Abstract 1812: In vitro and in vivo antiangiogenic activity of desacetylvinblastine monohydrazide through inhibition of VEGFR2 and Axl pathways

Abstract

Abstract Background and Objective: Tumor angiogenesis process is regulated by multiple proangiogenic pathways, such as VEGFR2 and Axl. Inhibition of VEGF/VEGFR2 signaling alone fails to block tumor neovascularization, and anti-VEGF resistance is often associated with Axl. Hence, discovery of novel agents that target multiple angiogenesis pathways is in demand. Here, we describe desacetylvinblastine monohydrazide (DAVLBH), a derivative of vinblastine (VLB) that exerts a more potent antiangiogenic effect than VLB in vitro and in vivo by inhibiting VEGFR2 and Axl pathways. Methods: The antiangiogenic effects of DAVLBH were studied in vitro (proliferation, migration, and tube formation assays) and ex vivo (aortic ring assay). In vitro pericyte migration to endothelial tubes was assessed using a three-dimensional co-culture assay. In vivo assay was performed in HeLa xenograft model. Western blotting, immunohistochemical and immunofluorescence assays were conducted to evaluate the key proteins of the VEGF/VEGFR2 and Gas6/Axl pathways. Results: DAVLBH (1 nM) inhibited VEGF- and Gas6-induced angiogenesis in vitro. At 0.75 μmol/kg, DAVLBH significantly delayed tumor growth and reduced vascular density in vivo, which was associated with the inactivation of VEGF/VEGFR2 and Gas6/Axl signalling pathways. DAVLBH blocked the compensatory upregulation of Axl in response to bevacizumab treatment in HUVECs. DAVLBH also suppressed the recruitment of pericytes to well-established endothelial tubes and reduced pericyte coverage in vivo, which was accompanied by inhibition of Axl. Conclusions: DAVLBH potently inhibited angiogenesis-mediated tumor growth by blocking the activation of VEGF/VEGFR2 and Gas6/Axl pathways. DAVLBH might serve as a promising antiangiogenic agent for cancer therapy. Note: This abstract was not presented at the meeting. Citation Format: Minfeng Chen, Xueping Lei, Qiulin Nie, Jianyang Hu, Zhenjian Zhuo, Anita Yiu, Heru Chen, Nanhui Xu, Maohua Huang, Kaihe Ye, Liangliang Bai, Wencai Ye, Dong-Mei Zhang. In vitro and in vivo antiangiogenic activity of desacetylvinblastine monohydrazide through inhibition of VEGFR2 and Axl pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1812. doi:10.1158/1538-7445.AM2017-1812