1.Vascular disrupting activity and the mechanism of action of EHT 6706, a novel anticancer tubulin polymerization inhibitor.
Belzacq-Casagrande AS1, Bachelot F, De Oliveira C, Coutadeur S, Maurier-Mahé F, Throo E, Chauvignac C, Pognante L, Petibon A, Taverne T, Beausoleil E, Leblond B, Pando MP, Désiré L. Invest New Drugs. 2013 Apr;31(2):304-19. doi: 10.1007/s10637-012-9858-y. Epub 2012 Aug 10.
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.
2.Assessment of the novel tubulin-binding agent EHT 6706 in combination with ionizing radiation or chemotherapy.
Clémenson C1, Chargari C, Désiré L, Casagrande AS, Bourhis J, Deutsch E. Invest New Drugs. 2012 Dec;30(6):2173-86. doi: 10.1007/s10637-011-9785-3. Epub 2012 Jan 14.
The potential of EHT 6706, a novel tubulin-binding agent, was investigated in combination with ionizing radiation (IR) and with conventional cytotoxic chemotherapy agents. Cell proliferation, cell cycle, apoptosis and clonogenic assays were performed in five human cancer cell lines: H460 (non small cell lung carcinoma, NSCLC), HCT116 and HCT116 p53-/- (colorectal cancer), MDA-MB-231 (breast cancer), and MiaPaca2 cells (pancreatic cancer). The drug inhibited cell proliferation in all cell lines. This effect was associated with G2/M arrest and activation of apoptosis in a dose-dependent manner. The drug was then tested in combination with chemotherapy and IR in vitro. Effects on proliferation and clonogenic survival were analyzed. EHT 6706 treatment inhibited clonogenic survival synergistically with IR in H460 and MiaPaca2 cell lines. In the remaining cell lines, the effects of EHT 6706 and IR were additive. For H460 and MiaPaca2 cell lines, the highest effect was seen when cells were exposed for 20 h to EHT 6706 before being irradiated.