The copper-chelating agent, trientine, attenuates liver enzyme-altered preneoplastic lesions in rats by angiogenesis suppression.
It has been shown that angiogenesis plays an important role not only in tumor growth, but also in carcinogenesis. We previously reported that the copper-chelating agent, trientine dihydrochloride (trientine), exerted strong anti-angiogenic activity and inhibited hepatocellular carcinoma (HCC) tumor growth. The aim of the current study was to elucidate the effect of trientine on liver enzyme-altered preneoplastic lesions in rats, especially in conjunction with angiogenesis alteration in the liver. In a diethylnitrosamine (DEN)-induced rat hepatocarcinogenesis model, trientine treatment, even at a clinically comparable low dose, significantly suppressed glutathione S-transferase placental form (GST-P)-positive preneoplastic lesions associated with a decrease in copper content in the liver. Trientine also markedly suppressed neovascularization in the liver to a similar level as that of development of the preneoplastic lesions. On the contrary, the proliferative cell nuclear antigen (PCNA)-positive cells were not altered with or without trientine treatment. These results suggested that the copper-chelating agent, trientine, exerted chemopreventive effects against rat liver carcinogenesis due to the suppression of angiogenesis, and suggest that it might be useful clinically as a chemopreventive agent of HCC.
Yoshiji
Hitoshi
H
Third Department of Internal Medicine, Nara Medical University, Nara 634-8522, Japan. yoshijih@naramed-u.ac.jp
Kuriyama
Shigeki
S
Yoshii
Junichi
J
Ikenaka
Yasuhide
Y
Noguchi
Ryuichi
R
Yanase
Koji
K
Namisaki
Tadashi
T
Yamazaki
Masaharu
M
Tsujinoue
Hirohisa
H
Imazu
Hiroo
H
Fukui
Hiroshi
H
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D002273:Carcinogens; D002455:Cell Division; D002614:Chelating Agents / Q000494:pharmacology*; D003300:Copper / Q000378:metabolism*; D004052:Diethylnitrosamine; D005982:Glutathione Transferase / Q000096:biosynthesis; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008113:Liver Neoplasms / Q000139:chemically induced / Q000188:drug therapy; D009389:Neovascularization, Pathologic; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D016133:Polymerase Chain Reaction; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014266:Trientine / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D002273:Carcinogens; D002614:Chelating Agents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D004052:Diethylnitrosamine; D003300:Copper; D005982:Glutathione Transferase; D014266:Trientine