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

• DOI: 10.1096/fj.02-0586fje
• Publication Date: 2003-03-29T02:03:22Z
• Authors: Tobias Linden; Dörthe M. Katschi...; Katrin Eckhardt; Annette Scheid; Horst Pagel; Roland H. Wenger
• Keywords: 0301 basic medicine; 1303 Biochemistry; Antifungal Agents; Iron; CHO Cells; Chick Embryo; Endothelial Growth Factors; Deferoxamine; In Vitro Techniques; Kidney; Binding, Competitive; 10052 Institute of Physiology; 03 medical and health sciences; 2,2'-Dipyridyl; 1311 Genetics; Allantois; Cricetinae; 1312 Molecular Biology; Animals; Luciferases; Binding Sites; Chorion; Ciclopirox; Hypoxia-Inducible Factor 1, alpha Subunit; Gene Expression Regulation; 1305 Biotechnology; 570 Life sciences; biology; Intercellular Signaling Peptides and Proteins

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