title: An andrographolide derivative AGP-26b exhibiting anti-angiogenic activity in HUVECs and zebrafish via blocking the VEGFA/VEGFR2 signaling pathway.
abstract: The aim of this study is to investigate the anti-angiogenic properties of andrographolide derivatives AGP-26a (12β-isomer), AGP-26b (12α-isomer) and AGP-26 (4 : 1 mixture of AGP-26a and AGP-26b) in vitro and in vivo. Human umbilical vein endothelial cells (HUVECs) and the Tg(fli-1a:EGFP)y1 zebrafish model were used to identify the anti-angiogenic activities of AGP-26, AGP-26a, and AGP-26b. The results showed that AGP-26b exhibits the strongest inhibitory effect on VEGF-induced proliferation, migration, invasion and formation of capillary-like structures in HUVECs. In the zebrafish model, AGP-26b also showed the strongest suppression of ISV development. Further studies showed that the underlying mechanism of the anti-angiogenic effects of AGP-26b was at least partly through the blockage of the VEGF/VEGFR2 signaling pathways. AGP-26b blocked the activation of VEGFR2. Consequently, the phosphorylation of key intracellular proangiogenic kinases such as Src family kinase (Src), focal adhesion kinase (Fak), mitogen-activated protein kinase (MEK), extracellular signal-regulated kinase 1 and 2 (Erk1/2) and Akt induced by VEGF was suppressed by treatment with AGP-26b. Moreover, AGP-26b reduced the protein expression of matrix metalloproteinases (MMP-9 but not MMP-2) in HUVECs. These results provide evidence supporting the notion that AGP-26b may serve as a potential therapeutic anti-angiogenic agent.
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China. simonlee@umac.mo maghoi@umac.mo.
authors.forename: Bin
authors.initials: B
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, China. gczhou@njtech.edu.cn.
authors.forename: Yuran
authors.initials: Y
authors.lastname: Peng
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China. simonlee@umac.mo maghoi@umac.mo and Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China. gphleung@hku.hk.
authors.forename: Jingjing
authors.identifier: http://orcid.org/0000-0003-3636-0537
authors.initials: J
authors.lastname: Li
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China. simonlee@umac.mo maghoi@umac.mo.
authors.forename: Shang
authors.initials: S
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, China. gczhou@njtech.edu.cn.
authors.forename: Yicheng
authors.initials: Y
authors.lastname: Sun
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, China. gczhou@njtech.edu.cn.
authors.forename: Decai
authors.initials: D
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China. simonlee@umac.mo maghoi@umac.mo.
authors.forename: Binrui
authors.initials: B
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China. simonlee@umac.mo maghoi@umac.mo.
authors.forename: Judy Yuet-Wa
authors.initials: JY
authors.lastname: Chan
authors.affiliation: Rongene Pharma Co., Ltd, International Business Incubator, Guangzhou Science Town, Guangdong 510663, China.
authors.forename: Huidong
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Pharmacology and Pharmacy, The University of Hong Kong, Hong Kong, China. gphleung@hku.hk.
authors.forename: George Pak-Heng
authors.initials: GP
authors.lastname: Leung
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China. simonlee@umac.mo maghoi@umac.mo.
authors.forename: Maggie Pui-Man
authors.initials: MP
authors.lastname: Hoi
authors.affiliation: School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing, China. gczhou@njtech.edu.cn.
authors.forename: Guo-Chun
authors.identifier: http://orcid.org/0000-0003-3145-223X
authors.initials: GC
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Quality Research in Chinese Medicine and Institute of Chinese Medical Sciences, University of Macau, Macao, China. simonlee@umac.mo maghoi@umac.mo.
authors.forename: Simon Ming-Yuen
authors.initials: SM
authors.lastname: Lee
mesh_terms: D020533:Angiogenesis Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D015415:Biomarkers; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004224:Diterpenes / Q000737:chemistry / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008968:Molecular Conformation; D015394:Molecular Structure; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D020533:Angiogenesis Inhibitors; D015415:Biomarkers; D004224:Diterpenes; D042461:Vascular Endothelial Growth Factor A; C030419:andrographolide; D040301:Vascular Endothelial Growth Factor Receptor-2