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The antimycotic ciclopirox olamine induces HIF‐1α stability, VEGF expression, and angiogenesis

The antimycotic ciclopirox olamine induces HIF‐1α stability, VEGF expression, and angiogenesis The heterodimeric hypoxia‐inducible factor (HIF)‐1 is a master regulator of oxygen homeostasis. Protein stability and transactivation function of the α subunit are controlled by iron‐ and oxygen‐dependent hydroxylation of proline and asparagine residues. The anti‐mycotic ciclopirox olamine (CPX) is a lipophilic bidentate iron chelator that stabilizes HIF‐1α under normoxic conditions at lower concentrations than other iron chelators, probably by inhibiting HIF‐1α hydroxylation. As shown by the inhibition of iron‐dependent quenching of FITC‐labeled deferoxamine (DFX) fluorescence, CPX appears to have an even higher affinity for iron than DFX. Initial observations that treatment with 1% CPX, but not with placebo, occasionally caused reddening of wound margins in a mouse skin wound model prompted us to investigate the capability of CPX to induce angiogenesis. CPX‐induced HIF‐1‐mediated reporter gene activity and endogenous HIF‐1 target gene expression, including elevation of transcription, mRNA, and protein levels of the vascular endothelial growth factor (VEGF). In the chick chorioallantoic membrane assay, inert polymer disks containing CPX but not the solvent alone induced angiogenesis. In summary, these results suggest that CPX induces angiogenesis in vivo via HIF‐1 and VEGF induction. Therefore, CPX might serve as an alternative to recombinant VEGF treatment or to VEGF gene therapy for therapeutic angiogenesis. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The FASEB journal Wiley

The antimycotic ciclopirox olamine induces HIF‐1α stability, VEGF expression, and angiogenesis

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References (64)

Publisher
Wiley
Copyright
© Federation of American Societies for Experimental Biology
ISSN
0892-6638
eISSN
1530-6860
DOI
10.1096/fj.02-0586fje
Publisher site
See Article on Publisher Site

Abstract

The heterodimeric hypoxia‐inducible factor (HIF)‐1 is a master regulator of oxygen homeostasis. Protein stability and transactivation function of the α subunit are controlled by iron‐ and oxygen‐dependent hydroxylation of proline and asparagine residues. The anti‐mycotic ciclopirox olamine (CPX) is a lipophilic bidentate iron chelator that stabilizes HIF‐1α under normoxic conditions at lower concentrations than other iron chelators, probably by inhibiting HIF‐1α hydroxylation. As shown by the inhibition of iron‐dependent quenching of FITC‐labeled deferoxamine (DFX) fluorescence, CPX appears to have an even higher affinity for iron than DFX. Initial observations that treatment with 1% CPX, but not with placebo, occasionally caused reddening of wound margins in a mouse skin wound model prompted us to investigate the capability of CPX to induce angiogenesis. CPX‐induced HIF‐1‐mediated reporter gene activity and endogenous HIF‐1 target gene expression, including elevation of transcription, mRNA, and protein levels of the vascular endothelial growth factor (VEGF). In the chick chorioallantoic membrane assay, inert polymer disks containing CPX but not the solvent alone induced angiogenesis. In summary, these results suggest that CPX induces angiogenesis in vivo via HIF‐1 and VEGF induction. Therefore, CPX might serve as an alternative to recombinant VEGF treatment or to VEGF gene therapy for therapeutic angiogenesis.

Journal

The FASEB journal – Wiley

Published: Apr 1, 2003

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