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

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

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1167-1177
Number of pages11
JournalBiochemical Pharmacology
Volume78
Issue number9
DOIs
StatePublished - Nov 1 2009

Keywords

  • Angiogenesis inhibitors
  • JG-03-14
  • Microtubule-binding drugs
  • VE-cadherin
  • Vascular-disrupting drugs

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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