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 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.