title: Delphinidin inhibits angiogenesis through the suppression of HIF-1α 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)‑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.
authors.affiliation: Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea.
authors.forename: Mun-Hyeon
authors.initials: MH
authors.lastname: Kim
authors.affiliation: Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea.
authors.forename: Yun-Jeong
authors.initials: YJ
authors.lastname: Jeong
authors.affiliation: Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea.
authors.forename: Hyun-Ji
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu 701-300, Republic of Korea.
authors.forename: Hyang-Sook
authors.initials: HS
authors.lastname: Hoe
authors.affiliation: Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea.
authors.forename: Kwan-Kyu
authors.initials: KK
authors.lastname: Park
authors.affiliation: Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea.
authors.forename: Yoon-Yub
authors.initials: YY
authors.lastname: Park
authors.affiliation: Department of Biochemistry, College of Oriental Medicine, Dongeui University, Busan 614-052, Republic of Korea.
authors.forename: Yung Hyun
authors.initials: YH
authors.lastname: Choi
authors.affiliation: Department of Biological Sciences, Sungkyunkwan University, Suwon, Gyeonggi 440-746, Republic of Korea.
authors.forename: Cheorl-Ho
authors.initials: CH
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 701-947, Republic of Korea.
authors.forename: Hyeun-Wook
authors.initials: HW
authors.lastname: Chang
authors.affiliation: Department of Clinical Pathology, Sorabol College, Gyeongju, Gyeongbuk 780-711, Republic of Korea.
authors.forename: Young-Ja
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Department of Biotechnology, Catholic University of Daegu, Gyeongsan, Gyeongbuk 712-702, Republic of Korea.
authors.forename: Il-Kyung
authors.initials: IK
authors.lastname: Chung
authors.affiliation: Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea.
authors.forename: Young-Chae
authors.initials: YC
authors.lastname: Chang
mesh_terms: D020533:Angiogenesis Inhibitors; D000818:Animals; D000872:Anthocyanins / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000872:Anthocyanins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; C497442:HIF1A protein, human; C467484:VEGFA protein, human; C546842:MTOR protein, human; C017185:delphinidin