Vitamins K2, K3 and K5 exert in vivo antitumor effects on hepatocellular carcinoma by regulating the expression of G1 phase-related cell cycle molecules.
A number of studies have shown that various vitamins K, specifically vitamin K2, possessed antitumor activity on various types of rodent- and human-derived neoplastic cell lines. However, there are only a small number of reports demonstrating in vivo antitumor effects of vitamins K. Furthermore, the mechanism of antitumor effects of vitamins K still remains to be examined. In the present study, we examined the antitumor effects of vitamins K2, K3 and K5 on PLC/PRF/5 human hepatocellular carcinoma (HCC) cells in vivo. Furthermore, to examine the mechanism of antitumor actions of these vitamins K, mRNA expression levels of various G1 phase-related cell cycle molecules were evaluated by using a real-time reverse transcription-polymerase chain reaction (RT-PCR) method. HCC-bearing animals were produced by implanting PLC/PRF/5 cells subcutaneously into athymic nude mice, and drinking water containing vitamin K2, K3 or K5 was given to the animals. Treatments with vitamins K2, K3 and K5 were shown to markedly inhibit the growth of HCC tumors. To examine the mechanism of in vivo antitumor effects of vitamins K, total RNA was extracted from HCC tumors, and the expression of G1 phase-related cell cycle molecules was quantitatively examined. Real-time RT-PCR demonstrated that the expression of the cell cycle-driving molecule, cyclin-dependent kinase 4 (Cdk4), in HCC was significantly reduced by the treatments with vitamin K2, K3 and K5. Conversely, the expression of the cell cycle-suppressing molecules, Cdk inhibitor p16INK4a and retinoblastoma, in HCC was significantly enhanced by the treatments with vitamins K2, K3 and K5. These results indicate that vitamins K2, K3 and K5 exert antitumor effects on HCC by regulating the expression of G1 phase-related cell cycle molecules. These results also indicate that vitamins K2, K3 and K5 may be useful agents for the treatment of patients with HCC.
Kuriyama
Shigeki
S
Third Department of Internal Medicine, Kagawa University School of Medicine, Kita-gun, Kagawa 761-0793, Japan. skuriyam@med.kagawa-u.ac.jp
Hitomi
Misuzu
M
Yoshiji
Hitoshi
H
Nonomura
Takako
T
Tsujimoto
Tatsuhiro
T
Mitoro
Akira
A
Akahane
Takami
T
Ogawa
Mutsumi
M
Nakai
Seiji
S
Deguchi
Akihiro
A
Masaki
Tsutomu
T
Uchida
Naohito
N
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D018797:Cell Cycle Proteins / Q000235:genetics*; D019938:Cyclin D1 / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D016193:G1 Phase / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014812:Vitamin K / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D024482:Vitamin K 2 / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D024483:Vitamin K 3 / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D024482:Vitamin K 2; D014812:Vitamin K; D019938:Cyclin D1; D024483:Vitamin K 3; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4; C024534:vitamin k5