title: Antitumor effects of vitamins K1, K2 and K3 on hepatocellular carcinoma in vitro and in vivo.
abstract: A number of studies have shown that various K vitamins, specifically vitamins K2 and K3, possess antitumor activity on various types of rodent- and human-derived neoplastic cell lines. In the present study, we examined the antitumor effects of vitamins K1, K2 and K3 on PLC/PRF/5 human hepatocellular carcinoma (HCC) cells in vitro and in vivo. Furthermore, we examined the mechanisms of antitumor actions of these vitamins in vitro and in vivo. Although vitamin K1 did not inhibit proliferation of PLC/PRF/5 cells at a 90-microM concentration (the highest tested), vitamins K2 and K3 suppressed proliferation of the cells at concentrations of 90 and 9 microM, respectively. By flow cytometric analysis, it was shown that not only vitamin K1, but also vitamin K2 did not induce apoptosis or cell cycle arrest on PLC/PRF/5 cells. In contrast, vitamin K3 induced G1 arrest, but not apoptosis on PLC/PRF/5 cells. Subsequent in vivo study using subcutaneous HCC-bearing athymic nude mice demonstrated that both vitamins K2 and K3 markedly suppressed the growth of HCC tumors to similar extent. Protein expression of cyclin D1 and cyclin-dependent kinase 4 (Cdk4), but not p16INK4a Cdk inhibitor in the tumor was significantly reduced by vitamin K2 or K3 treatment, indicating that vitamins K2 and K3 may induce G1 arrest of cell cycle on PLC/PRF/5 cells in vivo. Taken collectively, vitamins K2 and K3 were able to induce potent antitumor effects on HCC in vitro and in vivo, at least in part, by inducing G1 arrest of the cell cycle. The results indicate that vitamins K2 and K3 may be useful agents for the treatment of patients with HCC.
authors.affiliation: Third Department of Internal Medicine, Kagawa University School of Medicine, Kagawa 761-0793, Japan.
authors.forename: Misuzu
authors.initials: M
authors.lastname: Hitomi
authors.forename: Fumi
authors.initials: F
authors.lastname: Yokoyama
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kita
authors.forename: Takako
authors.initials: T
authors.lastname: Nonomura
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masaki
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Inoue
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Kinekawa
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Kurokohchi
authors.forename: Naohito
authors.initials: N
authors.lastname: Uchida
authors.forename: Seishiro
authors.initials: S
authors.lastname: Watanabe
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kuriyama
mesh_terms: D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D010837:Vitamin K 1 / Q000494:pharmacology*; D024482:Vitamin K 2 / Q000494:pharmacology*; D024483:Vitamin K 3 / Q000494:pharmacology*
chemical_list: D000933:Antifibrinolytic Agents; D024482:Vitamin K 2; D024483:Vitamin K 3; D010837:Vitamin K 1