Preclinical model in HCC: the SGK1 kinase inhibitor SI113 blocks tumor progression in vitro and in vivo and synergizes with radiotherapy

摘要: // Cristina Talarico 1, * , Lucia D’Antona Domenica Scumaci 2 Agnese Barone Francesco Gigliotti 1 Claudia Vincenza Fiumara Vincenzo Dattilo Enzo Gallo 3 Paolo Visca Ortuso Abbruzzese 4 Lorenzo Botta 5 Silvia Schenone 6 Giovanni Cuda Stefano Alcaro Cataldo Bianco Patrizia Lavia 7 Marco G. Paggi Nicola Perrotti Rosario Amato Department of “Scienze della Salute”, University “Magna Graecia” Catanzaro, Viale Europa, Italy “Medicina Sperimentale e Clinica”, Section Pathology, Regina Elena National Cancer Institute, IRCCS, Rome, Experimental Oncology, Biotecnologie, Chimica Farmacia, Siena, Genova, Institute Molecular Biology and Pathology (IBPM), Research Council (CNR), c/o “La Sapienza”, These authors have contributed equally to this work Correspondence to: Amato, e-mail: rosario.amato@unicz.it Perrotti, perrotti@unicz.it Keywords: SGK1, HCC, kinase inhibitor, radiotherapy, apoptosis Received: June 04, 2015      Accepted: September 28, Published: October 08, 2015 ABSTRACT The SGK1 is pivotal in signal transduction pathways operating cell transformation tumor progression. Here, we characterize depth a novel potent selective pyrazolo[3,4-d]pyrimidine-based inhibitor. This compound, named SI113, active vitro the sub-micromolar range, inhibits SGK1-dependent signaling lines dose- time-dependent manner. We recently showed that SI113 slows down growth induces death colon carcinoma cells, when used monotherapy or combination with paclitaxel. now demonstrate for first time tumour hepatocarcinoma models vivo . SI113-dependent inhibition time-dependent. In determined dramatic increase apotosis/necrosis, inhibited proliferation altered cycle profile treated cells. Proteome-wide biochemical studies confirmed down-regulates abundance proteins downstream established roles neoplastic transformation, e.g. MDM2, NDRG1 RAN network members. Consistent knock-down over-expressing cellular potentiated synergized radiotherapy killing. No short-term toxicity was observed animals during administration. data show direct can be effective hepatic cancer therapy, either alone radiotherapy.