title: Therapeutic effect of a multi-targeted imidazolium compound in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed lethal cancers in the world. We previously showed two imidazolium salts (IBN-1 and IBN-9) with a moderate efficacy for HCC. Here we report a more potent imidazolium compound IBN-65 (1-benzyl-2-phenyl-3-(4-isopropyl)-benzyl-imidazolium chloride) and the associated mechanisms of action in a mouse model of HCC. The IC50 of this compound in various liver cancer cell lines was around 5 μm. IBN-65 dose-dependently arrested cell cycle at G1 phase and was associated with the down-regulation of the cyclin-dependent kinase-4, -6, cyclin D1, and cyclin E. In addition, IBN-65 induced apoptosis by down-regulating Survivin, Bcl-2 and up-regulating Bax, leading to sequential activation of Caspase-3, Caspase-9 and the cleavage of poly(ADP-ribose) polymerase (PARP). Dysregulation of the epidermal growth factor receptor (EGFR) signaling network has been frequently reported in HCC. We found that IBN-65 displayed a profound inhibitory effect on the EGFR/Raf/MEK/ERK signaling at the phosphorylation level. In Huh7 or Hep3B cells, pretreatment with IBN-65 attenuated EGF-induced phosphorylation of both EGFR and the downstream p44/42 MAPK. A siRNA knockdown of EGFR also proved that IBN-65 induced apoptosis mostly through inhibiting downstream EGFR pathway signaling, much less at the receptor level. Infrequent administration of IBN-65 (i.p., 5 mg/kg once weekly for four weeks) to mice bearing the Huh7 cells significantly reduced the tumor volume by 65% without affecting the body weight. Critically, many of the anti-tumor signaling features observed in the HCC cell lines were recaptured in the xenografted tissues. Thus, the metal-free imidazolium compound IBN-65 could be a potential candidate towards therapeutic development for HCC.
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #04-01, Biopolis, Singapore 138669, Singapore.
authors.forename: Began
authors.initials: B
authors.lastname: Gopalan
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #04-01, Biopolis, Singapore 138669, Singapore.
authors.forename: Karthikeyan
authors.initials: K
authors.lastname: Narayanan
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #04-01, Biopolis, Singapore 138669, Singapore.
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Ke
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #04-01, Biopolis, Singapore 138669, Singapore.
authors.forename: Ting
authors.initials: T
authors.lastname: Lu
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #04-01, Biopolis, Singapore 138669, Singapore.
authors.forename: Yugen
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos, #04-01, Biopolis, Singapore 138669, Singapore; Research and Development Center for Innovative Pharmaceuticals, Guangxi Botanic Garden of Medicinal Plants, Chinese Academy of Medical Sciences, 189 Changgang Road, Nanning, Guangxi 530023, China. Electronic address: zhuolang@yahoo.com.
authors.forename: Lang
authors.initials: L
authors.lastname: Zhuo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D058990:Molecular Targeted Therapy; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D007093:Imidazoles; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: Apoptosis; Cell cycle; EGFR; Hepatocellular carcinoma; Imidazolium salts; p44/42 MAPK