銅キレート剤トリエンチンの抗血管新生作用と肝癌発育および肝発癌抑制効果の検討

Abstract

Angiogenesis is now recognized to play a pivotal role in tumor development, and even in the process of carcinogenesis. Trientine dihydrochloride (trientine) is used in clinical practice as a copper (Cu)-chelating agent. In this study, we elucidate that the effect of trientine on tumor development and carcinogenesis is due to the suppression of angiogenesis in the murine hepatocellular carcinoma cell (HCC) xenograft model and in the rat hepatocarcinogenesis model, respectively. Trientine suppressed the tumor development associated with suppression of intra-tumoral angiogenesis. Trientine treatment also resulted in a marked increase of apoptosis in the tumor, although tumor cell proliferation itself was not altered. In vitro studies also showed that trientine is not cytotoxic for the tumor cells, but it significantly suppressed the endothelial cell proliferation. In a diethylnitrosamine (DEN)-induced rat hepatocarcinogenesis model, trientine treatment significantly suppressed glutathione S-transferase placental form (GST-P)-positive preneoplastic lesions. Trientine also markedly suppressed neovascularization in the liver to a similar level as that of development of preneoplastic lesions. On the contrary, the intrahepatic cell proliferation was not altered with or without trientine treatment. These results suggested that Cu plays a pivotal role in HCC tumor development and carcinogenesis via angiogenesis suppression. Since trientine is already used in clinical practice without any serious side effects, it may be an effective new strategy for future HCC therapy.