The copper-chelating agent, trientine, suppresses tumor development and angiogenesis in the murine hepatocellular carcinoma cells

Abstract

Angiogenesis is now recognized as a crucial process in tumor development, including hepatocellular carcinoma (HCC). Since HCC is known as a hypervascular tumor, antiangiogenesis is a promising approach to inhibit the HCC development. Trientine dihydrochloride (trientine) is used in clinical practice as an alternative copper (Cu)-chelating agent for patients with Wilson's disease of penicillamine intolerance. In our study, we examined the effect of Cu-chelating agents on tumor development and angiogenesis in the murine HCC xenograft model. Although both trientine and penicillamine in the drinking water suppressed the tumor development, trientine exerted a more potent inhibitory effect than penicillamine. In combination with a Cu-deficient diet, both trientine and penicillamine almost abolished the HCC development. Trientine treatment resulted in a marked suppression of neovascularization and increase of apoptosis in the tumor, whereas tumor cell proliferation itself was not altered. In vitro studies also exhibited that trientine is not cytotoxic for the tumor cells. On the other hand, it significantly suppressed the endothelial cell proliferation. These results suggested that Cu plays a pivotal role in tumor development and angiogenesis in the murine HCC cells, and Cuchelators, especially trientine, could inhibit angiogenesis and enhance apoptosis in the tumor with consequent suppression of the tumor growth in vivo. Since trientine is already used in clinical practice without any serious side effects as compared to penicillamine, it may be an effective new strategy for future HCC therapy.

Bioavailable copper modulates oxidative phosphorylation and growth of tumors

“…2B), indicating that differential levels of copper intake affect the rate of cancer cell proliferation. Unrestricted growth of tumors depends on formation of new blood vessels, and copper has been shown to be involved in this process (5)(6)(7)(8). However, vascular density in tumors was not affected by copper status under our experimental conditions ( Fig.…”

“…Serum copper levels are elevated in cancer patients and correlate with the severity of the disease and response to therapies (3,4). In animal models, copperchelating drugs have been reported to have antiangiogenic activity (5)(6)(7)(8). The molecular and cellular mechanisms by which copper levels modulate tumor angiogenesis and the generality of its effects on angiogenesis in different cancer types remain unclear, as are its potentially broader effects on tumor growth.…”

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

“…Tumors are dependent on angiogenesis for their growth, invasion and metastasis (39)(40), and Cu plays an important role in this process. Due to the importance of angiogenesis and copper to tumor development, the use of copper chelators for antiangiogenic therapy has emerged as an interesting concept in cancer therapeutics (41)(42).…”

Triethylenetetramine Pharmacology and Its Clinical Applications

“…Chelation of copper by TETA suppresses several angiogenic mediators, including vascular endothelial growth factor-1 (VEGF-1), fibroblast growth factor-1 (FGF-1), interleukin-1 (IL-1), IL-6, IL-8, and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB; refs. [9][10][11][77][78][79][80]. As a result, TETA exhibits antiangiogenic effects in tumor cells.…”

“…It has also been suggested that TETA can be used in the treatment of cancer because it is a telomerase inhibitor (8), and has anti-angiogenesis properties (9)(10)(11), on the basis of preclinical investigations. In addition, a recent report showed that TETA treatment could overcome cisplatin resistance in human ovarian cancer cell culture via inhibition of superoxide dismutase 1/Cu/Zn superoxide dismutase (12).…”