Abstract
This study aimed to investigate the effect of Ru (Rut) on angiogenesis, and the underlying regulation mechanism of signal transduction. 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, adhesion inhibition experiment, migration inhibition experiment, and chick embryo chorioallantoic membrane (CAM) assays were performed on models of angiogenesis. The potential targets of rutaecarpine (Ru) were reverse screened with Discovery Studio 2017. The interaction between the compound and target were detected by surface plasmon resonance (SPR), enzyme-activity experiment, and Western blot assay. The obtained results confirmed that Ru exhibited modest inhibitory activity against human umbilical vein endothelial cells (HUVECs) (IC50 =16.54 ± 2.4 μM) and remarkable inhibitive effect against the migration and adhesion of HUVECs, as well as significant anti-angiogenesis activities in the CAM assay. The possible targets of vascular endothelial growth factor receptor 2 (VEGFR2) were identified by computer-aided simulation. Results showed a good binding relationship between the ligand and target through molecular docking, and this relationship was confirmed by SPR analysis. Furthermore, enzyme-activity experiment and western blot assay showed that Ru remarkably inhibited the activity of VEGFR2 and blocked the VEGFR2-mediated Akt/ (mTOR)/p70s6k signaling pathway in vitro. Ru can be a potential drug candidate for cancer prevention and cancer therapy.
Highlights
Malignant tumors are some of the major diseases that seriously affect human health and threaten human life
We identified the possible targets for vascular endothelial growth factor receptor 2 (VEGFR2) by computer-aided simulation, and we found a good binding relationship between Ru and VEGFR2 through molecular docking and molecular dynamics simulation
VEGFR2 is expressed on the surface of most blood endothelial cells
Summary
Malignant tumors are some of the major diseases that seriously affect human health and threaten human life. Malignant tumors have become the second highest cause of human death and they are difficult to treat [1]. Angiogenesis is a key process in tumor growth and metastasis, and the largest tumor can grow to 1–2 mm without angiogenesis. A complete process of angiogenesis involves the proliferation, migration, and differentiation of endothelial cells. A large number of discovered angiogenesis inhibitors target endothelial cells [5,6,7]. In pathological and physiological angiogenesis, vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) play crucial roles. The signaling cascade mediated by VEGF/VEGFR2 regulates the proliferation, migration, survival, and permeability of vascular
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