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.
| Original language | English |
|---|---|
| Pages (from-to) | 2006-2018 |
| Number of pages | 13 |
| Journal | Cellular Physiology and Biochemistry |
| Volume | 35 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 6 2015 |
Fingerprint
Keywords
- Apoptosis
- Cancer
- Kinase inhibitor
- Necrosis
- SGK1
- Small molecule
ASJC Scopus subject areas
- Physiology
- Medicine(all)
Cite this
SI113, a specific inhibitor of the Sgk1 kinase activity that counteracts cancer cell proliferation. / D'Antona, Lucia; Amato, Rosario; Talarico, Cristina; Ortuso, Francesco; Menniti, Miranda; Dattilo, Vincenzo; Iuliano, Rodolfo; Gigliotti, Francesco; Artese, Anna; Costa, Giosuè; Schenone, Silvia; Musumeci, Francesca; Abbruzzese, Claudia; Botta, Lorenzo; Trapasso, Francesco; Alcaro, Stefano; Paggi, Marco G.; Perrotti, Nicola.
In: Cellular Physiology and Biochemistry, Vol. 35, No. 5, 06.05.2015, p. 2006-2018.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - SI113, a specific inhibitor of the Sgk1 kinase activity that counteracts cancer cell proliferation
AU - D'Antona, Lucia
AU - Amato, Rosario
AU - Talarico, Cristina
AU - Ortuso, Francesco
AU - Menniti, Miranda
AU - Dattilo, Vincenzo
AU - Iuliano, Rodolfo
AU - Gigliotti, Francesco
AU - Artese, Anna
AU - Costa, Giosuè
AU - Schenone, Silvia
AU - Musumeci, Francesca
AU - Abbruzzese, Claudia
AU - Botta, Lorenzo
AU - Trapasso, Francesco
AU - Alcaro, Stefano
AU - Paggi, Marco G.
AU - Perrotti, Nicola
PY - 2015/5/6
Y1 - 2015/5/6
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Cancer
KW - Kinase inhibitor
KW - Necrosis
KW - SGK1
KW - Small molecule
UR - http://www.scopus.com/inward/record.url?scp=84927945625&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84927945625&partnerID=8YFLogxK
U2 - 10.1159/000374008
DO - 10.1159/000374008
M3 - Article
C2 - 25871776
AN - SCOPUS:84927945625
VL - 35
SP - 2006
EP - 2018
JO - Cellular Physiology and Biochemistry
JF - Cellular Physiology and Biochemistry
SN - 1015-8987
IS - 5
ER -