Amelioration of carcinogenesis and tumor growth in the rat liver by combination of vitamin K2 and angiotensin-converting enzyme inhibitor via anti-angiogenic activities.
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.
Yoshiji
Hitoshi
H
Third Department of Internal Medicine, Nara Medical University, 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
Akahane
Takemi
T
Asada
Kiyoshi
K
Tsujimoto
Tatsuhito
T
Uemura
Masahito
M
Fukui
Hiroshi
H
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000187:drug effects / Q000235:genetics; D004052:Diethylnitrosamine / Q000633:toxicity; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000737:chemistry / Q000187:drug effects / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D051381:Rats; D024482:Vitamin K 2 / Q000494:pharmacology / Q000627:therapeutic use*
D000806:Angiotensin-Converting Enzyme Inhibitors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D024482:Vitamin K 2; D004052:Diethylnitrosamine