GSK-3 inhibition in vitro and in vivo enhances antitumor effect of sorafenib in renal cell carcinoma (RCC).

Sorafenib is a multikinase inhibitor approved for the systemic treatment of renal cell carcinoma (RCC). However, sorafenib treatment has a limited effect due to acquired chemoresistance of RCC. Previously, we identified glycogen synthase kinase-3 (GSK-3) as a new therapeutic target in RCC. Here, we observed that sorafenib inhibits proliferation and survival of RCC cells. Significantly, we revealed that sorafenib enhances GSK-3 activity in RCC cells, which could be a potential mechanism of acquired chemoresistance. We found that pharmacological inhibition of GSK-3 potentiates sorafenib antitumor effect in vitro and in vivo. Our results suggest that combining GSK-3 inhibitor and sorafenib might be a potential new therapeutic approach for RCC treatment.

Changes in osteoblast, chondrocyte, and adipocyte lineages mediate the bone anabolic actions of PTH and small molecule GSK-3 inhibitor.

Parathyroid hormone (PTH) and glycogen synthase kinase-3 (GSK-3) inhibitor 603281-31-8, administered once daily increased bone formation in vivo. We investigated the molecular mechanisms of the anabolic responses of PTH and 603281-31-8 in rat osteopenia model. Female 6-month-old rats were ovariectomized (Ovx) and permitted to lose bone for 1 month, followed by treatment with PTH (1-38) at 10 microg/kg/day s.c. or 603281-31-8 at 3 mg/kg/day p.o. for 60 days. Twenty-four hours after the last treatment, RNA from distal femur metaphysis was subjected to gene expression analysis. Differentially expressed genes (P<0.05) were subjected to pathway analysis to delineate relevant bio-processes involved in skeletal biology. Genes involved in morphogenesis, cell growth/differentiation, and apoptosis were significantly altered by Ovx and the treatments. Analysis of morphogenesis genes showed an overrepresentation of genes involved in osteogenesis, chondrogenesis, and adipogenesis. A striking finding was that Ovx decreased several markers of osteogenesis/chondrogenesis and increased markers of adipogenesis/lipid metabolism. Treatment with either PTH or the GSK-3 inhibitor reversed these effects, albeit at different levels. Histological analysis confirmed that osteopenia in Ovx animals was associated with three-fold increase in marrow adiposity. PTH and GSK-3 inhibitor restored bone volume, and reversed or normalized marrow adiposity. Ex vivo studies showed that PTH and GSK-3 inhibitor increased the ratio of colony forming marrow stromal progenitors (CFU-fs) that were alkaline phosphatase positive (putative osteoblasts). Our results suggest that the bone anabolic actions of PTH and GSK-3 inhibitor in vivo involve concerted effects on mesenchymal lineages; osteoblasts, chondrocytes, and adipocytes.

[Future targets in the treatment of type 2 diabetes]. / Zukünftige Angriffspunkte für die Therapie des Typ-2-Diabetes.

Prevention and treatment of type 2 diabetes mellitus (T2DM) and the metabolic syndrome represent a major clinical challenge, because effective strategies such as fat restriction and exercise are difficult to implement into diabetes treatment. Based on the increasing knowledge on the pathogenesis of T2DM, new therapeutic approaches are currently under investigation. Potential targets of new therapeutic approaches include: (i) Inhibition of hepatic glucose production, (ii) stimulation of glucose-dependent insulin secretion, (iii) enhancement of insulin signal transduction, and (iv) reduction of body fat mass. Agonists of glucagon-like-peptide 1 (GLP-1) and antagonists of dipeptidylpeptidase IV, which inactivates GLP-1, stimulate glucose-dependent insulin secretion, improve hyperglycemia and are already tested in clinical trials. In humans, glucagon antagonists and an amylin analogue reduce glucagon-dependent glucose production. The glucose-lowering effect of current modulators of lipid oxidation is not pronounced and their use could be limited by side effects. In addition to clinically approved thiazolidendiones, new agonists of the peroxisome proliferator activator receptor gamma (PPAR gamma) as well as combined PPAR alpha/gamma agonists are developed at present. The direct modulation of insulin signal transduction is still limited to experimental studies.