here, that i) SGK1 is over-expressed in highly malignant gliomas and that the treatment with SI113 leads to ii) significant increase in caspase-mediated apoptotic cell death in GBM cell lines but not in normal fibroblasts; iii)enhancement of the effects of ionizing radiations; iv) modulation of the response to oxidative reticulum stress; v) induction of cytotoxic autophagy. Evidence reported here underlines the therapeutic potential of SI113 in GBM, suggesting a new therapeutic strategy either alone or in combination with radiotherapy.
authors.affiliation: Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Talarico
authors.affiliation: Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Dattilo
authors.affiliation: Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, 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, Catanzaro, Italy.
authors.forename: Agnese
authors.initials: A
authors.lastname: Barone
authors.affiliation: Department of "Medicina Sperimentale e Clinica", University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Amodio
authors.affiliation: Department of "Medicina Sperimentale e Clinica", University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Belviso
authors.affiliation: Department of Farmacia, University of Genova, Genova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Musumeci
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 "Medicina Sperimentale e Clinica", University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
authors.forename: Cataldo
authors.initials: C
authors.lastname: Bianco
authors.affiliation: Department of "Medicina Sperimentale e Clinica", University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Trapasso
authors.affiliation: Department of Farmacia, University of Genova, Genova, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schenone
authors.affiliation: Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Alcaro
authors.affiliation: Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Ortuso
authors.affiliation: Department of Medicina Interna e Specialità Mediche e Center of Excellence per la Ricerca Biomedica (CEBR), University of Genova, Genova, Italy.
authors.forename: Tullio
authors.initials: T
authors.lastname: Florio
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, Catanzaro, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Perrotti
authors.affiliation: Department of "Scienze della Salute", University "Magna Graecia" of Catanzaro, Catanzaro, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Amato
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D059248:Chemoradiotherapy / Q000379:methods; D005909:Glioblastoma / Q000188:drug therapy* / Q000532:radiotherapy; D006801:Humans; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors; D018384:Oxidative Stress / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D000970:Antineoplastic Agents; D017874:Immediate-Early Proteins; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011743:Pyrimidines; D011838:Radiation-Sensitizing Agents; D000099184:Serum-Glucocorticoid Regulated Kinases; C000603764:SI113 compound
keywords: SGK1; SI113; glioblastoma; oxidative stress; radiotherapy