title: Effects of clioquinol analogues on the hypoxia-inducible factor pathway and intracelullar mobilization of metal ions.
abstract: We previously found that clioquinol (CQ) increases functional hypoxia-inducible factor-1α (HIF-1α) with enhanced transcription of its target genes. Here we report that compounds derived from 8-hydroxyquinoline including CQ, broxyquinoline (BQ), iodoquinol (IQ) and chloroacetoxyquinoline (CAQ) promote neovascularization effectively based on chick chorioallantoic membrane assays. The CQ analogues induce stabilization of HIF-1α as well as enhance HIF-1-mediated vascular endothelial growth factor transcription. These analogues also exert inhibitory effects on the activity of prolyl and asparaginyl hydroxylations of HIF-1α in vitro. Despite metal ion-dependent restoration of the inhibited HIF-1α hydroxylase activity, the cellular HIF-1α-inducing effects of the CQ analogues are reversed to varying degrees by Zn(2+) and Fe(2+). While CQ and BQ are completely reversed by Zn(2+), co-administration of Zn(2+) and IQ has only a partial reversing effect. On the other hand, CAQ-mediated stabilization of HIF-1α is reversed by Fe(2+) but not by Zn(2+). These phenomena are found to coincide with elevation of the intracellular Zn(2+) and Fe(2+) levels by the CQ analogues, suggesting that metal ion effects on HIF-1α in cells likely reflect the differential transporting capability of the analogues.
authors.affiliation: Biomedical Research Institute, Korea Institute of Science and Technology, Hwarangno 14-gil 5, Seongbuk-gu, Seoul 136–791, Republic of Korea.
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Myong Jin
authors.initials: MJ
authors.lastname: Lee
authors.forename: Jeong Won
authors.initials: JW
authors.lastname: Kim
authors.forename: Yu-Ran
authors.initials: YR
authors.lastname: Na
authors.forename: Ho-Youl
authors.initials: HY
authors.lastname: Lee
authors.forename: Hyunju
authors.initials: H
authors.lastname: Cho
authors.forename: Keun Byeol
authors.initials: KB
authors.lastname: Lee
authors.forename: You Mie
authors.initials: YM
authors.lastname: Lee
authors.forename: Cheolju
authors.initials: C
authors.lastname: Lee
authors.forename: Hyunsung
authors.initials: H
authors.lastname: Park
authors.forename: Eun Gyeong
authors.initials: EG
authors.lastname: Yang
mesh_terms: D000818:Animals; D001692:Biological Transport; D001808:Blood Vessels / Q000187:drug effects*; D002413:Cations, Divalent / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology*; D002642:Chick Embryo; D049033:Chorioallantoic Membrane / Q000502:physiology; D007464:Clioquinol / Q000031:analogs & derivatives / Q000494:pharmacology*; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015032:Zinc / Q000378:metabolism*
chemical_list: D002413:Cations, Divalent; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D007464:Clioquinol; D007501:Iron; D006899:Mixed Function Oxygenases; D015032:Zinc