Derivatives of 8‐hydroxyquinoline induce HIF‐1α accumulation, VEGF expression, and angiogenesis

Inhibition of HIF‐1α prolyl‐ and asparaginyl‐ hydroxylases has been predicted to produce activation of the HIF‐1 system with enhanced transcription of its target genes. Here we report that 8‐hydroxyquinoline and its derivatives including Clioquinol, Broxyquinoline, Iodoquinol and Chloroacetoxyquinoline inhibit hydroxylation of both proline and asparagine, leading to accumulation of HIF‐1α, while the compounds have minimal effects on the interactions of HIF‐1α with VBC or with p300. In addition, 8‐hydroxyquinoline derivatives induce HIF‐1‐mediated reporter gene activity and VEGF transcription. Furthermore, in vivo organ models based on the chick chorioallantoic membrane assay demonstrate that 8‐hydroxyquinoline derivatives promote new blood vessel formation. Taken together, our results provide evidence that 8‐hydroxyquinoline and its derivatives possess a pro‐angiogenesis potential, which might serve as an alternative to recombinant VEGF treatment or to VEGF gene therapy for therapeutic angiogenesis. [This study was supported by a grant (2004‐01967) from the Molecular and Cellular BioDiscovery Research Program and a grant (2004‐01969) from the Neurobiology Research Program]