title: Itraconazole inhibits HMEC-1 angiogenesis.
abstract: Abnormal angiogenesis is implicated in a number of human diseases and endothelial growth inhibition represents a common approach in tumor therapy. Recently itraconazole, frequently used in humans as antifungal drug, which blocks the biosynthesis of cholesterol, has been found to be antiangiogenic in primary umbilical vein endothelial cells. However, the exact antiangiogenic mechanisms remain largely unknown. In this paper, we studied the effect of itraconazole in human dermal microvascular endothelial cells (HMEC-1), an immortalized cell line to study adult angiogenesis. A 50% reduction of microtubule formation was observed after itraconazole treatment which was partially rescued by cholesterol addition. We found that itraconazole inhibits angiogenesis markers such as VEGF, AAMP and e-NOS. mTOR and ERK1/2 phosphorylation as well as the expression of Gli1, one of the main controllers of the Shh pathway, were also inhibited by itraconazole. Cholesterol addition did not completely rescue inhibition of these pathways, suggesting that the itraconazole antiangiogenic activity could be due to multiple mechanisms. Our results may contribute to novel approaches to block angiogenesis with therapeutic application.
authors.affiliation: Institute of Clinical Physiology, National Research Council-CNR, Via Moruzzi 1, Pisa 56124, Italy. rdc@ifc.cnr.it
authors.forename: Renata
authors.initials: R
authors.lastname: Del Carratore
authors.forename: Angelo
authors.initials: A
authors.lastname: Carpi
authors.forename: Pascale
authors.initials: P
authors.lastname: Beffy
authors.forename: Valter
authors.initials: V
authors.lastname: Lubrano
authors.forename: Lucia
authors.initials: L
authors.lastname: Giorgetti
authors.forename: Bianca Elena
authors.initials: BE
authors.lastname: Maserti
authors.forename: Maria Annunziata
authors.initials: MA
authors.lastname: Carluccio
authors.forename: Marcella
authors.initials: M
authors.lastname: Simili
authors.forename: Giorgio
authors.initials: G
authors.lastname: Iervasi
authors.forename: Silvana
authors.initials: S
authors.lastname: Balzan
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D002460:Cell Line; D002784:Cholesterol / Q000008:administration & dosage; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D017964:Itraconazole / Q000494:pharmacology*; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D055806:Microvessels / Q000166:cytology; D009389:Neovascularization, Pathologic / Q000188:drug therapy
chemical_list: D020533:Angiogenesis Inhibitors; D000935:Antifungal Agents; D017964:Itraconazole; D002784:Cholesterol