title: An indirubin derivative, E804, exhibits potent angiosuppressive activity.
abstract: Angiogenesis, the development of neovessels from pre-existing vessels, is obligatory for solid tumors survival, growth, invasion, and metastasis. Many anti-angiogenic agents are small molecules originated from natural sources. Recently, angiosuppressive effects of indirubin and its derivatives, the active components in indigo-producing herbs, have been shown to possess anti-viral and anti-inflammatory potentials. In this study, we identified another indirubin derivative, indirubin-3'-(2,3 dihydroxypropyl)-oximether (E804), could exhibit potent angiosuppressive effects. In vitro study showed that E804 could significantly inhibit human umbilical vein endothelial cells proliferation, migration, and tube formation in a concentration-dependent manner (0.4-40 μM); at the concentration of 1 μmol or above, angiosuppressive potency of E804 was found to be more significant than indirubin-3'-oxime. Using in vivo Matrigel plug model and directed-in vivo-angiogenesis-assay (DIVAA), E804 was shown more effective to attenuate the VEGF/bFGF-induced neovessel formation. The hemoglobin content and the invaded endothelial cells in the implants were also greatly reduced. Results from the aortic ring assay indicated E804 (4 μM) could completely suppress ex vivo sprouting of endothelial cells from the rat aorta fragments; with concomitant reduction of gelatinolytic activities of matrix metalloproteinase-2 and -9. E804 also concentration-dependently (0.04-10 μM) inhibited the subintestinal vessels formation in zebrafish embryos. This study provides the first evidence that E804, a novel indirubin derivative, could more effectively inhibit angiogenesis. With the improved anti-angiogenic potency when compared with indirubin-3'oxime, E804 would be a new potential candidate in the treatment of angiogenesis-dependent diseases.
authors.affiliation: Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong, China.
authors.forename: Yuk-Kit
authors.initials: YK
authors.lastname: Chan
authors.forename: Hoi-Hin
authors.initials: HH
authors.lastname: Kwok
authors.forename: Lai-Sheung
authors.initials: LS
authors.lastname: Chan
authors.forename: Kelvin Sze-Yin
authors.initials: KS
authors.lastname: Leung
authors.forename: Jue
authors.initials: J
authors.lastname: Shi
authors.forename: Nai-Ki
authors.initials: NK
authors.lastname: Mak
authors.forename: Ricky Ngok-Shun
authors.initials: RN
authors.lastname: Wong
authors.forename: Patrick Ying-Kit
authors.initials: PY
authors.lastname: Yue
mesh_terms: D000818:Animals; D001011:Aorta / Q000166:cytology; D002478:Cells, Cultured; D004625:Embryo, Nonmammalian / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D015394:Molecular Structure; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D010091:Oximes; D051381:Rats; D015027:Zebrafish
chemical_list: C509867:Indirubin E804; D007211:Indoles; D010091:Oximes; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9