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 .

Diseases
Validation

Diseases presenting "cancer" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

alpha-thalassemia

benign recurrent intrahepatic cholestasis

cadasil

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

coats disease

congenital adrenal hyperplasia

congenital diaphragmatic hernia

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

familial hypocalciuric hypercalcemia

familial mediterranean fever

gm1 gangliosidosis

heparin-induced thrombocytopenia

hereditary cerebral hemorrhage with amyloidosis

hirschsprung disease

hodgkin lymphoma, classical

inclusion body myositis

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

kindler syndrome

lamellar ichthyosis

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

pleomorphic liposarcoma

primary effusion lymphoma

proteus syndrome

pyomyositis

pyruvate dehydrogenase deficiency

severe combined immunodeficiency

sneddon syndrome

systemic capillary leak syndrome

triple a syndrome

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

This symptom has already been validated