Effects of clioquinol analogues on the hypoxia-inducible factor pathway and intracelullar mobilization of metal ions

So Yeon Kim, Myong Jin Lee, Jeong Won Kim, Yu Ran Na, Ho Youl Lee, Hyunju Cho, Keun Byeol Lee, You Mie Lee, Cheolju Lee, Hyunsung Park, Eun Gyeong Yang

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

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 Zn2+ and Fe2+. While CQ and BQ are completely reversed by Zn2+, co-administration of Zn2+ and IQ has only a partial reversing effect. On the other hand, CAQ-mediated stabilization of HIF-1α is reversed by Fe2+ but not by Zn2+. These phenomena are found to coincide with elevation of the intracellular Zn 2+ and Fe2+ levels by the CQ analogues, suggesting that metal ion effects on HIF-1α in cells likely reflect the differential transporting capability of the analogues.

Original languageEnglish
Pages (from-to)2160-2169
Number of pages10
JournalBiological and Pharmaceutical Bulletin
Volume35
Issue number12
DOIs
StatePublished - Dec 2012

Keywords

  • 8-hydroxyquinoline derivative
  • Angiogenesis
  • Factor-inhibiting hypoxia-inducible factor-1
  • Hypoxia-inducible factor-1α
  • Prolyl hydroxylase domain 2
  • Zinc ion

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