1. SI113, a specific inhibitor of the Sgk1 kinase activity that counteracts cancer cell proliferation.
- Author
-
D'Antona L, Amato R, Talarico C, Ortuso F, Menniti M, Dattilo V, Iuliano R, Gigliotti F, Artese A, Costa G, Schenone S, Musumeci F, Abbruzzese C, Botta L, Trapasso F, Alcaro S, Paggi MG, and Perrotti N
- Subjects
- Antineoplastic Agents, Phytogenic pharmacology, Antineoplastic Agents, Phytogenic therapeutic use, Apoptosis drug effects, Cell Line, Tumor, Colonic Neoplasms drug therapy, Colonic Neoplasms metabolism, Colonic Neoplasms pathology, G1 Phase Cell Cycle Checkpoints drug effects, Humans, Immediate-Early Proteins metabolism, Insulin pharmacology, MCF-7 Cells, Necrosis, Paclitaxel pharmacology, Paclitaxel therapeutic use, Phosphorylation drug effects, Protein Kinase Inhibitors chemistry, Protein Kinase Inhibitors therapeutic use, Protein Serine-Threonine Kinases metabolism, Protein Stability, Proto-Oncogene Proteins c-mdm2 metabolism, Pyrazoles chemistry, Pyrazoles therapeutic use, Pyrimidines chemistry, Pyrimidines therapeutic use, Tumor Suppressor Protein p53 metabolism, Cell Proliferation drug effects, Immediate-Early Proteins antagonists & inhibitors, Protein Kinase Inhibitors pharmacology, Protein Serine-Threonine Kinases antagonists & inhibitors, Pyrazoles pharmacology, Pyrimidines pharmacology
- Abstract
Background/aims: Published observations on serum and glucocorticoid regulated kinase 1 (Sgk1) knockout murine models and Sgk1-specific RNA silencing in the RKO human colon carcinoma cell line point to this kinase as a central player in colon carcinogenesis and in resistance to taxanes., Methods: By in vitro kinase activity inhibition assays, cell cycle and viability analysis in human cancer model systems, we describe the biologic effects of a recently identified kinase inhibitor, SI113, characterized by a substituted pyrazolo[3,4-d]pyrimidine scaffold, that shows specificity for Sgk1., Results: SI113 was able to inhibit in vitro cell growth in cancer cells derived from tumors with different origins. In RKO cells, this kinase inhibitor blocked insulin-dependent phosphorylation of the Sgk1 substrate Mdm2, the main regulator of p53 protein stability, and induced necrosis and apoptosis when used as a single agent. Finally, SI113 potentiated the effects of paclitaxel on cell viability., Conclusion: Since SI113 appears to be effective in inducing cell death in RKO cells, potentiating paclitaxel sensitivity, we believe that this new molecule could be efficiently employed, alone or in combination with paclitaxel, in colon cancer chemotherapy., (© 2015 S. Karger AG, Basel.)
- Published
- 2015
- Full Text
- View/download PDF