title: In vitro and in vivo antiangiogenic activity of desacetylvinblastine monohydrazide through inhibition of VEGFR2 and Axl pathways.
abstract: Tumor angiogenic process is regulated by multiple proangiogenic pathways, such as vascular endothelial growth factor receptor 2 (VEGFR2) and Axl receptor tyrosine kinase (Axl). Axl is one of many important factors involved in anti-VEGF resistance. Inhibition of VEGF/VEGFR2 signaling pathway alone fails to block tumor neovascularization. Therefore, discovery of novel agents targeting multiple angiogenesis pathways is in demand. Desacetylvinblastine monohydrazide (DAVLBH), a derivative of vinblastine (VLB), has been reported exhibit an anticancer activity via its cytotoxic effect. However, little attention has been paid to the antiangiogenic properties of DAVLBH. Here, we firstly reported that DAVLBH exerted a more potent antiangiogenic effect than VLB in vitro and in vivo, which was associated with inactivation of VEGF/VEGFR2 and Gas6/Axl signaling pathways. We found that DAVLBH inhibited VEGF- and Gas6-induced HUVECs proliferation, migration, tube formation and vessel sprouts formation in vitro and ex vivo. It significantly inhibited in vivo tumor angiogenesis and tumor growth in HeLa xenografts. It also inhibited Gas6-induced pericytes recruitment to endothelial tubes accompanied with a decrease in expression and activation of Axl. Besides, it could block the compensatory up-regulating expression and activation of Axl in response to bevacizumab treatment in HUVECs. Taken together, our results suggest that DAVLBH potently inhibits angiogenesis-mediated tumor growth through blockage of the activation of VEGF/VEGFR2 and Gas6/Axl pathways and it might serve as a promising antiangiogenic agent for the cancer therapy.
authors.affiliation: College of Pharmacy, Jinan University Guangzhou 510632, China.
authors.forename: Xueping
authors.initials: X
authors.lastname: Lei
authors.affiliation: College of Pharmacy, Jinan University Guangzhou 510632, China.
authors.forename: Minfeng
authors.initials: M
authors.lastname: Chen
authors.affiliation: College of Pharmacy, Jinan University Guangzhou 510632, China.
authors.forename: Qiulin
authors.initials: Q
authors.lastname: Nie
authors.affiliation: College of Pharmacy, Jinan University Guangzhou 510632, China.
authors.forename: Jianyang
authors.initials: J
authors.lastname: Hu
authors.affiliation: College of Pharmacy, Jinan University Guangzhou 510632, China.
authors.forename: Zhenjian
authors.initials: Z
authors.lastname: Zhuo
authors.affiliation: School of Life Sciences, The Chinese University of Hong Kong Hong Kong, China.
authors.forename: Anita
authors.initials: A
authors.lastname: Yiu
authors.affiliation: College of Pharmacy, Jinan University Guangzhou 510632, China.
authors.forename: Heru
authors.initials: H
authors.lastname: Chen
authors.affiliation: College of Pharmacy, Jinan University Guangzhou 510632, China.
authors.forename: Nanhui
authors.initials: N
authors.lastname: Xu
authors.affiliation: College of Pharmacy, Jinan University Guangzhou 510632, China.
authors.forename: Maohua
authors.initials: M
authors.lastname: Huang
authors.affiliation: College of Pharmacy, Jinan University Guangzhou 510632, China.
authors.forename: Kaihe
authors.initials: K
authors.lastname: Ye
authors.affiliation: College of Pharmacy, Jinan University Guangzhou 510632, China.
authors.forename: Liangliang
authors.initials: L
authors.lastname: Bai
authors.affiliation: College of Pharmacy, Jinan University Guangzhou 510632, China.
authors.forename: Wencai
authors.initials: W
authors.lastname: Ye
authors.affiliation: College of Pharmacy, Jinan University Guangzhou 510632, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Zhang
keywords: Axl receptor tyrosine kinase (Axl); Desacetylvinblastine monohydrazide (DAVLBH); antiangiogenesis; pericytes recruitment; vascular endothelial growth factor receptor 2 (VEGFR2)