The Ras antagonist, farnesylthiosalicylic acid (FTS), inhibits experimentally-induced liver cirrhosis in rats

Background/Aims: Protooncogenes may play an important role, not only in car cinogenesis, but also in the regulation of normal cellular proliferation an d differentiation. Several studies have indicated increased expression of t he Ras protooncogenes in the liver in animal models and in patients with li ver cirrhosis. The aim of the present study was to examine whether a synthe tic Ras antagonist, S-farnesylthiosalicylic acid FTS), which specifically d islodges Ras from the membrane of Ras-transformed fibroblasts (EJ cells), c an prevent experimentally-induced liver cirrhosis in rats. Methods: Cirrhosis was induced in male Wistar rats by intraperitoneal admin istration of thioacetamide (200 mg/kg twice weekly for 12 weeks). The Ras a ntagonist, farnesylthiosalicylic acid (FTS, 5 mg/kg), was administered duri ng the study period 3 times a week. Ras expression in the liver was determi ned by Western blot analysis with pan anti-aas antibodies and by immunohist ochemistry. Results: Rats treated with thioacetamide and the Ras antagonist, farnesylth iosalicylic acid (FTS), for 12 weeks had lower histopathologic scores of fi brosis and inflammation Or-values of 0.003 and 0.008, respectively) than th ose treated with thioacetamide only. There were no differences between the histopathologic scores in vehicle (control) and in Ras-antagonist (FTS) onl y treatments. Analysis of hepatic hydroxyproline levels from the two thio a cetamide-treated groups and controls confirmed the histopathologic scores ( 7.7+/-0.9 mg/g protein in the TAA-treated vs. 3.8+/-0.5 mg/g protein in the TAA+FTS treated group, p=0.007). Ras levels, determined by Western blot an alysis, were markedly increased in the livers treated with TAA (17-fold ove r control) and significantly decreased (by about 70%) in the livers of rats treated with TAA and FTS, Studies in isolated human hepatic stellate cells demonstrated that FTS inhibited both DNA synthesis and migration of those cells (p<0.05). Conclusion: These results indicate that inhibition of Ras expression in the liver during fibrogenesis, prevents the development of experimentally-indu ced hepatic cirrhosis.