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TR-644 a novel potent tubulin binding agent induces impairment of endothelial cells function and inhibits angiogenesis

By E. Porcu`, G. Viola, R. Bortolozzi, L. Persano, S. Mitola, R, Ronca, M. Presta, R. Romagnoli, P. G. Baraldi and G. Basso

Abstract

TR-644 is a novel combretastatin A-4 (CA-4) analogue endowed with potent microtubule depolymerizing activity superior to that of the lead compound and it also has high affinity to colchicines binding site of tubulin. We tested TR-644 anti-angiogenic effects in human umbilical endothelial cells (HUVEC). It showed no significant effects on the growth of HUVEC cells at concentrations below 1,000 nM, but at much lower concentrations (10–100 nM) it induced inhibition of capillary tube formation, inhibition of endothelial cell migration and affected endothelial cell morphology as demonstrated by the disruption of the microtubule network. TR-644 also increased permeability of HUVEC cells in a time dependent manner. The molecular mechanism for the anti-vascular activity of TR- 644 was investigated in detail. TR-644 caused G2/M arrest in endothelial cells and this effect correlated with downregulation of the expression of Cdc25C and Cdc2Tyr15. Moreover TR-644 inhibited VEGF-induced phosphorylation of VE-cadherin but did not prevent the VEGF-induced phosphorylation of FAK. In chick chorioallantoic membrane in vivo assay, TR-644 (0.1–1.0 pmol/egg) efficiently counteracted the strong angiogenic response induced by FGF. Also CA-4, used as reference compound, caused an antagonistic effect, but in contrast, it induced per se, a remarkable angiogenic response probably due to an inflammatory reaction in the site of treatment. In a mice allogenic tumor model, immunohistochemical staining of tumors with anti-CD31 antibody showed that TR-644 significantly reduced the number of vessel, after 24 h from the administration of a single dose (30 mg/Kg)

Year: 2013
OAI identifier: oai:iris.unife.it:11392/1826712
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