title: ZLM-7 exhibits anti-angiogenic effects via impaired endothelial cell function and blockade of VEGF/VEGFR-2 signaling.
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.
authors.affiliation: Molecular Biology Research Center, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
authors.forename: Min
authors.initials: M
authors.lastname: Su
authors.affiliation: Molecular Biology Research Center, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
authors.forename: Jingjia
authors.initials: J
authors.lastname: Huang
authors.affiliation: Molecular Biology Research Center, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
authors.forename: Jijia
authors.initials: J
authors.lastname: Li
authors.affiliation: Molecular Biology Research Center, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
authors.forename: Xiyuan
authors.initials: X
authors.lastname: Qin
authors.affiliation: Molecular Biology Research Center, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
authors.forename: Xiaoning
authors.initials: X
authors.lastname: Tang
authors.affiliation: Molecular Biology Research Center, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Jin
authors.affiliation: Molecular Biology Research Center, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
authors.forename: Shali
authors.initials: S
authors.lastname: Chen
authors.affiliation: Molecular Biology Research Center, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
authors.forename: Chuanming
authors.initials: C
authors.lastname: Jiang
authors.affiliation: Molecular Biology Research Center, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
authors.forename: Zizheng
authors.initials: Z
authors.lastname: Zou
authors.affiliation: Molecular Biology Research Center, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
authors.forename: Kunjian
authors.initials: K
authors.lastname: Peng
authors.affiliation: Molecular Biology Research Center, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Nuruzzaman
authors.affiliation: Molecular Biology Research Center, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
authors.forename: Jianting
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Molecular Biology Research Center, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
authors.forename: Junli
authors.initials: J
authors.lastname: Luo
authors.affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Central South University, Changsha 410006, China.
authors.forename: Suyou
authors.initials: S
authors.lastname: Liu
authors.affiliation: Molecular Biology Research Center, State Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha 410078, China.
authors.forename: Zhiyong
authors.initials: Z
authors.lastname: Luo
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010766:Phosphorylation; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013440:Sulfides / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D000814:Aniline Compounds; D000972:Antineoplastic Agents, Phytogenic; D013440:Sulfides; D042461:Vascular Endothelial Growth Factor A; C000613742:ZLM-7 compound; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: VEGF; VEGFR2; ZLM-7; angiogenesis; microtubule