Toluquinol, a methylhydroquinone produced by a marine fungus, was selected in the course of a blind screening for new potential inhibitors of angiogenesis. In the present study we provide the first evidence that
toluquinol is a new anti-angiogenic-compound. In a variety of experimental systems, representing the sequential events of the angiogenic process,
toluquinol treatment of activated endothelial cells resulted in strong inhibitory effect.
Toluquinol inhibited the growth of endothelial and
tumor cells in culture in the micromolar range. Our results indicate that the observed growth inhibitory effect could be due, at least in part, to an induction of apoptosis.
Toluquinol induced endothelial cell death is mediated via apoptosis after a cell cycle block and
caspase activation. Capillary tube formation on
Matrigel and migratory, invasive and proteolytic capabilities of endothelial cells were inhibited by addition of
toluquinol at subtoxic concentrations. Inhibition of the mentioned essential steps of in vitro angiogenesis agrees with the observed inhibition of the in vivo angiogenesis, substantiated by using the chick chorioallatoic membrane assay and confirmed by the murine
Matrigel plug, the zebrafish embryo neovascularization and the zebrafish caudal fin regeneration assays. Data here shown altogether indicate that
toluquinol has antiangiogenic effects both in vitro and in vivo that are exerted partly by suppression of the
VEGF and FGF-induced Akt activation of endothelial cells. These effects are carried out at lower concentrations to those required for other inhibitors of angiogenesis, what makes
toluquinol a promising
drug candidate for further evaluation in the treatment of
cancer and other angiogenesis-related pathologies.