Vascular disrupting activity and the mechanism of action of EHT 6706, a novel anticancer tubulin polymerization inhibitor
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Tumor blood vessels are an important emerging target for anticancer therapy. Here, we characterize the in vitro antiproliferative and antiangiogenic properties of the synthetic small molecule, 7-ethoxy-4-(3,4,5-trimethoxybenzyl)isoquinolin-8-amine dihydrochloride, EHT 6706, a novel microtubule-disrupting agent that targets the colchicine-binding site to inhibit tubulin polymerization. At low nM concentrations, EHT 6706 exhibits highly potent antiproliferative activity on more than 60 human tumor cell lines, even those described as being drug resistant. EHT 6706 also shows strong efficacy as a vascular-disrupting agent, since it prevents endothelial cell tube formation and disrupts pre-established vessels, changes the permeability of endothelial cell monolayers and inhibits endothelial cell migration. Genome-wide transcriptomic analysis of EHT 6706 effects on human endothelial cells shows that the antiangiogenic activity elicits gene deregulations of antiangiogenic pathways. These findings indicate that EHT 6706 is a promising tubulin-binding compound with potentially broad clinical antitumor efficacy.
KeywordsEHT 6706 Tubulin Antiproliferative agent Vascular disrupting agent Microarray transcriptomic analysis
The authors would like to thank Ms Rachel Carton, Hélène Peillon, and Maud Rochais for technical assistance in the cell proliferation assay and microarray-based transcriptional profiling.
Conflict of Interest
The authors declare that they have no conflict of interest.
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