Delphinidin inhibits angiogenesis through the suppression of HIF-1 alpha and VEGF expression in A549 lung cancer cells

Abstract

Delphinidin, a polyphenol that belongs to the group of anthocyanidins and is abundant in many pigmented fruits and vegetables, possesses important antioxidant, anti-inflammatory, anti-mutagenic and anticancer properties. In the present study, we investigated the inhibitory effects of delphinidin on vascular endothelial growth factor (VEGF) expression, an important factor involved in angiogenesis and tumor progression, in A549 human lung cancer cells. Delphinidin inhibited CoCl2- and epidermal growth factor (EGF)-induced VEGF mRNA expression and VEGF protein production. Delphinidin also decreased CoCl2- and EGF-stimulated expression of hypoxia-inducible factor (HIF)-1 alpha, which is a transcription factor of VEGF. Delphinidin suppressed CoCl2- and EGF-induced hypoxia-response element (HRE) promoter activity, suggesting that the inhibitory effects of delphinidin on VEGF expression are caused by the suppression of the binding of HIF-1 to the HRE promoter. We also found that delphinidin specifically decreased the CoCl2- and EGF-induced HIF-1 alpha protein expression by blocking the ERK and PI3K/Akt/mTOR/p70S6K signaling pathways, whereas the p38-mediated pathways were not involved. In animal models, EGF-induced new blood vessel formation was significantly inhibited by delphinidin. Therefore, our results indicate that delphinidin has a potentially new role in anti-angiogenic action by inhibiting HIF-1 alpha and VEGF expression.