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

Benjamin A. Nacev, Woon Kai Low, Zhennian Huang, Tina T. Su, Zhuang Su, Hisham Alkuraya, Dan Kasuga, Woong Sun, Mario Träger, Manfred Braun, Gunter Fischer, Kang Zhang, Jun O. Liu

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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.

Original languageEnglish
Pages (from-to)466-475
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume338
Issue number2
DOIs
Publication statusPublished - 2011 Aug 1
Externally publishedYes

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ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

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. (2011). A calcineurin-independent mechanism of angiogenesis inhibition by a nonimmunosuppressive cyclosporin A analog. Journal of Pharmacology and Experimental Therapeutics, 338(2), 466-475. https://doi.org/10.1124/jpet.111.180851