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, Rosario Amato

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)37511-37525
Number of pages15
JournalOncotarget
Volume6
Issue number35
DOIs
Publication statusPublished - 2015

Keywords

  • Apoptosis
  • HCC
  • Kinase inhibitor
  • Radiotherapy
  • SGK1

ASJC Scopus subject areas

  • Oncology

Fingerprint Dive into the research topics of 'Preclinical model in HCC: The SGK1 kinase inhibitor SI113 blocks tumor progression in vitro and in vivo and synergizes with radiotherapy'. Together they form a unique fingerprint.

Cite this