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

Dalyot-Herman, Nava; Delgado-Lopez, Fernando; Gewirtz, David A.; Gupton, John T.; Schwartz, Edward L.


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 P-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, P-catenin, and/or actin. They also provide the first report of anti-vascular activity for this class of compounds. (C) 2009 Elsevier Inc. All rights reserved.

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Título según WOS: ID WOS:000270483000009 Not found in local WOS DB
Volumen: 78
Número: 9
Fecha de publicación: 2009
Página de inicio: 1167
Página final: 1177


Notas: ISI