The Novel Non-Toxic Tellurium Compound SAS Blocks Angiogenesis and Tumor Formation by Inhibition of Cell Migration and Adhesion: Interference with avβ3 Activity via Redox Modulation

A novel Te(IV) small molecule, octa-O-bis-(R,R)-Tartarate Ditellurane (SAS), is shown in the present study to have anti-tumor and anti-angiogenic activity in vitro and in vivo. SAS inhibited endothelial cell migration induced by angiogenic stimuli in various models. The chemistry of SAS allows it to interact with thiols enabling it to inhibit the activity of specific proteins, in which a particular redox status of cysteine is essential to their biological activity. This redox-modulating attribute of SAS is used here to functionally inhibit the activity of αvβ3. Indeed, SAS diminished integrin-mediated endothelial cell adhesion to fibronectin and to a bioactive angiogenic laminin-derived peptide, via blocking of αvβ3 integrin binding. SAS interfered with the cysteine-rich domain of αvβ3 and not with its RGD binding site, and this interference, at least partly, accounted for the inhibition of endothelial αvβ3 binding to extracellular matrix proteins. Furthermore, SAS could modulate the redox status of αvβ3. Treatment of SVEC4-10 endothelial cells with SAS, reduced significantly the amount of free thiols on cellular αvβ3. In addition, free thiols, which reside within the αvβ3 but not within the αv chain of recombinant αvβ3, were decreased in the presence of SAS. Signaling events downstream of integrin binding were substantially inhibited. More importantly, interference with αvβ3 binding by SAS was associated with both its direct anti-angiogenic effects on endothelial cells and its direct effect on tumor cells. The integrated results emphasize the potential use of the tellurium redox-modulating non-toxic molecule, SAS, as a new class of anti-angiogenic, compound.