Inhibition of Colonic Tumor Growth by the Selective SGK Inhibitor EMD638683

Abstract

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.

SGK1 inhibitor reverses hyperglycemia partly through decreasing glucose absorption

“…Moreover, EMD638683 is readily soluble in water and is the first SGK inhibitor shown to be effective in vivo (Ackermann et al 2011). A newly published study showed that EMD638683 can decrease the number of colonic tumors following chemical carcinogenesis (Towhid et al 2013). Our study adds new evidence of the effectiveness of EMD638683 in vivo.…”

“…Until now, several SGK1 inhibitors have been developed, including GSK650394, LY294002, SI113, and EMD638683 (Towhid et al 2013, D'Antona et al 2015. Compared with others, EMD638683 is the most selective SGK1 inhibitor (Towhid et al 2013).…”

“…Compared with others, EMD638683 is the most selective SGK1 inhibitor (Towhid et al 2013). Moreover, EMD638683 is readily soluble in water and is the first SGK inhibitor shown to be effective in vivo (Ackermann et al 2011).…”

“…db/db mice received either no drug treatment (n = 8) or the SGK1 inhibitor (n = 8) EMD638683 via chow (4.46 mg EMD638683/g chow) for 8 weeks starting at 10 weeks of age. The dosage of EMD638683 was determined by referring several reports (Ackermann et al 2011, Towhid et al 2013. Age-matched db/m mice (n = 8) were used as controls in all the experiments.…”

Akt3 inhibits adipogenesis and protects from diet-induced obesity via signaling pathway

“…We next tested whether increased weight gain and fat expansion in Akt3 -/-mice fed an HFD is SGK1 dependent. EMD638683 is a small molecule SGK1 inhibitor with good oral bioavailability that has been successfully used to treat hypertension and colonic tumors in mice (34,35). Oral administration of the EMD638683 suppressed increased weight gain in Akt3 -/-mice fed an HFD ( Figure 6A).…”