Amelioration of carcinogenesis and tumor growth in the rat liver by combination of vitamin K2 and angiotensin-converting enzyme inhibitor via anti-angiogenic activities

Oncol Rep. 2006 Jan;15(1):155-9.


Recent studies have revealed that angiogenesis plays a pivotal role in carcinogenesis and tumor growth. We previously reported that the clinically used vitamin K(2) (VK) and angiotensin-converting enzyme inhibitor (ACE-I) exerted potent anti-angiogenic activities. The aim of our current study was to examine the combination effect of VK and ACE-I on hepatocarcinogenesis induced by diethyl-nitrosamine, and orthotopic hepatocellular carcinoma (HCC) growth in rats. When used individually, both VK and ACE-I at clinically comparable low doses exerted significant inhibitory effects on tumor development in the liver. A combination treatment of VK and ACE-I showed a more potent suppressive effect against hepatocarcinogenesis. Neovascularization increased during hepatocarcinogenesis, and VK and ACE-I significantly attenuated angiogenesis in the tumor. In orthotopic HCC transplantation, VK and ACE-I also showed marked suppressive effects against HCC development similar to those against hepatocarcinogenesis. In both experiments, the suppressive effects of VK and ACE-I against angiogenesis were similar in magnitude to their inhibitory effects against hepatocarcinogenesis and orthotopic HCC development. In the orthotopic model, VK and ACE-I treatment resulted in a marked increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. Since both VK and ACE-I are widely used in clinical practice without serious side effects, this combination therapy may be an effective new therapeutic strategy against hepatocarcinogenesis and HCC growth in the future.

MeSH terms

  • Angiotensin-Converting Enzyme Inhibitors / pharmacology
  • Angiotensin-Converting Enzyme Inhibitors / therapeutic use*
  • Animals
  • Cell Transformation, Neoplastic / chemically induced
  • Cell Transformation, Neoplastic / drug effects
  • Cell Transformation, Neoplastic / genetics
  • Diethylnitrosamine / toxicity
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Liver / chemistry
  • Liver / drug effects
  • Liver / pathology
  • Liver Neoplasms, Experimental / drug therapy*
  • Liver Neoplasms, Experimental / genetics
  • Mice
  • Neoplasm Transplantation
  • Neovascularization, Pathologic / drug therapy*
  • Platelet Endothelial Cell Adhesion Molecule-1 / genetics
  • Proliferating Cell Nuclear Antigen / analysis
  • RNA, Messenger / analysis
  • RNA, Messenger / metabolism
  • Rats
  • Vitamin K 2 / pharmacology
  • Vitamin K 2 / therapeutic use*


  • Angiotensin-Converting Enzyme Inhibitors
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Proliferating Cell Nuclear Antigen
  • RNA, Messenger
  • Vitamin K 2
  • Diethylnitrosamine