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 language | English |
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Pages (from-to) | 2160-2169 |
Number of pages | 10 |
Journal | Biological and Pharmaceutical Bulletin |
Volume | 35 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2012 |
Keywords
- 8-hydroxyquinoline derivative
- Angiogenesis
- Factor-inhibiting hypoxia-inducible factor-1
- Hypoxia-inducible factor-1α
- Prolyl hydroxylase domain 2
- Zinc ion