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Liver Cancer
Figure 1: Induction of Apoptosis by Vitamin K
2
Figure 2: Involvement of Extracellular Signal-related Kinase
Activation in Vitamin K
2
-induced Apoptosis
G1 G2/M G1 G2/M
subG1 VK2 x10
-4
M
592 240
0 x24 h x48 h x72 h x96 h
444 180
42kDa P ERK 1/2
296 120
Count Count
148
BH
60
BH
42kDa
Total ERK 1/2
CH CH
0 0
-1 1 10 100 1000 -1 1 10 100 1000
PILog PILog
42kDa
β-actin
*
120
*
100
*p<0.001
80
Control 10
-4
M VK
2
x96h
60
model in mice and rats, treatment with VK
2
significantly inhibited the
Cell viability (%)
development of pre-neoplastic foci associated with suppression of
40
angiogenesis, which was accelerated when combined with an
angiotensin-converting enzyme inhibitor (ACE-I) perindopril.
17,18
20
There is an increasing body of clinical evidence that VK
0
2
exhibited
Control U0126 VK2 U0126+VK2
preventative effects on the development of HCC. Habu et al. reported that
ERK = extracellular signal-regulated kinase.
VK
2
prevented the development of HCC when administered to patients
with viral cirrhosis.
19
In that report, HCC was detected in two of the 21 enzyme (ACE)-I
22
and vitamin E,
23
respectively. Currently, we are
patients given VK
2
at 45mg daily and in nine of the 19 patients in conducting a larger-scale clinical study to verify the preventative effects of
the control group, revealing that the cumulative incidence of HCC in the VK
2
on the recurrence of HCC.
treatment group with VK
2
was significantly lower than that in the control
group. Preventative effects of VK
2
on the recurrence of HCC after curative Conclusion and Perspective
therapies have also been reported.
20,21
Interestingly, there are two recent As the prognosis of patients with HCC is dismal, the discovery of novel drugs
case reports demonstrating that a dysplastic nodule and HCC were useful for the prevention and treatment of HCC is an urgent need. VK
2
may
successfully treated with VK
2
when combined with angiotensin-converting become a new strategy for chemoprevention and treatment of HCC. ■
1. Bosch FX, Ribes J, Borras J, Epidemiology of primary liver 10. Bouzahzah B, Nishikawa Y, Simon D, Carr BI, Growth control anti-angiogenic activities, Oncol Rep, 2006;15:155–9.
cancer, Semin Liver Dis, 1999;19:271–85. and gene expression in a new hepatocellular carcinoma cell 18. Yoshiji H, Kuriyama S, Noguchi R, et al., Combination of
2. Okuda H, Hepatocellular carcinoma development in cirrhosis, line, Hep40: inhibitory actions of vitamin K, J Cell Physiol, 1995; vitamin K2 and the angiotensin-converting enzyme inhibitor,
Best Pract Res Clin Gastroenterol, 2007;21:161–73. 165:459–67 . perindopril, attenuates the liver enzyme-altered preneoplastic
3. Tabb MM, Sun A, Zhou C, et al., Vitamin K2 regulation of bone 11. Otsuka M, Kato N, Shao RX, et al.,Vitamin K2 inhibits the lesions in rats via angiogenesis suppression, J Hepatol, 2005;
homeostasis is mediated by the steroid and xenobiotic receptor growth and invasiveness of hepatocellular carcinoma cells via 42:687–93.
SXR, J Biol Chem, 2003;278:43919–27. protein kinase A activation, Hepatology, 2004;40:243–51. 19. Habu D, Shiomi S, Tamori A, et al., Role of vitamin K2 in the
4. Yoshida T, Miyazawa K, Kasuga I, et al., Apoptosis induction of 12. Kuriyama S, Hitomi M, Yoshiji H, et al., Vitamins K2, K3 and K5 development of hepatocellular carcinoma in women with viral
vitamin K2 in lung carcinoma cell lines: the possibility of exert in vivo antitumor effects on hepatocellular carcinoma by cirrhosis of the liver, JAMA, 2004;292:358–61.
vitamin K2 therapy for lung cancer, Int J Oncol, 2003;23: regulating the expression of G1 phase-related cell cycle 20. Mizuta T, Ozaki I, Eguchi Y, et al., The effect of menatetrenone,
627–32. molecules, Int J Oncol, 2005;27:505–11. a vitamin K2 analog, on disease recurrence and survival in
5. Tokita H, Tsuchida A, Miyazawa K, et al., Vitamin K2-induced 13. Liu W, Nakamura H, Yamamoto T, et al., Vitamin K2 inhibits patients with hepatocellular carcinoma after curative treatment:
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6. Shibayama-Imazu T, Sonoda I, Sakairi S, et al., Production of 14. Ozaki I, Zhang H, Mizuta T, et al., Menatetrenone, a vitamin K2 vitamin K on recurrent disease in patients with hepatocellular
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cancer TYK-nu cells, Apoptosis, 2006;11:1535–43. factor kappaB activation, Clin Cancer Res, 2007;13:2236–45. 22. Yoshiji H, Noguchi R, Yamazaki M, et al., Combined treatment
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46 ASIA-PACIFIC ONCOLOGY & HAEMATOLOGY
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