title: A calcineurin-independent mechanism of angiogenesis inhibition by a nonimmunosuppressive cyclosporin A analog.
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.
authors.affiliation: Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Nacev
authors.forename: Woon-Kai
authors.initials: WK
authors.lastname: Low
authors.forename: Zhennian
authors.initials: Z
authors.lastname: Huang
authors.forename: Tina T
authors.initials: TT
authors.lastname: Su
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Su
authors.forename: Hisham
authors.initials: H
authors.lastname: Alkuraya
authors.forename: Dan
authors.initials: D
authors.lastname: Kasuga
authors.forename: Woong
authors.initials: W
authors.lastname: Sun
authors.forename: Mario
authors.initials: M
authors.lastname: Träger
authors.forename: Manfred
authors.initials: M
authors.lastname: Braun
authors.forename: Gunter
authors.initials: G
authors.lastname: Fischer
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.forename: Jun O
authors.initials: JO
authors.lastname: Liu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude
chemical_list: D020533:Angiogenesis Inhibitors; D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D019703:Calcineurin