A Calcineurin-Independent Mechanism of Angiogenesis Inhibition by a Nonimmunosuppressive Cyclosporin A Analog

Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, 725 N. Wolfe St., Baltimore, MD 21205, USA.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 05/2011; 338(2):466-75. DOI: 10.1124/jpet.111.180851
Source: PubMed


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.

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Available from: Woong Sun, Jan 19, 2014
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    • "Whether combining cyclosporine A with cisplatinum can help to overcome PPIA induced chemoresistance in patients with malignant glioma is currently under investigation [31]. In addition, cyclosporin A plays a further potentially useful role as an inhibitor of angiogenesis [30] [31], and non-immunosuppressive analogues of might be safely applied as part of an anti-angiogenetic drug regimen [32]. As in our study, PPIC positive CTCs were more likely in follow-up samples of the platinum resistant than in platinum sensitive patients, we speculate that PPIC positive CTCs represent a subpopulation of circulating tumor cells which " survived " chemotherapy and have a more aggressive potential. "
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    • "The ability of CsA to inhibit endothelial cell proliferation and angiogenesis has also been known for some time, but CsA has not been used as a clinical angiogenesis inhibitor due to its immunosuppressive properties and nephrotoxic side effects at high doses [28], [29]. Interestingly, while the mechanism for immunosuppression by CsA is due to inhibition of the protein phosphatase calcineurin in T cells, the antiangiogenic properties of the drug are independent of calcineurin [30], [31]. "
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