A zinc chelator inhibiting gelatinases exerts potent in vitro anti-invasive effects.
Matrix metalloproteinases are zinc metalloenzymes involved in remodelling of the extracellular matrix. We compared the anti-invasive properties of a zinc ejector matrix metalloproteinase inhibitor with those of reference compounds (hydroxamic acid-based BB-94 and Ro-31-9790) which form inactive ternary complexes with the enzymes and the catalytic zinc. We show that the compound undecadenedioic acid bis-[[2-(3 H-imidazol-4-yl)-ethyl]-amide] (S 30372) is active against gelatinases, chelates zinc and exhibits enzymatic features compatible with the potential to extract zinc from gelatinases. We then used five invasive cell lines in the Matrigel invasion chamber assay (NIH-3T3 fibroblasts, Lewis lung carcinoma cells, EJ138 and J82 bladder carcinoma and HT1080 fibrosarcoma cells). With the exception of J82 cells which were unaffected by the three inhibitors, all remaining cells were substantially more sensitive to S 30372 in terms of maximal inhibition of invasion attained. This suggests that matrix metalloproteinase inhibitors with zinc chelating/ejecting properties may be more efficient in preventing tumor progression.
Institut de Recherches Servier, Department of Oncology, Suresnes, France.
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G
Ferry
J A
JA
Boutin
P
P
Hennig
A
A
Genton
C
C
Desmet
J L
JL
Fauchère
G
G
Atassi
G C
GC
Tucker
D016475:3T3 Cells; D000818:Animals; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000494:pharmacology; D018093:Gelatinases / Q000037:antagonists & inhibitors*; D006632:Histamine / Q000494:pharmacology; D006877:Hydroxamic Acids; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015032:Zinc
D002614:Chelating Agents; D005231:Fatty Acids, Unsaturated; D006877:Hydroxamic Acids; D007093:Imidazoles; D011480:Protease Inhibitors; C097661:Ro 31-9790; C114897:S 30372; D013876:Thiophenes; D010649:Phenylalanine; D006632:Histamine; C080985:batimastat; D018093:Gelatinases; D008666:Metalloendopeptidases; D015032:Zinc