Inconsistent hepatic antifibrotic effects with the iron chelator deferasirox

Background and AimDevelopment of effective antifibrotic treatments that can be translated to clinical practice is an important challenge in contemporary hepatology. A recent report on -thalassemia patients demonstrated that deferasirox treatment reversed or stabilized liver fibrosis independent of its iron-chelating properties. In this study, we investigated deferasirox in cell and animal models to better understand its potential antifibrotic effects. MethodsThe LX-2 stellate cell line was treated with 5M or 50M deferasirox (Exjade, Novartis Pharmaceuticals Australia, North Ryde, NSW, Australia) for up to 120h. Three-week-old multidrug resistance 2 null (Mdr2(-/-)) mice received oral deferasirox or vehicle for 4 weeks (30mg/kg/day). Cells and liver tissue were collected for assessment of fibrosis and fibrogenic gene expression. ResultsIn LX-2 cells treated with 50M deferasirox for 12h, 1(I)procollagen expression was decreased by 25%, with maximal reductions (10-fold) seen following 24-120h of treatment. Similarly, -smooth muscle actin (SMA) expression was significantly lower. Alterations in matrix remodeling genes, specifically decreased expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2, were observed. There was no significant difference in hepatic hydroxyproline content in Mdr2(-/-) mice following deferasirox administration (vehicle: 39527g/g vs deferasirox: 421 +/- 33g/g). Similarly, no changes in the expression of fibrogenic genes were observed. ConclusionDespite reductions in 1(I)procollagen and SMA expression and alterations in matrix degradation genes in LX-2 cells, deferasirox did not exhibit antifibrotic activity in Mdr2(-/-) mice. Given the positive outcomes seen in human trials, it may be appropriate to study deferasirox in other animal models of fibrosis and/or for a longer duration of therapy.