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Published on: September 30, 2016
Inhibition of colonic tumor growth by the selective SGK inhibitor EMD638683
Syeda T Towhid1, Gui-Lai Liu, Teresa F Ackermann
1Department of Physiology, University of Tübingen, Tübingen, Germany.
Background:
The serum and glucocorticoid inducible kinase SGK1, which was originally cloned from mammary tumor cells, is highly expressed in some but not all tumors. SGK1 confers survival to several tumor cells. Along those lines, the number of colonic tumors following chemical carcinogenesis was decreased in SGK1 knockout mice. Recently, a highly selective SGK inhibitor (EMD638683) has been developed. The present study explored whether EMD638683 affects survival of colon carcinoma cells in vitro and impacts on development of colonic tumors in vivo.
Methods:
Colon carcinoma (Caco-2) cells were exposed to EMD638683 with or without exposure to radiation (3 Gray) and cell volume was estimated from forward scatter, phosphatidylserine exposure from annexin V binding, mitochondrial potential from JC-9 fluorescence, caspase 3 activity from CaspGlow Fluorescein staining, DNA degradation from propidium iodide staining as well as late apoptosis from annexin-V FITC and propidium iodide double staining. In vivo tumor growth was determined in wild type mice subjected to chemical carcinogenesis (intraperitoneal injection of 20 mg/kg 1,2-dimethylhydrazine followed by three cycles of 30 g/L synthetic dextran sulfate sodium in drinking water for 7 days).
Results:
EMD638683 treatment significantly augmented the radiation-induced decrease of forward scatter, increase of phosphatidylserine exposure, decrease of mitochondrial potential, increase of caspase 3 activity, increase of DNA fragmentation and increase of late apoptosis. The in vivo development of tumors following chemical carcinogenesis was significantly blunted by treatment with EMD638683.
Conclusions:
EMD638683 promotes radiation-induced suicidal death of colon tumor cells in vitro and decreases the number of colonic tumors following chemical carcinogenesis in vivo.
Insights
The SGK1 inhibitor EMD638683 enhances radiation therapy's cancer cell death effects. This compound also reduced colon tumor development in mice, showing potential for cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Serum and glucocorticoid inducible kinase (SGK1) is highly expressed in some tumors and promotes cancer cell survival.
- Previous studies showed reduced colonic tumors in SGK1 knockout mice.
- A selective SGK inhibitor, EMD638683, has been developed.
Purpose of the Study:
- To investigate the effect of EMD638683 on colon carcinoma cell survival in vitro.
- To determine the impact of EMD638683 on colon tumor development in vivo.
Main Methods:
- Colon carcinoma cells (Caco-2) were treated with EMD638683 and/or radiation (3 Gray).
- Cell death markers including phosphatidylserine exposure, mitochondrial potential, caspase 3 activity, and DNA fragmentation were assessed.
- In vivo tumor growth was evaluated in mice undergoing chemical carcinogenesis and treated with EMD638683.
Main Results:
- EMD638683 significantly enhanced radiation-induced apoptosis, indicated by increased phosphatidylserine exposure, caspase 3 activity, and DNA fragmentation.
- EMD638683 treatment also led to decreased cell volume and mitochondrial potential.
- In vivo studies demonstrated that EMD638683 significantly blunted the development of colonic tumors.
Conclusions:
- EMD638683 promotes radiation-induced apoptosis in colon tumor cells.
- EMD638683 effectively reduces colon tumor formation in a chemical carcinogenesis model.
- The SGK1 inhibitor EMD638683 shows promise as an adjuvant therapy for colon cancer.
