ABSTRACT
Hepatic fibrosis is the result of chronic liver injuries underlined by diverse etiologies. The massive accumulation of extracellular matrix (ECM) proteins during fibrogenesis leads to structural distortion and functional disruption of the liver. There is currently no effective standard treatment for liver fibrosis. We previously identified a class of imidazolium salts (IMSs) with anti-fibrotic properties in a cell-based screen. In this report, we investigated the anti-fibrotic efficacy and mechanisms of a small IMS, 1,3-diisopropylimidazolium tetrafluoroborate (DPIM), in a hepatic fibrosis model induced by bile duct ligation (BDL) in mice. The orally available DPIM was administered to BDL mice via drinking water at three concentrations (0.5, 0.75, and 1 g/l) for 4 weeks. We observed a significant reduction in inflammation and collagen deposition in the liver, which could be mediated by a reduction in the expression of monocyte chemoattractant protein-1 (MCP-1) and by an enhancement in the matrix metalloproteinase-mediated ECM remodeling. The current findings highlight the importance for simultaneously targeting multiple pathways to more effectively attenuate and resolve liver fibrosis and warrant further studies on this compound in additional models of hepatic fibrosis.
Subject(s)
Cholestasis/drug therapy , Fibrosis/drug therapy , Imidazoles/therapeutic use , Inflammation/drug therapy , Administration, Oral , Animals , Cell Line , Collagen/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Electrophoresis, Polyacrylamide Gel , Imidazoles/administration & dosage , Immunohistochemistry , In Situ Nick-End Labeling , Male , Matrix Metalloproteinases/metabolism , Mice , Polymerase Chain Reaction , Tissue Inhibitor of Metalloproteinase-1/metabolismABSTRACT
Imidazolium salts (IMSs) are precursors to N-heterocyclic carbenes (NHCs), which are routinely used as ligands or organo-catalysts in synthetic chemistry. We recently identified several IMSs as anti-fibrotic agents in liver fibrosis, which often has a consequence in the oncogenesis of hepatocellular carcinoma (HCC). Here, we investigate the potential anti-tumor property of three IMSs (named IBN-1, IBN-9, and DPIM) in HCC cell lines and in a xenograft mouse model. Our results showed that both IBN-1 and IBN-9 significantly inhibited the cell proliferation and arrested HCC cells in the G1-phase, whereas DPIM did not have any anti-tumor activity. When tested in a Huh7 HCC xenograft mouse model, IBN-1 reduced the tumor volume by 31% (P<0.05), however accompanied by a 9% loss in body weight (P<0.005), suggesting a general toxicity. In contrast, IBN-9 significantly reduced the tumor volume by 45% (P<0.05) and 60% (P<0.01) at doses of 0.6 and 1.5 g/l in drinking water, respectively, without any loss in body weight. Our in vitro and in vivo data suggested that IBN-1 and IBN-9 inhibited the growth of HCC by suppressing the expression of Survivin and Cyclin-dependent kinases. The current study provides a proof of concept for using the metal-free IMSs to develop novel anti-cancer agents.
