Interference with endothelial cell function by JG-03-14, an agent that binds to the colchicine site on microtubules.
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 (IC(50) of 40nM) 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 beta-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, beta-catenin, and/or actin. They also provide the first report of anti-vascular activity for this class of compounds.
Dalyot-Herman
Nava
N
Department of Oncology, Albert Einstein College of Medicine, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467, USA.
Delgado-Lopez
Fernando
F
Gewirtz
David A
DA
Gupton
John T
JT
Schwartz
Edward L
EL
D001665:Binding Sites; D002478:Cells, Cultured; D003078:Colchicine / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D008870:Microtubules / Q000378:metabolism*; D010766:Phosphorylation; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology*; D014945:Wound Healing
C521391:3,5-dibromo-4-(3,4-dimethoxyphenyl)-1H-pyrrole-2-carboxylic acid ethyl ester; D011758:Pyrroles; D051416:Focal Adhesion Protein-Tyrosine Kinases; D003078:Colchicine