Abstract 5309: Antivascular activities of novel tubulin binding agent BPR0L075

Abstract

Abstract BPR0L075, 6-methoxy-3-(3′,4′,5′-trimethoxy-benzoyl)-1H-indole, is a novel tubulin binding agent that inhibits tubulin polymerization through binding to the colchicine binding site. We evaluated the antiangiogenic and antivascular properties of BPR0L075 in vitro and in vivo. Human umbilical vein endothelial cells (HUVEC) were treated with BPR0L075, and effects on endothelial cell morphology, migration, and inhibition of tube formation on extracellular matrix were determined in vitro. The BPR0L075 induced inhibition of neovasculature formation was evaluated by rat aortic ring ex vivo assay. Using a validated dynamic bioluminescence imaging method, we assessed acute vascular disrupting effects of BPR0L075 on luciferase-expressing MCF7 human breast mammary fat pad xenografts. The disruption of tumor vascular perfusion after BPR0L075 treatment was confirmed using the perfusion marker Hoechst 33342 and CD31 staining by fluorescence microscopy. Exposure of BPR0L075 (10 nM) inhibits the endothelial cell migration (within 24 hr) and tube formation on Matrigel (3-6 hr). BPR0L075 treatment also blocked angiogenesis in rat aortic ring assay. A single dose of BPR0L075 induced rapid temporary tumor vascular shutdown evidenced by rapid and reproducible decrease of light emission from luciferase-expressing breast tumors. Histological staining using Hoechst dye and anti-CD31 antibody revealed a time-dependent reduction of tumor perfusion after 2, 4, and 24h of BPR0L075 treatment. Taken together, our results show that the novel tubulin-binding agent BPR0L075 alters endothelial cell tubule formation, prevents cell migration, and inhibits the formation of neovessels. These properties of BPR0L075 may ultimately contribute to the loss of tumor blood vessel integrity causing rapid tumor vascular shutdown in experimental breast tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5309. doi:10.1158/1538-7445.AM2011-5309