Interference with endothelial cell function by JG-03–14, an agent that binds to the colchicine site on microtubules☆


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Abstract

Graphical abstractThe microtubule-binding agent JG-03–14 (left) disrupted the structure of adherens junctions (middle) and caused membrane blebbing (right) in endothelial cells, suggesting it may have anti-angiogenic and vascular-disrupting actions.JG-03–14, a novel tetrasubstituted pyrrole with microtubule-depolymerizing and anti-proliferative activities, was tested for its effect on endothelial cell (EC) functions in vitro. JG-03–14 was a potent inhibitor of EC vessel-like tube formation on extracellular matrix (IC50 of 40 nM) and caused the involution of established vessels, potential anti-angiogenic and vascular-disrupting activities, respectively. These actions were not due to the inhibition of EC proliferation or to the induction of apoptosis by JG-03–14. While similar effects were observed with the microtubule-depolymerizing and vascular-disrupting drug combretastatin-A4 (CoA4), JG-03–14 had a more selective effect on tube formation, relative to its cytotoxic actions, than did CoA4. Potential molecular mechanisms for JG-03–14's anti-vascular actions were explored. In contrast to the taxanes, which also have anti-vascular actions, JG-03–14 did not disrupt focal adhesion formation or block VEGF-induced phosphorylation of focal adhesion kinase. It did, however, inhibit VEGF-induced phosphorylation of VE-cadherin and reduce the association of β-catenin with VE-cadherin. It caused cell retraction, intercellular gaps, and abnormally elongated adherens junctions at low concentrations, and prominent, but reversible, plasma membrane blebbing at higher concentrations. These results suggest that JG-03–14 may affect vascular morphogenesis by disrupting the interaction of adjacent endothelial cells, possibly as a consequence of effects on VE-cadherin, β-catenin, and/or actin. They also provide the first report of anti-vascular activity for this class of compounds.

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