Cyclosporin A and itraconazole synergistically inhibit endothelial cell proliferation and tube formation

Abstract

Angiogenesis underlies a number of pathologies including cancer and macular degeneration, but current single agent antiangiogenic therapies are only modestly effective in the treatment of these diseases. Thus, we sought to identify compounds which combinatorially and synergistically inhibit angiogenesis. From a screen of 741 binary clinical drug combinations for the synergistic inhibition of endothelial cell proliferation we identified cyclosporin A (CsA), an immusuppressant, and itraconazole, an antifungal drug. The IC50 dose of each drug is reduced by 3 to 9 fold in combination. The combination also synergistically inhibited endothelial cell tube formation and was specifically active against endothelial cells when compared with human foreskin fibroblast viability as well as Jurkat T cell and HeLa cell proliferation. We conclude that it is a viable strategy to combine existing clinical drugs to synergistically inhibit endothelial cell proliferation. Drawing on a pool of clinical drugs has the potential advantage of a faster transition to phase II studies when potent combinations are identified. This model may be useful for the development of new antiangiogenic treatments. This work was supported in part by NCI, FAMRI, CTSA, the Keck Foundation, the Walsh Prostate Cancer Fund, and the Commonwealth Foundation (J.O.L.), and by the NIH Medical Scientist Training Program (B.A.N).