A ZINC CHELATOR INHIBITING GELATINASES EXERTS POTENT IN-VITRO ANTI-INVASIVE EFFECTS

Matrix metalloproteinases are zinc metalloenzymes involved in remodell ing of the extracellular matrix. We compared the anti-invasive propert ies of a zinc ejector matrix metalloproteinase inhibitor with those of reference compounds (hydroxamic acid-based BE-94 and Ro-31-9790) whic h form inactive ternary complexes with the enzymes and the catalytic z inc. We show that the compound undecadene-dioic acid bis-{[2-(3H-imida zol-4-yl)-ethyl]-amide} (S 30372) is active against gelatinases, chela tes zinc and exhibits enzymatic features compatible with the potential to extract zinc from gelatinases. We then used five invasive cell lin es in the Matrigel invasion chamber assay (NIH-3T3 fibroblasts, Lewis lung carcinoma cells, EJ138 and J82 bladder carcinoma and HT1080 fibro sarcoma cells). With the exception of J82 cells which were unaffected by the three inhibitors, all remaining cells were substantially more s ensitive to S 30372 in terms of maximal inhibition of invasion attaine d. This suggests that matrix metalloproteinase inhibitors with zinc ch elating/ejecting properties may be more efficient in preventing tumor progression. (C) 1998 Elsevier Science B.V. All rights reserved.