s-trans-trans-farnesylthiosalicylic-acid and Diabetes-Mellitus--Type-2

Farnesylthiosalisylic acid (FTS) is a potent non-toxic anticancer drug that targets oncogenic and pathologically activated Ras. The mechanism of action of FTS is well understood. It interferes with the binding of activated Ras proteins to their escort chaperons and with Ras tethering to the plasma membrane. This agent has been evaluated successfully in phase II clinical trials of pancreatic and lung cancer patients. It is generally agreed that Ras proteins play an important role in cancer, but they also drive activation of the immune system. Therefore we hypothesized that inhibiting Ras might be beneficial in autoimmune and inflammatory conditions. Over the past decade we have extensively studied the effects of FTS in multiple animal models of such diseases. We were able to show potent anti-inflammatory properties of FTS in autoimmune disease models such as systemic lupus erythematous, antiphospholipd syndrome, Guillain-Barré syndrome, multiple sclerosis, and inflammatory bowel diseases. Its potential was also shown in type I and type II diabetes. Animal models of contact dermatitis, allergic inflammation, and proliferative nephritis were studied as well. We have also investigated the molecular mechanisms, signaling pathways, and inflammatory mediators underlying these conditions. In this review we summarize our (and others) published data, and conclude that FTS has great potential as a safe anti-inflammatory drug.

Topics: Animals; Anti-Inflammatory Agents; Autoimmune Diseases; Diabetes Mellitus, Type 2; Disease Models, Animal; Farnesol; Humans; Protein Binding; ras Proteins; Salicylates

Reduced glucose uptake due to insulin resistance is a pivotal mechanism in the pathogenesis of type 2 diabetes. It is also associated with increased inflammation. Ras inhibition downregulates inflammation in various experimental models. The aim of this study was to examine the effect of Ras inhibition on insulin sensitivity and glucose uptake, as well as its influence on type 2 diabetes development.. The effect of Ras inhibition on glucose uptake was examined both in vitro and in vivo. Ras was inhibited in cells transfected with a dominant-negative form of Ras or by 5-fluoro-farnesylthiosalicylic acid (F-FTS), a small-molecule Ras inhibitor. The involvement of IκB and NF-κB in Ras-inhibited glucose uptake was investigated by immunoblotting. High fat (HF)-induced diabetic mice were treated with F-FTS to test the effect of Ras inhibition on induction of hyperglycemia. Each of the Ras-inhibitory modes resulted in increased glucose uptake, whether in insulin-resistant C2C12 myotubes in vitro or in HF-induced diabetic mice in vivo. Ras inhibition also caused increased IκB expression accompanied by decreased expression of NF-κB . In fat-induced diabetic mice treated daily with F-FTS, both the incidence of hyperglycemia and the levels of serum insulin were significantly decreased.. Inhibition of Ras apparently induces a state of heightened insulin sensitization both in vitro and in vivo. Ras inhibition should therefore be considered as an approach worth testing for the treatment of type 2 diabetes.

Topics: Animals; Blotting, Western; Cell Line; Diabetes Mellitus, Type 2; Farnesol; Glucose; Insulin Resistance; Mice; Polymerase Chain Reaction; Proto-Oncogene Proteins p21(ras); Salicylates