title: Involvement of p53 and nuclear factor-kappaB signaling pathway for the induction of G1-phase cell cycle arrest of cholangiocarcinoma cell lines by isomorellin.
abstract: Cell cycle arrest is closely linked to apoptosis. Isomorellin-a caged xanthone isolated from Garcinia hanburyi-induced apoptosis in cholangiocarcinoma (CCA) cell lines. To elucidate potential anticancer mechanisms, we investigated the effects of isomorellin on the growth, cell cycle progression, cell cycle regulated protein expression and nuclear factor-kappa B (NF-κB) activation of KKU-100 and KKU-M156 CCA cell lines; using sulforhodamine B assay, flow cytometry and Western blot analysis. The growth of both CCA cell lines was significantly inhibited by isomorellin treatment in a time- and dose-dependent manner. The respective IC(50) value of isomorellin for KKU-100 cells was 6.2±0.13, 5.1±0.11 and 3.5±0.25 µM at 24, 48 and 72 h. By comparison, the respective IC(50) value for KKU-M156 cells was 1.9±0.22, 1.7±0.14 and 1.5±0.14 µM at 24, 48 and 72 h. The growth inhibition of CCA cells by isomorellin was through the G0/G1 phase arrest mediated by inhibition of NF-κB activation, up-regulation of p53, p21 and p27 and down-regulation of cyclin D1, cyclin E, Cdk4 and Cdk2 protein levels. Our research suggests that isomorellin induces cell cycle arrest and apoptosis in CCA cell lines through p53 and the NF-κB-signaling pathway. The growth inhibitory potential of isomorellin was comparable to that of gambogic acid. Isomorellin shows potential as a therapeutic agent against human cholangiocarcinoma.
authors.affiliation: Department of Microbiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand.
authors.forename: Chariya
authors.initials: C
authors.lastname: Hahnvajanawong
authors.forename: Supaluk
authors.initials: S
authors.lastname: Ketnimit
authors.forename: Kovit
authors.initials: K
authors.lastname: Pattanapanyasat
authors.forename: Natthinee
authors.initials: N
authors.lastname: Anantachoke
authors.forename: Banchob
authors.initials: B
authors.lastname: Sripa
authors.forename: Khosit
authors.initials: K
authors.lastname: Pinmai
authors.forename: Wunchana
authors.initials: W
authors.lastname: Seubwai
authors.forename: Vichai
authors.initials: V
authors.lastname: Reutrakul
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018281:Cholangiocarcinoma; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D029760:Garcinia; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044004:Xanthones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D016159:Tumor Suppressor Protein p53; D044004:Xanthones; C579425:isomorellin