title: Inconsistent hepatic antifibrotic effects with the iron chelator deferasirox.
abstract: OBJECTIVE
  Development of effective antifibrotic treatments that can be translated to clinical practice is an important challenge in contemporary hepatology. A recent report on β-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.
  
  
  METHODS
  The LX-2 stellate cell line was treated with 5 μM or 50 μM deferasirox (Exjade, Novartis Pharmaceuticals Australia, North Ryde, NSW, Australia) for up to 120 h. Three-week-old multidrug resistance 2 null (Mdr2(-/-) ) mice received oral deferasirox or vehicle for 4 weeks (30 mg/kg/day). Cells and liver tissue were collected for assessment of fibrosis and fibrogenic gene expression.
  
  
  RESULTS
  In LX-2 cells treated with 50 μM deferasirox for 12 h, α1(I)procollagen expression was decreased by 25%, with maximal reductions (10-fold) seen following 24-120 h of treatment. Similarly, α-smooth muscle actin (αSMA) 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: 395 ± 27 μg/g vs deferasirox: 421 ± 33 μg/g). Similarly, no changes in the expression of fibrogenic genes were observed.
  
  
  CONCLUSIONS
  Despite reductions in α1(I)procollagen and αSMA 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.
authors.affiliation: School of Medicine, The University of Queensland, Gallipoli Medical Research Foundation, Greenslopes Private Hospital, Brisbane, Queensland, Australia.
authors.forename: Amy
authors.initials: A
authors.lastname: Sobbe
authors.forename: Kim R
authors.initials: KR
authors.lastname: Bridle
authors.forename: Lesley
authors.initials: L
authors.lastname: Jaskowski
authors.forename: C Erika
authors.initials: CE
authors.lastname: de Guzman
authors.forename: Nishreen
authors.initials: N
authors.lastname: Santrampurwala
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Clouston
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Campbell
authors.forename: V Nathan
authors.initials: VN
authors.lastname: Subramaniam
authors.forename: Darrell H G
authors.initials: DH
authors.lastname: Crawford
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001565:Benzoates / Q000008:administration & dosage* / Q000494:pharmacology*; D002478:Cells, Cultured; D000077588:Deferasirox; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D055166:Hepatic Stellate Cells; D006801:Humans; D007502:Iron Chelating Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011347:Procollagen / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage* / Q000494:pharmacology*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D001565:Benzoates; D007502:Iron Chelating Agents; D011347:Procollagen; D014230:Triazoles; D020778:Matrix Metalloproteinase 2; D000077588:Deferasirox
keywords: animal models; iron-chelating agents; liver fibrosis; stellate cells