title: Ellagic acid, a phenolic compound, exerts anti-angiogenesis effects via VEGFR-2 signaling pathway in breast cancer.
abstract: Anti-angiogenesis targeting VEGFR-2 has been considered as an important strategy for cancer therapy. Ellagic acid is a naturally existing polyphenol widely found in fruits and vegetables. It was reported that ellagic acid interfered with some angiogenesis-dependent pathologies. Yet the mechanisms involved were not fully understood. Thus, we analyzed its anti-angiogenesis effects and mechanisms on human breast cancer utilizing in-vitro and in-vivo methodologies. The in-silico analysis was also carried out to further analyze the structure-based interaction between ellagic acid and VEGFR-2. We found that ellagic acid significantly inhibited a series of VEGF-induced angiogenesis processes including proliferation, migration, and tube formation of endothelial cells. Besides, it directly inhibited VEGFR-2 tyrosine kinase activity and its downstream signaling pathways including MAPK and PI3K/Akt in endothelial cells. Ellagic acid also obviously inhibited neo-vessel formation in chick chorioallantoic membrane and sprouts formation of chicken aorta. Breast cancer xenografts study also revealed that ellagic acid significantly inhibited MDA-MB-231 cancer growth and P-VEGFR2 expression. Molecular docking simulation indicated that ellagic acid could form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR-2 kinase unit. Taken together, ellagic acid could exert anti-angiogenesis effects via VEGFR-2 signaling pathway in breast cancer.
authors.affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Estates Building, 10 Sassoon Road, Hong Kong, China.
authors.forename: Neng
authors.initials: N
authors.lastname: Wang
authors.forename: Zhi-Yu
authors.initials: ZY
authors.lastname: Wang
authors.forename: Sui-Lin
authors.initials: SL
authors.lastname: Mo
authors.forename: Tjing Yung
authors.initials: TY
authors.lastname: Loo
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Wang
authors.forename: Hai-Bin
authors.initials: HB
authors.lastname: Luo
authors.forename: De-Po
authors.initials: DP
authors.lastname: Yang
authors.forename: Yu-Ling
authors.initials: YL
authors.lastname: Chen
authors.forename: Jian-Gang
authors.initials: JG
authors.lastname: Shen
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Chen
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics; D001665:Binding Sites; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004610:Ellagic Acid / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D051379:Mice; D062105:Molecular Docking Simulation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000737:chemistry / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D042461:Vascular Endothelial Growth Factor A; D004610:Ellagic Acid; D000255:Adenosine Triphosphate; D040301:Vascular Endothelial Growth Factor Receptor-2