Oncotarget

Research Papers:

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

Cristina Talarico _, Lucia D'Antona, Domenica Scumaci, Agnese Barone, Francesco Gigliotti, Claudia Vincenza Fiumara, Vincenzo Dattilo, Enzo Gallo, Paolo Visca, Francesco Ortuso, Claudia Abbruzzese, Lorenzo Botta, Silvia Schenone, Giovanni Cuda, Stefano Alcaro, Cataldo Bianco, Patrizia Lavia, Marco G. Paggi, Nicola Perrotti and Rosario Amato

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Oncotarget. 2015; 6:37511-37525. https://doi.org/10.18632/oncotarget.5527

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Abstract

Cristina Talarico1,*, Lucia D’Antona1,*, Domenica Scumaci2, Agnese Barone2, Francesco Gigliotti1, Claudia Vincenza Fiumara2, Vincenzo Dattilo1, Enzo Gallo3, Paolo Visca3, Francesco Ortuso1, Claudia Abbruzzese4, Lorenzo Botta5, Silvia Schenone6, Giovanni Cuda2, Stefano Alcaro1, Cataldo Bianco2, Patrizia Lavia7, Marco G. Paggi4, Nicola Perrotti1,*, Rosario Amato1,*

1Department of “Scienze della Salute”, University “Magna Graecia” of Catanzaro, Viale Europa, Catanzaro, Italy

2Department of “Medicina Sperimentale e Clinica”, University “Magna Graecia” of Catanzaro, Viale Europa, Catanzaro, Italy

3Section of Pathology, Regina Elena National Cancer Institute, IRCCS, Rome, Italy

4Experimental Oncology, Regina Elena National Cancer Institute, IRCCS, Rome, Italy

5Department of Biotecnologie, Chimica e Farmacia, University of Siena, Siena, Italy

6Department of Farmacia, University of Genova, Genova, Italy

7Institute of Molecular Biology and Pathology (IBPM), National Research Council of Italy (CNR), c/o University “La Sapienza”, Rome, Italy

*These authors have contributed equally to this work

Correspondence to:

Rosario Amato, e-mail: rosario.amato@unicz.it

Nicola Perrotti, e-mail: perrotti@unicz.it

Keywords: SGK1, HCC, kinase inhibitor, radiotherapy, apoptosis

Received: June 04, 2015     Accepted: September 28, 2015     Published: October 08, 2015

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 apotosis/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.


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