SI113, a SGK1 inhibitor, potentiates the effects of radiotherapy, modulates the response to oxidative stress and induces cytotoxic autophagy in human glioblastoma multiforme cells
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Cristina Talarico1, Vincenzo Dattilo1, Lucia D’Antona1, Agnese Barone2, Nicola Amodio2, Stefania Belviso2, Francesca Musumeci3, Claudia Abbruzzese5, Cataldo Bianco2, Francesco Trapasso2, Silvia Schenone3, Stefano Alcaro1, Francesco Ortuso1, Tullio Florio4, Marco G. Paggi5, Nicola Perrotti1 and Rosario Amato1
1 Department of “Scienze della Salute”, University ”Magna Graecia” of Catanzaro, Catanzaro, Italy
2 Department of “Medicina Sperimentale e Clinica”, University ”Magna Graecia” of Catanzaro, Catanzaro, Italy
3 Department of Farmacia, University of Genova, Genova, Italy
4 Department of Medicina Interna e Specialità Mediche e Center of Excellence per la Ricerca Biomedica (CEBR), University of Genova, Genova, Italy
5 Experimental Oncology, Regina Elena National Cancer Institute, IRCCS, Rome, Italy
Rosario Amato, email:
Nicola Perrotti, email:
Keywords: SGK1, SI113, radiotherapy, glioblastoma, oxidative stress
Received: December 18, 2015 Accepted: February 08, 2016 Published: February 19, 2016
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.
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