Evaluation of original dual thromboxane A2 modulators as antiangiogenic agents

Xavier de Leval, Thibaut Dassesse, Jean-Michel Dogné, David Waltregny, Akeila Bellahcène, Valérie Benoit, Bernard Pirotte, Vincent Castronovo

Research output: Contribution to journalArticlepeer-review

Abstract

Angiogenesis is a promising target for the therapy of several diseases including cancer. This study was undertaken to characterize the antiangiogenic properties of a series of original dual thromboxane A(2) (TXA(2)) inhibitors derived from torasemide, a marketed loop diuretic with TXA(2) antagonistic properties, by evaluating their effects on human endothelial cell migration, adhesion, and viability in vitro, as well as in the ex vivo rat aortic ring assay. All drugs tested exhibited a marked affinity toward human platelet TXA(2) receptor, significantly prevented platelet aggregation induced by U-46,619, a stable TXA(2) receptor agonist, and inhibited platelet TXA(2) synthase without affecting cyclooxygenase (COX)-1 or COX-2 enzymatic activities. These dual TXA(2) inhibitors dose dependently inhibited endothelial cell migration in chemotaxis assays using vascular endothelial growth factor (VEGF) as a chemoattractant but failed to affect cell adhesion and viability. The highest rates of cell migration inhibition were obtained with original compounds BM-567 and BM-573 (50.3 and 59.4% inhibition, respectively) when used at the final concentration of 10 microM. In addition, pretreatment of endothelial cells with these two drugs significantly prevented U-46,619-induced intracellular Ca(2+) pool mobilization, thus suggesting a mechanistic link between inhibition of the TXA(2) pathway and reduced endothelial cell migration. Treatment of rat aortic explants with U-46,619 (9,11-dideoxy-9,11-methanoepoxy-prostaglandin F(2)) significantly enhanced vessel sprouting whereas aortic rings treated with some of the compounds, including BM-567 (N-n-pentyl-N'-[2-(cyclohexylamino)-5-nitrobenzenesulfonyl]urea) and BM-573 (N-tert-butyl-N'-[5-nitro-2-p-toluylaminobenzenesulfonyl]urea), showed a significant decrease in vessel sprouting, which was not reversed by the addition of VEGF. These data suggest that our original dual TXA(2) inhibitors bear antiangiogenic properties, mainly by inhibiting endothelial cell migration.
Original languageEnglish
Pages (from-to)1057-67
Number of pages11
JournalThe Journal of pharmacology and experimental therapeutics
Volume318
Issue number3
DOIs
Publication statusPublished - Sep 2006

Keywords

  • Angiogenesis Inhibitors
  • Animals
  • Calcium
  • Cell Adhesion
  • Cell Movement
  • Cells, Cultured
  • Cyclooxygenase Inhibitors
  • Endothelial Cells
  • Humans
  • Hydrazines
  • Male
  • Platelet Aggregation
  • Rats
  • Rats, Wistar
  • Receptors, Thromboxane A2, Prostaglandin H2
  • Sulfonamides
  • Thromboxane A2
  • Thromboxane-A Synthase

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