calcimycin and myricetin

Flavonoids are dietary antioxidants that may play a role as adjunct nutritional supplements in cancer or during inflammatory disorders. Hypoxia and the transcription factor hypoxia-inducible factor-1alpha also appear to play a key role in many human cancers. In this study, we investigated the role of quercetin in the hypoxia-dependent HIF-1alpha induction. It was shown that quercetin induced HIF-1alpha expression and HIF-1 activity under normoxia and hypoxia in human HepG2 hepatoma cells. By using actinomycin D and cycloheximide, we showed that quercetin acted post-transcriptionally by prolonging the HIF-1alpha protein half-life. Thereby quercetin interfered with the proline hydroxylation-dependent HIF-1alpha protein destabilization in the N-terminal HIF-1alpha transactivation domain. Experiments with quercetin analogues revealed that a flavonol structure and the presence of hydroxyl groups at position 3' and 4' are a prerequisite for the HIF-1alpha stabilizing effects. Further, quercetin inhibited cell proliferation and induced expression of the cell cycle inhibitor p21WAF and knocking-down HIF-1alpha disrupted these effects. These results provide evidence that quercetin inhibits the cell cycle and that induction of the HIF-system contributes to these effects of quercetin.

Topics: Antioxidants; Blotting, Northern; Blotting, Western; Calcimycin; Cell Line, Tumor; Cell Proliferation; Chelating Agents; Cyclin-Dependent Kinase Inhibitor p21; Egtazic Acid; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Flavanones; Flavones; Flavonoids; Flavonols; Hep G2 Cells; HT29 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Luteolin; Procollagen-Proline Dioxygenase; Protein Stability; Quercetin; Reactive Oxygen Species