Cu/Zn superoxide dismutase plays a role in angiogenesis.
Endothelial cells produce oxygen radicals spontaneously and this process is augmented by hypoxia/reoxygenation. Cu/Zn superoxide dismutase (SOD-1) is an important enzyme in cellular oxygen metabolism. To determine whether alterations in SOD-1 activity affect angiogenesis we used transgenic SOD-1 (Tg-SOD) mice with elevated level of SOD-1. Angiogenesis induced subcutaneously by bFGF in Tg-SOD mice was 3-fold higher than in control non-transgenic (ntg) mice. Oral administration of disulfiram (DSF), an inhibitor of SOD-1, inhibited angiogenesis in Tg-SOD mice as well as in CD1 nude mice. Effects of DSF on cultured cells were also tested. Application of DSF to cultured bovine capillary endothelial (BCE) cells caused inhibition of DNA synthesis and induction of apoptosis. These effects were prevented by addition of antioxidants, further indicating involvement of reactive oxygen species. DSF also reduced the level of glutathione and the production of H(2)O(2) in BCE cells. Moreover, PC12-SOD cells with elevated SOD-1 were less sensitive to DSF treatment then control cells. These data indicate that the effects of DSF are mediated by inhibition of SOD-1 activity. Tumor development is known to largely depend on angiogenesis. We found that oral administration of DSF to mice caused significant inhibition of C6 glioma tumor development and marked reduction (by 10-19-fold) in metastatic growth of Lewis lung carcinoma. The data suggest a role for SOD-1 in angiogenesis, establish DSF as a potential inhibitor of angiogenesis and raise the possibility that attenuating SOD-1 activity may be important in treatment of angiogenesis-dependent pathologies.
Marikovsky
Moshe
M
Department of Animal Sciences, Faculty of Agriculture, Hebrew University of Jerusalem, Rehovot, Israel. marikovs@agri.huji.ac.il
Nevo
Nava
N
Vadai
Ezra
E
Harris-Cerruti
Catherine
C
D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000098:blood supply / Q000517:prevention & control; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000517:prevention & control; D004221:Disulfiram / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005910:Glioma / Q000098:blood supply / Q000517:prevention & control; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008175:Lung Neoplasms / Q000098:blood supply / Q000517:prevention & control / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000201:enzymology*; D051381:Rats; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004791:Enzyme Inhibitors; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D005978:Glutathione; D004221:Disulfiram