Effects of clioquinol analogues on the hypoxia-inducible factor pathway and intracelullar mobilization of metal ions
- Effects of clioquinol analogues on the hypoxia-inducible factor pathway and intracelullar mobilization of metal ions
- 김소연; 이명진; 김정원; 나유란; 이호열; 조현주; 이큰별; 이유미; 이철주; 박현성; 양은경
- 8-hydroxyquinoline derivative; hypoxia-inducible factor-1α; zinc ion; prolyl hydroxylase domain 2; factor-inhibiting hypoxia-inducible factor-1; angiogenesis
- Issue Date
- Biological & pharmaceutical bulletin
- VOL 35, NO 12, 2160-2169
- 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 Zn2+ 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.
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