title: Combination of vitamin K2 and the angiotensin-converting enzyme inhibitor, perindopril, attenuates the liver enzyme-altered preneoplastic lesions in rats via angiogenesis suppression.
abstract: 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.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara 634-8522, Japan. yoshijih@naramed-u.ac.jp
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.forename: Shigeki
authors.initials: S
authors.lastname: Kuriyama
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Noguchi
authors.forename: Junichi
authors.initials: J
authors.lastname: Yoshii
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Ikenaka
authors.forename: Koji
authors.initials: K
authors.lastname: Yanase
authors.forename: Tadashi
authors.initials: T
authors.lastname: Namisaki
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Kitade
authors.forename: Masaharu
authors.initials: M
authors.lastname: Yamazaki
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Masaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukui
mesh_terms: 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*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000933:Antifibrinolytic Agents; D024482:Vitamin K 2; D020913:Perindopril