Inconsistent hepatic antifibrotic effects with the iron chelator deferasirox
Sobbe, A., Bridle, K.R., Jaskowski, L., de Guzman, C.E., Santrampurwala, N., Clouston, A.D., Campbell, C.M., Subramaniam, V.N., & Crawford, D.H.G. (2015) Inconsistent hepatic antifibrotic effects with the iron chelator deferasirox. Journal of Gastroenterology and Hepatology (Australia), 30(3), pp. 638-645.
Background and Aim
- 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.
- 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.
- 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.
- 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.
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|Item Type:||Journal Article|
|Keywords:||deferasirox; ACTA2 protein, human; actin; benzoic acid derivative; deferasirox; gelatinase A; iron chelating agent; procollagen; triazole derivative, animal cell; animal experiment; animal model; animal tissue; antifibrotic effect; Article; beta thalassemia; cell proliferation; cell viability; clinical practice; controlled study; drug effect; female; gene expression; human; iron chelation; iron storage, Actins; Administration, Oral; Animals; Benzoates; Cells, Cultured; Disease Models, Animal; Gene Expression; Hepatic Stellate Cells; Humans; Iron Chelating Agents; Liver; Liver Cirrhosis; Male; Matrix Metalloproteinase 2; Mice; Mice, Transgenic; Procollagen; Triazoles|
|Divisions:||Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
|Copyright Owner:||© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.|
|Deposited On:||12 Oct 2016 01:10|
|Last Modified:||14 Oct 2016 04:25|
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