title: The antimycotic ciclopirox olamine induces HIF-1alpha stability, VEGF expression, and angiogenesis.
abstract: The heterodimeric hypoxia-inducible factor (HIF)-1 is a master regulator of oxygen homeostasis. Protein stability and transactivation function of the alpha 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-1alpha under normoxic conditions at lower concentrations than other iron chelators, probably by inhibiting HIF-1alpha 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.
authors.affiliation: Institute of Physiology, Medical University of Lübeck, Lübeck, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Linden
authors.forename: Dörthe M
authors.initials: DM
authors.lastname: Katschinski
authors.forename: Katrin
authors.initials: K
authors.lastname: Eckhardt
authors.forename: Annette
authors.initials: A
authors.lastname: Scheid
authors.forename: Horst
authors.initials: H
authors.lastname: Pagel
authors.forename: Roland H
authors.initials: RH
authors.lastname: Wenger
mesh_terms: D015082:2,2'-Dipyridyl / Q000494:pharmacology; D000482:Allantois / Q000098:blood supply; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D001665:Binding Sites / Q000235:genetics; D001667:Binding, Competitive; D016466:CHO Cells; D002642:Chick Embryo; D002823:Chorion / Q000098:blood supply; D000077768:Ciclopirox; D006224:Cricetinae; D003676:Deferoxamine / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D007501:Iron / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008222:Lymphokines / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011728:Pyridones / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D014157:Transcription Factors / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: D000935:Antifungal Agents; D016228:Endothelial Growth Factors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011728:Pyridones; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000077768:Ciclopirox; D015082:2,2'-Dipyridyl; D007501:Iron; D008156:Luciferases; D003676:Deferoxamine