title: Vitamin K3 analogs induce selective tumor cytotoxicity in neuroblastoma.
abstract: We investigated the cytotoxicity of eight vitamin K3 (VK3) analogs against neuroblastoma cell lines (IMR-32, LA-N-1, NB-39, and SK-N-SH) and normal cell lines (human umbilical vein endothelial cells (HUVEC) and human dermal fibroblasts (HDF)) using a 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. 2-[(2-Methoxy)ethylthio]-3-methyl-1,4-naphthoquinone (VK3-OCH(3)) showed especially potent cytotoxic activities against neuroblastoma cells compared with normal cells. In a Hoechst 33342 staining experiment, apoptotic morphologies characterized by cell shrinkage, nuclear condensation, and nuclear fragmentation were observed in IMR-32 and LA-N-1 cells after 48 h of treatment with 10(-5) M of VK3-OCH(3). To clarify the molecular mechanisms of apoptosis induced by VK3-OCH(3), we examined the expression of apoptosis related proteins using a Proteome Profiler Array and western blotting. Heme oxygenase (HO)-1 was remarkably increased by VK3-OCH(3) compared with the control (173% in IMR-32 and 170% in LA-N-1 at 24 h). Moreover, caveolin-1 was induced by VK3-OCH(3) at 48 h. In addition, VK3-OCH(3) arrested the cell cycle at the G2/M phase in IMR-32 cells. These results suggest that VK3-OCH(3) exhibited a selective antitumor activity via HO-1-related mechanisms.
authors.affiliation: School of Pharmacy, Nihon University, Funabashi, Chiba, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kitano
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yoda
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tabata
authors.forename: Motofumi
authors.initials: M
authors.lastname: Miura
authors.forename: Masaharu
authors.initials: M
authors.lastname: Toriyama
authors.forename: Shigeyasu
authors.initials: S
authors.lastname: Motohashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D051242:Caveolin 1; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D051547:Heme Oxygenase-1; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D009447:Neuroblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020543:Proteome; D024483:Vitamin K 3 / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D051242:Caveolin 1; D020543:Proteome; D024483:Vitamin K 3; D051547:Heme Oxygenase-1