The anti-angiogenic effect and novel mechanisms of action of Combretastatin A-4

• Published in: Scientific reports Vol. 6; no. 1; p. 28139
• Main Authors: Su, Min, Huang, Jingjia, Liu, Suyou, Xiao, Yuhang, Qin, Xiyuan, Liu, Jia, Pi, Chaoqiong, Luo, Tiao, Li, Jijia, Chen, Xianghui, Luo, Zhiyong
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.06.2016; Nature Publishing Group
• Subjects: 631/337; 692/308; 82/80; 96/1; 96/98; Angiogenesis; Animals; Antineoplastic Agents, Phytogenic - pharmacology; Apoptosis - drug effects; Blood vessels; Breast Neoplasms - blood supply; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell adhesion & migration; Cell cycle; Cell growth; Cell Movement - drug effects; Cell Proliferation - drug effects; Chickens; Chorioallantoic Membrane - drug effects; Chorioallantoic Membrane - metabolism; Chorioallantoic Membrane - pathology; Cytotoxicity; Female; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humanities and Social Sciences; Humans; Kinases; Mice; Mice, Inbred BALB C; Mice, Nude; multidisciplinary; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Science; Stilbenes - pharmacology; Tumor Cells, Cultured; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Xenograft Model Antitumor Assays
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep28139

Combretastatin A-4 (CA4) is the lead compound of a relatively new class of vascular disrupting agents that target existing tumor blood vessels. Recent studies showed the CA4 might inhibit angiogenesis. However, the underlying molecular mechanisms by which CA4 exerts its anti-angiogenic effects are not fully understood. In this study, we revealed that CA4 inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration and capillary-like tube formation of human umbilical vascular endothelial cells (HUVECs). In in vivo assay, CA4 suppressed neovascularization in chicken chorioallantoic membrane (CAM) model and decreased the microvessel density in tumor tissues of a breast cancer MCF-7 xenograft mouse model. In addition, CA4 decreased the expression level and secretion of VEGF both in MCF-7 cells and HUVECs under hypoxia, as well as the activation of VEGFR-2 and its downstream signaling mediators following VEGF stimulation in HUVECs. Moreover, VEGF and VEGFR-2 expression in tumor tissues of the mouse xenograft model were down-regulated following CA4 treatment. Taken together, results from the current work provide clear evidence that CA4 functions in endothelial cell system to inhibit angiogenesis, at least in part, by attenuating VEGF/VEGFR-2 signaling pathway.