title: K20E, an oxidative-coupling compound of methyl caffeate, exhibits anti-angiogenic activities through down-regulations of VEGF and VEGF receptor-2.
abstract: Anti-angiogenesis is one of the most popular clinical interventions for cancer chemotherapy. A series of synthesized derivative of methyl caffeate were used to evaluate the anti-angiogenic activity and to investigate possible pharmacological mechanisms in the present study. The most potent anti-angiogenic compound was evaluated in the experiments of murine allograft tumor model and Matrigel plug assay as well as cell models in the human umbilical vascular endothelial cells (HUVECs) and the LLC1 lung cancer cells. Our results suggested that K20E suppressed the tumor growth in the allograft tumor model and exhibited anti-angiogenic activity in Matrigel plug assay. Besides, HUVEC viability was found to be significantly reduced by arresting cell cycle at G2/M phase and apoptosis. Cell migration, invasion, and tube formation of the HUVECs were also markedly suppressed by K20E treatment. K20E largely down-regulated the intracellular and secreted vascular endothelial growth factor (VEGF) in the LLC1 cancer cells. Besides, VEGF receptor-2 (VEGFR-2) and its downstream signaling cascades (AKT-mTOR and MEK1/2-ERK1/2) as well as gelatinases were all evidently reduced in the HUVECs treated with K20E. Inversely, K20E can up-regulate the expression levels of p53 and p21 proteins in the HUVECs. Based on these results, our study suggested that K20E possessed inhibiting angiogenesis through regulation of VEGF/VEGFR-2 and its downstream signaling cascades in the vascular endothelial cells (VECs).
authors.affiliation: Department of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Chun-Hsu
authors.initials: CH
authors.lastname: Pan
authors.affiliation: School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
authors.forename: Wen-Hsin
authors.initials: WH
authors.lastname: Lin
authors.affiliation: School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
authors.forename: Yi-Chung
authors.initials: YC
authors.lastname: Chien
authors.affiliation: School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
authors.forename: Fon-Chang
authors.initials: FC
authors.lastname: Liu
authors.affiliation: School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
authors.forename: Ming-Jyh
authors.initials: MJ
authors.lastname: Sheu
authors.affiliation: Tsuzuki Institute for Traditional Medicine, China Medical University, Taichung 40402, Taiwan; Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung 40402, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan. Electronic address: kuoyh@mail.cmu.edu.tw.
authors.forename: Yueh-Hsiung
authors.initials: YH
authors.lastname: Kuo
authors.affiliation: Department of Pharmacy, Taipei Medical University, Taipei 11031, Taiwan; School of Pharmacy, China Medical University, Taichung 40402, Taiwan; Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan. Electronic address: chhswu@tmu.edu.tw.
authors.forename: Chieh-Hsi
authors.initials: CH
authors.lastname: Wu
mesh_terms: D000179:Acrylates / Q000494:pharmacology*; D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D002109:Caffeic Acids / Q000494:pharmacology*; D018827:Carcinoma, Lewis Lung / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis*
chemical_list: C000596171:4-(7-acetoxy-5-(3-methoxy-3-oxoprop-1-enyl)-3-(methoxycarbonyl)-2,3-(dihydrobenzofuran-2-yl)-1,2-phenylene diacetate; D000179:Acrylates; D020533:Angiogenesis Inhibitors; D001572:Benzofurans; D002109:Caffeic Acids; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; C042405:methyl caffeate; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Angiogenesis; Human umbilical vein endothelial cells; K20E; Methyl caffeate; VEGF receptor-2; Vascular endothelial growth factor