The antifungal drug ciclopirox inhibits deoxyhypusine and proline hydroxylation, endothelial cell growth and angiogenesis in vitro.
The hypusine biosynthetic steps represent novel targets for intervention in cell proliferation. Hypusine is a rare amino acid, formed posttranslationally in one cellular protein, eIF5A, and is essential for cell proliferation. Deoxyhypusine hydroxylase, the metalloenzyme catalyzing the final step in hypusine biosynthesis, and prolyl 4-hydroxylase, a non-heme iron enzyme critical for collagen processing, can be inhibited by small chelating molecules that target their essential metal atom. We examined the effects of 5 compounds (ciclopirox, deferiprone, deferoxamine, mimosine and 2,2'-dipyridyl) on these protein hydroxylases in HUVECs, on cell proliferation and on angiogenesis using 2 model assays: tube-like vessel formation on Matrigel and the chick aortic arch sprouting assay. These compounds inhibited cellular deoxyhypusine hydroxylase in a concentration-dependent manner, but their efficacy varied widely in the following order: ciclopirox--> deferoxamine-->2,2'-dipyridyl-->deferiprone-->mimosine (IC(50) 5-200 microM). Inhibition of DNA synthesis, following the same order (IC(50) 10-450 microM), correlated with G(1) arrest of the cell cycle. These compounds also inhibited proline hydroxylation and maturation of collagen in HUVECs and caused inhibition of angiogenesis in vitro. Of the compounds tested, ciclopirox was by far the most effective inhibitor of HUVEC proliferation and angiogenesis. The strong antiangiogenic activity of this readily available antifungal drug along with its antiproliferative effects suggests a new potential application for ciclopirox in the treatment of solid tumors.
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Paul M J
PM
Clement
Hartmut M
HM
Hanauske-Abel
Edith C
EC
Wolff
Hynda K
HK
Kleinman
Myung Hee
MH
Park
D000935:Antifungal Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D000077768:Ciclopirox; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D006900:Hydroxylation / Q000187:drug effects; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism*; D008954:Models, Biological; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011392:Proline / Q000378:metabolism*; D011728:Pyridones / Q000494:pharmacology*
D000935:Antifungal Agents; D011728:Pyridones; D000077768:Ciclopirox; C034924:deoxyhypusine; D004247:DNA; D011392:Proline; D008239:Lysine