A new inorganic tetra-valent TeIV compound with a novel dimeric structure, Octa-O-bis-(R,R)-tartarate
ditellurane (SAS), was recently prepared in our lab. SAS interacts in-vitro with thiols, and inhibits the
activity of human cysteine proteases. Moreover, SAS is non-toxic and it protects the hemopoietic system from
chemotherapy-induced damage in mice.
The present study addresses the biochemical mechanism of SAS activity at the molecular level. We demonstrate
by FRET that SAS interacts with the VLA-4 (α4b1) integrin, affecting its conformation and inhibiting its
activity. In order to explore the functional implications of VLA-4 inhibition by SAS, we conducted several
experiments with murine B16 melanoma cells. SAS inhibited attachment of melanoma cells, abundantly
expressing the VLA-4 integrin, to its natural ligand fibronectin (FN). Anti VLA-4 neutralizing antibody inhibited
cell attachment to FN, while SAS did not further enhance this suppression. These results suggest that B16
melanoma cells attach FN via VLA-4, being an important target for SAS activity. Moreover, inhibition of
cellular attachment by SAS was associated with suppression of matrix metallo proteinases (MMP's) 2 and 9
secretion, known to be regulated by VLA-4, in a dose dependent manner. Importantly, the consequence of these
accumulated activities was in-vitro inhibition of melanoma cells migration. Finally, we demonstrated that
integrins are possible target of redox inactivation by SAS, by its selective binding to vicinal thiols of cysteine
residues within the exofacial domain of the integrins, affecting their biological activity in a reversible manner.
These results highlight the role of the non-toxic tellurium compound SAS in the unique inhibition of the VLA-4
integrin activity in B16 melanoma cells, resulting in suppression of biological processes related to melanoma
migration and invasive properties.
References
1) M. Albeck, T. Tamari, B. Sredni, Synthesis 1989, 635–636.
2) B. Sredni, R. Geffen-Aricha, W. Duan, M. Albeck, F. Shalit, et al. FASEB J 2007, 21, 1870–1883.
3) S. Yosef, M. Brodsky, B. Sredni, A. Albeck, M. Albeck, ChemMedChem 2007, 2, 1601–1606.
