Combination of vitamin K2 and the angiotensin-converting enzyme inhibitor, perindopril, attenuates the liver enzyme-altered preneoplastic lesions in rats via angiogenesis suppression.
OBJECTIVE
Chemoprevention should be a promising approach to improve the prognosis of the patients with hepatocellular carcinoma (HCC). Angiogenesis is now recognized as a crucial step not only in tumor growth, but also in early carcinogenesis. The aim of this study was to elucidate the combination effect of the clinically used vitamin K(2) (VK) and the angiotensin-converting enzyme inhibitor, perindopril (PE), on hepatocarcinogenesis, especially in conjunction with angiogenesis.


METHODS
In a diethylnitrosamine-induced rat hepatocarcinogenesis model, the effects of VK and PE on the development of liver enzyme-altered preneoplastic lesions and angiogenesis were examined.


RESULTS
Treatment with both VK and PE markedly inhibited the development of preneoplastic lesions in association with suppression of neovascularization in the liver. The combination treatment with VK and PE exerted a more potent inhibitory effect as compared with the single agent treatments. The in vitro study demonstrated that VK and PE inhibited the endothelial cell (EC) tubular formation. VK also suppressed the EC proliferation in a dose-dependent manner.


CONCLUSIONS
The combination of VK and PE exerted a chemopreventive effect against rat liver carcinogenesis via suppression of angiogenesis. Since both agents are widely used in the clinical practice, this combination therapy may represent a potential new strategy for chemoprevention against HCC in the future.
Yoshiji
Hitoshi
H
Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara 634-8522, Japan. yoshijih@naramed-u.ac.jp
Kuriyama
Shigeki
S
Noguchi
Ryuichi
R
Yoshii
Junichi
J
Ikenaka
Yasuhide
Y
Yanase
Koji
K
Namisaki
Tadashi
T
Kitade
Mitsuteru
M
Yamazaki
Masaharu
M
Masaki
Tsutomu
T
Fukui
Hiroshi
H
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy / Q000517:prevention & control*; D002455:Cell Division / Q000187:drug effects; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D008099:Liver / Q000098:blood supply / Q000201:enzymology; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000517:prevention & control*; D008297:Male; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000517:prevention & control; D020913:Perindopril / Q000494:pharmacology*; D011230:Precancerous Conditions / Q000098:blood supply / Q000188:drug therapy*; D051381:Rats; D011916:Rats, Inbred F344; D024482:Vitamin K 2 / Q000494:pharmacology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D000933:Antifibrinolytic Agents; D024482:Vitamin K 2; D020913:Perindopril