title: Metal-free imidazolium salts inhibit the growth of hepatocellular carcinoma in a mouse model.
abstract: 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.
authors.affiliation: Institute of Bioengineering and Nanotechnology, Biopolis, Singapore, Singapore.
authors.forename: Began
authors.initials: B
authors.lastname: Gopalan
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Ke
authors.forename: Chunyan
authors.initials: C
authors.lastname: Zhang
authors.forename: Yinling
authors.initials: Y
authors.lastname: Kng
authors.forename: Nur-Afidah Mohamed
authors.initials: NA
authors.lastname: Suhaimi
authors.forename: Siti Nurhanna
authors.initials: SN
authors.lastname: Riduan
authors.forename: Yugen
authors.initials: Y
authors.lastname: Zhang
authors.forename: Lang
authors.initials: L
authors.lastname: Zhuo
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D007093:Imidazoles / Q000494:pharmacology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012097:Repressor Proteins / Q000378:metabolism; D012492:Salts; D000077022:Survivin
chemical_list: C117749:Birc5 protein, mouse; D007093:Imidazoles; D051034:Inhibitor of Apoptosis Proteins; D012097:Repressor Proteins; D012492:Salts; D000077022:Survivin; D018844:Cyclin-Dependent Kinases