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A calcineurin-independent mechanism of angiogenesis inhibition by a nonimmunosuppressive cyclosporin A analog

Authors
Nacev B.A.Low W.-K.Huang Z.Su T.T.Su Z.Alkuraya H.Kasuga D.Sun W.Träger M.Braun M.Fischer G.Zhang K.Liu J.O.
Issue Date
2011
Publisher
American Society for Pharmacology and Experimental Therapeutics
Citation
Journal of Pharmacology and Experimental Therapeutics, v.338, no.2, pp 466 - 475
Pages
10
Indexed
SCI
SCIE
SCOPUS
Journal Title
Journal of Pharmacology and Experimental Therapeutics
Volume
338
Number
2
Start Page
466
End Page
475
URI
https://scholarworks.korea.ac.kr/kumedicine/handle/2020.sw.kumedicine/14123
DOI
10.1124/jpet.111.180851
ISSN
0022-3565
1521-0103
Abstract
Cyclosporin A (CsA) is a widely used immunosuppressant drug. Its immunosuppressive activity occurs through the inhibition of the protein phosphatase calcineurin via formation of a ternary complex with cyclophilin A (CypA). CsA also inhibits endothelial cell proliferation and angiogenesis. This has been thought to occur through calcineurin inhibition as well. However, CsA is also a potent inhibitor of cyclophilins, a class of prolyl isomerases. Because calcineurin inhibition requires binding, and therefore inhibition of CypA, the relative contributions of calcineurin and cyclophilin inhibition in antiangiogenesis have not been addressed. We have taken a chemical biology approach to explore this question by dissociating the two activities of CsA at the molecular level. We have identified a nonimmunosuppressive analog of CsA that does not inhibit calcineurin but maintains inhibition of endothelial cell proliferation and in vivo angiogenesis. The same analog also maintains inhibition of all cyclophilin isoforms tested. We also show that a second, structurally distinct, cyclophilin inhibitor is sufficient to block endothelial cell proliferation. These results suggest that the inhibition of cyclophilins may play a larger role in the antiangiogenic activity of CsA than previously believed, and that cyclophilins may be potential antiangiogenic drug targets. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics.
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