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

Title
Effects of clioquinol analogues on the hypoxia-inducible factor pathway and intracelullar mobilization of metal ions
Authors
김소연이명진김정원나유란이호열조현주이큰별이유미이철주박현성양은경
Keywords
8-hydroxyquinoline derivative; hypoxia-inducible factor-1α; zinc ion; prolyl hydroxylase domain 2; factor-inhibiting hypoxia-inducible factor-1; angiogenesis
Issue Date
2012-12
Publisher
Biological & pharmaceutical bulletin
Citation
VOL 35, NO 12, 2160-2169
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 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.
URI
http://pubs.kist.re.kr/handle/201004/46679
ISSN
09186158
Appears in Collections:
KIST Publication > Article
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