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)‑1α, 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-1α 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-1α and VEGF expression.
Delphinidin is a blue-red pigment and one of the major anthocyanins in plants. It plays an important role in anti-oxidant, anti-inflammatory, anti-mutagenic and anti-cancer properties. In this study, we investigated the inhibitory effects of delphinidin on vascular endothelial growth factor (VEGF) gene expression, an important factor involved in angiogenesis and tumor progression in human prostate cancer. Delphinidin decreased levels of epidermal growth factor (EGF)-induced VEGF mRNA expression in PC-3M cells. The expression of the EGF-induced hypoxia inducible factor-1α (HIF-1α) and signaling transducer and activator of transcription 3 (STAT3) proteins, which are the major transcription factors for VEGF, were inhibited by delphinidin. In addition, delphinidin decreases HRE-promoter reporter gene activity, suggesting that delphinidin can suppress the transcription of HIF-1α under EGF induction, leading to a decrease in the expression of VEGF. Delphinidin specifically suppressed the phosphorylation of Akt, p70S6K, and 4EBP1, but not the phosphorylation of EGFR. Therefore, our results suggest that delphinidin may inhibit human prostate cancer progression and angiogenesis by inhibiting HIF-1α, STAT3 and VEGF gene expression.
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