TY - JOUR
T1 - Interference with endothelial cell function by JG-03-14, an agent that binds to the colchicine site on microtubules
AU - Dalyot-Herman, Nava
AU - Delgado-Lopez, Fernando
AU - Gewirtz, David A.
AU - Gupton, John T.
AU - Schwartz, Edward L.
N1 - Funding Information:
Grant support: NCI/NIH grants RO1 CA98456 and RO1 CA89352 (E.L. Schwartz).
PY - 2009/11/1
Y1 - 2009/11/1
N2 - 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.
AB - 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.
KW - Angiogenesis inhibitors
KW - JG-03-14
KW - Microtubule-binding drugs
KW - VE-cadherin
KW - Vascular-disrupting drugs
UR - http://www.scopus.com/inward/record.url?scp=70249135233&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70249135233&partnerID=8YFLogxK
U2 - 10.1016/j.bcp.2009.06.093
DO - 10.1016/j.bcp.2009.06.093
M3 - Article
C2 - 19576183
AN - SCOPUS:70249135233
SN - 0006-2952
VL - 78
SP - 1167
EP - 1177
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 9
ER -