In vitro and in vivo antitumor effects of vitamin K5 on hepatocellular carcinoma.
Although a number of studies have shown that vitamins K1, K2 and K3 exerted antitumor effects on various types of rodent- and human-derived neoplastic cell lines, it has not been examined whether or not vitamin K5 also possesses antitumor activity. In the present study, we examined the antitumor effects of vitamin K5 on PLC/PRF/5 human hepatocellular carcinoma (HCC) cells in vitro and in vivo. Furthermore, we examined the mechanisms of antitumor actions of vitamin K5 not only in vitro but also in vivo. Vitamin K5 was shown to suppress the proliferation of PLC/PRF/5 cells at a concentration of 30 microM. By a flow cytometric analysis, it was shown that although vitamin K5 did not induce apoptosis on PLC/PRF/5 cells, it did induce G1 arrest on PLC/PRF/5 cells. Subsequent in vivo study using subcutaneous HCC-bearing athymic nude mice demonstrated that vitamin K5 markedly suppressed the growth of HCC tumors. Although protein expression levels of cyclin D1 and p16INK4a cyclin-dependent kinase (Cdk) inhibitor in HCC tumors were not decreased by vitamin K5 treatment, those of Cdk4 were reduced significantly by the treatment. Taken collectively, vitamin K5 could induce potent antitumor effects on HCC not only in vitro but also in vivo, at least in part by inducing G1 arrest of cell cycle through downregulation of Cdk4 expression. The results demonstrated here indicate that vitamin K5 may be a useful agent for the treatment of patients with HCC.
Hitomi
Misuzu
M
Third Department of Internal Medicine, Kagawa University School of Medicine, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Nonomura
Takako
T
Yokoyama
Fumi
F
Yoshiji
Hitoshi
H
Ogawa
Mutsumi
M
Nakai
Seiji
S
Deguchi
Akihiro
A
Masaki
Tsutomu
T
Inoue
Hideyuki
H
Kimura
Yasuhiko
Y
Kurokohchi
Kazutaka
K
Uchida
Naohito
N
Kuriyama
Shigeki
S
D000818:Animals; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000096:biosynthesis; D015536:Down-Regulation; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D014407:Tumor Cells, Cultured; D024483:Vitamin K 3 / Q000031:analogs & derivatives* / Q000494:pharmacology*
D011518:Proto-Oncogene Proteins; D024483:Vitamin K 3; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; C024534:vitamin k5