An indirubin derivative, E804, exhibits potent angiosuppressive activity

Yuk-Kit Chan, Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong
Hoi-Hin Kwok, Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong
Lai-Sheung Chan, Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong
Kelvin Sze-Ying Leung, Department of Chemistry, Faculty of Science, Hong Kong Baptist University, Hong Kong
Jue Shi, Department of Physics, Faculty of Science, Hong Kong Baptist University
Nai-Ki Mak, Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong
Ricky Ngok-Shun Wong, Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong
Patrick-Ying Kit Yue, Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong

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.