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

• Abstract: 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.
• Authors: Hitoshi Yoshiji, Shigeki Kuriyama, Ryuichi Noguchi, Junichi Yoshii, Yasuhide Ikenaka, Koji Yanase, Tadashi Namisaki, Mitsuteru Kitade, Masaharu Yamazaki, Takemi Akahane, Kiyoshi Asada, Tatsuhito Tsujimoto, Masahito Uemura, Hiroshi Fukui (Affiliation: Third Department of Internal Medicine, Nara Medical University, Japan. yoshijih at naramed-u.ac.jp)
• Journal: Oncology reports (Oncol Rep) Vol. 15 Issue 1 Pg. 155-9 (Jan 2006) ISSN: 1021-335X [Print] Greece
• PMID: 16328049 (Publication Type: Journal Article)

Chemical References

• Angiotensin-Converting Enzyme Inhibitors
• Antigens, CD31
• Proliferating Cell Nuclear Antigen
• RNA, Messenger
• Vitamin K 2
• Diethylnitrosamine

Topics

• Angiotensin-Converting Enzyme Inhibitors (pharmacology, therapeutic use)
• Animals
• Antigens, CD31 (genetics)
• Cell Transformation, Neoplastic (chemically induced, drug effects, genetics)
• Diethylnitrosamine (toxicity)
• Immunohistochemistry
• In Situ Nick-End Labeling
• Liver (chemistry, drug effects, pathology)
• Liver Neoplasms, Experimental (drug therapy, genetics)
• Mice
• Neoplasm Transplantation
• Neovascularization, Pathologic (drug therapy)
• Proliferating Cell Nuclear Antigen (analysis)
• RNA, Messenger (analysis, metabolism)
• Rats
• Vitamin K 2 (pharmacology, therapeutic use)