The flavonoid quercetin induces hypoxia-inducible factor-1 alpha (HIF-1 alpha) and inhibits cell proliferation by depleting intracellular iron

Quercetin, a flavonoid with anti- oxidant, metal chelating, kinase modulating and anti- proliferative properties, can induce hypoxia- inducible factor-1 alpha (HIF-1 alpha) in normoxia, but its mechanism of action has not been determined. In this study we characterized the induction of HIF-1 alpha and the inhibition of cell proliferation caused by quercetin in HeLa and ASM ( airway smooth muscle) cells and examined the effect of iron on these processes. Furthermore, we investigated the relevance of the intracellular levels of quercetin to HIF-1 alpha expression and cell proliferation. Our data demonstrate that quercetin depletes intracellular calcein - chelatable iron and that supplying additional iron from extracellular or intracellular pools abrogates the induction of HIF-1 alpha by quercetin. Moreover, addition of iron reverses the quercetin- induced inhibition of DNA synthesis, cell proliferation and cycle progression, but to different extents, depending on cell type. We propose that quercetin stabilises HIF-1 alpha and inhibits cell proliferation predominantly by decreasing the concentration of intracellular iron through chelation.