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SI113, a specific inhibitor of the Sgk1 kinase activity that counteracts cancer cell proliferation.
- Source :
-
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology [Cell Physiol Biochem] 2015; Vol. 35 (5), pp. 2006-18. Date of Electronic Publication: 2015 Mar 27. - Publication Year :
- 2015
-
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.<br />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.<br />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.<br />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.<br /> (© 2015 S. Karger AG, Basel.)
- 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
Subjects
Details
- Language :
- English
- ISSN :
- 1421-9778
- Volume :
- 35
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 25871776
- Full Text :
- https://doi.org/10.1159/000374008