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

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 apoptosis/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.

• Authors: 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
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 35 Pg. 37511-25 (Nov 10 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26462020 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Immediate-Early Proteins
• Proteome
• Pyrazoles
• Pyrimidines
• SI113 compound
• Protein Serine-Threonine Kinases
• serum-glucocorticoid regulated kinase

Topics

• Animals
• Apoptosis (drug effects, radiation effects)
• Blotting, Western
• Carcinoma, Hepatocellular (drug therapy, enzymology, pathology, radiotherapy)
• Cell Cycle (drug effects, radiation effects)
• Cell Proliferation (drug effects, radiation effects)
• Female
• Gamma Rays
• Gene Expression Regulation, Neoplastic (drug effects, radiation effects)
• Humans
• Immediate-Early Proteins (antagonists & inhibitors, metabolism)
• Immunoenzyme Techniques
• In Vitro Techniques
• Liver Neoplasms (drug therapy, enzymology, pathology, radiotherapy)
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proteome (analysis)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• Radiation Tolerance (drug effects)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays