The copper chelator trientine has an antiangiogenic effect against hepatocellular carcinoma, possibly through inhibition of interleukin‐8 production

Abstract

Recent studies have revealed that copper is an important cofactor for several angiogenic agents. We examined the antiangiogenic effect against hepatocellular carcinoma (HCC) of the copper chelator trientine, especially focusing on the relationship between copper and interleukin-8 (IL-8), a potent angiogenic factor produced by hepatoma cells. HuH-7 hepatoma cells were transplanted into nude mice and the growth of xenograft tumors was compared to and without administration of trientine. Using the resected tumor, microvessel density, apoptotic potential and proliferative activity were analyzed histologically and IL-8 mRNA was semiquantified by RT-PCR. In addition, HuH-7 cells were cultured in control medium, medium supplemented with copper, medium supplemented with trientine and medium supplemented with both copper and trientine. Human IL-8 levels were measured in the supernatants by ELISA. Using the extracts from cultured cells, IL-8 mRNA was semiquantified by RT-PCR. Trientine suppressed the growth of xenograft tumors significantly. Histologically, apoptotic potential was increased significantly and microvessel density, decreased. The production of IL-8 from the tumor was suppressed by trientine. In vitro, IL-8 production by HuH-7 cells in coppercontaining medium was significantly greater than that in copper-free medium, and this effect was weakened when trientine was added. However, no significant change was apparent when trientine was added to the medium alone. In conclusion, the chelating effect of trientine prevented copper from functioning as a cofactor in angiogenesis, which resulted in reduced IL-8 production from HuH-7 cells.

New uses for old copper-binding drugs: converting the pro-angiogenic copper to a specific cancer cell death inducer

“…Recently, additional findings demonstrate that tumor growth and metastasis depend upon angiogenesis [33,34] that requires growth factors, proteases, and trace element Cu. Copper, but not other transition metals, is a co-factor required for several angiogenic mediators including VEGF [32], basic fibroblast growth factor (bFGF) [35], IL-1 (IL-1) and IL-8 (IL-8) [36], which are essential for tumor angiogenesis processes (Figure 1) [37][38][39][40].…”

Cholangiocarcinoma in Wilson’s Disease – a Case Report

“…Copper may also play a central role in the BRAF associated tumorigenesis in melanomas, thyroid cancers and hairy cell leukaemias [12]. Thus, chelating agents might have an antitumor effect and be effective as an anticancer therapy [8,11,13].…”

New applications of old metal-binding drugs in the treatment of human cancer

“…Studies in cell cultures and animal models have demonstrated that Cu is able to induce VEGF mRNA transcription and protein expression (31)(32). Copper, but not other metals, is a co-factor required for several angiogenic mediators including VEGF (32), basic fibroblast growth factor (bFGF) (33), interleukin 1 (IL-1) and interleukin 8 (IL-8) (34), all of which are essential regulators for tumor angiogenesis (35)(36)(37)(38). Tumors are dependent on angiogenesis for their growth, invasion and metastasis (39)(40), and Cu plays an important role in this process.…”