Is copper chelation an effective anti-angiogenic strategy for cancer treatment?

[oral submucous fibrosis]

Angiogenesis and the acquisition of an angiogenic phenotype is important for cancer cell proliferation . Copper in an essential trace element that participates in many enzymatic complexes like the cytochrome c , superoxide dismutase and lysyl oxidase and it is involved in processes , like embryogenesis , growth , angiogenesis and carcinogenesis . In particular , its involvement in carcinogenesis was described for the first time in oral submucous fibrosis , where fibroblasts produce large amounts of collagen in the presence of copper . Copper 's action in carcinogenesis is two-fold : (1 ) it participates in reactions with an increased redox potential that result in the production of oxidative products and oxidative stress . Through this mechanism , copper may cause DNA mutations in the nucleus and mitochondria or alterations to membrane phospholipids , (2 ) it participates in angiogenesis even in the absence of angiogenic molecules , as it was reported for the first time in rabbit cornea models with copolymer pellets charged with PGE 1 . Copper chelation regimens like penicillamine and tetrathiomolybdate are being described in the literature as having anti-angiogenic , anti-fibrotic and anti-inflammatory actions . Animal models of brain cancer that evaluated the anti-angiogenic properties of copper , have proven evidence of the reduction of tumor 's microvascular supply , tumor volume and vascular permeability after plasma copper levels reduction . Interestingly , plasma copper levels reduction was shown to suppress micrometastases generation in mice models of breast cancer . We hypothesize that copper chelation therapy : increases oxidative stress in cancer cells to a level that does not allow survival because of the reduction of anti-oxidative enzymes production . It may also result in inhibition of angiogenesis and of the initiation of the angiogenic switch , because copper normally enhances endothelial cell migration and proliferation , improves binding of growth factors to endothelial cells and enhances the expression of angiogenic molecules . Copper chelation may also reduce extracellular matrix degradation and cancer spread , through reduction of MMP-9 production and probably of other collagenases and may inhibit propagation of micrometastases . However , copper chelation therapy may enhance angiogenesis through reduction of thrombospondin-1 , that results into an increase in VEGF-VEGFR 2 complexes and a high level of active MMP-9 . These hypotheses help in understanding of the anti-angiogenic action of copper chelation therapies and of the complex network of interactions between copper and other molecules involved in angiogenesis . It may also stimulate further research regarding differences in copper metabolism , the effects of anti-copper regimens on organs , the development of resistance , and their possible angiogenic action through thrombospondin expression reduction .

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