ZLM-7 exhibits anti-angiogenic effects via impaired endothelial cell function and blockade of VEGF/VEGFR-2 signaling.

// Min Su 1 , Jingjia Huang 1 , Jijia Li 1 , Xiyuan Qin 1 , Xiaoning Tang 1 , Fang Jin 1 , Shali Chen 1 , Chuanming Jiang 1 , Zizheng Zou 1 , Kunjian Peng 1 , Mohammed Nuruzzaman 1 , Jianting Zhang 1 , Junli Luo 1 , Suyou Liu 2 , Zhiyong Luo 1 1 Molecular Biology Research Center, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China 2 Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Central South University, Changsha 410006, China Correspondence to: Zhiyong Luo, e-mail: luozhiyong@csu.edu.cn Suyou Liu, e-mail: suyouliu@csu.edu.cn Keywords: angiogenesis, ZLM-7, microtubule, VEGF, VEGFR2 Received: October 21, 2015    Accepted: February 05, 2016    Published: March 08, 2016 ABSTRACT Inhibition of angiogenesis is a promising therapeutic strategy against cancer. In this study, we reported that ZLM-7, a combretastain A-4 (CA-4) derivative, exhibited anti-angiogenic activity in vitro and in vivo . In vitro , ZLM-7 induced microtubule cytoskeletal disassembly. It decreased VEGF-induced proliferation, migration, invasion and tube formation in endothelial cells, which are critical steps in angiogenesis. In vivo , ZLM-7 significantly inhibited neovascularization in a chicken chorioallantoic membrane (CAM) model and reduced the microvessel density in tumor tissues of MCF-7 xenograft mouse model. ZLM-7 also displayed comparable antiangiogenic and anti-tumor activities associated with the lead compound CA-4, but exhibited lower toxicity compared with CA-4. The anti-angiogenic effect of ZLM-7 was exerted via blockade of VEGF/VEGFR-2 signaling. ZLM-7 treatment suppressed the expression and secretion of VEGF in endothelial cells and MCF-7 cells under hypoxia. Further, ZLM-7 suppressed the VEGF-induced phosphorylation of VEGFR-2 and its downstream signaling mediators including activated AKT, MEK and ERK in endothelial cells. Overall, these results demonstrate that ZLM-7 exhibits anti-angiogenic activities by impairing endothelial cell function and blocking VEGF/VEGFR-2 signaling, suggesting that ZLM-7 might be a potential angiogenesis inhibitor.