Inhibitory effects of ubenimex (bestatin) on the invasion of uterine cervical carcinoma cells and their production and activation of gelatinase A.

The present study was undertaken to investigate the effects of the aminopeptidase inhibitor ubenimex (bestatin) on the invasive activity of cultured human uterine cervical carcinoma cells. The invasion of squamous cell carcinoma OMC-1 and SKG-IIIb cells, and adeno-carcinoma OMC-4 and CAC-1 cells into reconstituted basement membrane (Matrigel) was inhibited by the presence of bestatin in a concentration-dependent manner. However, bestatin did not have any effect on tumor cell proliferation or migration. Immunoblot analysis of tumor-conditioned medium showed that the treatment of tumor cells with bestatin resulted in the reduction of the 72 kDa gelatinase level (gelatinase A, latent form) in the four cell lines examined, and the reduction of the 68 kDa gelatinase level (gelatinase A, active form) in SKG-IIIb cells. Bestatin inhibited hydrolyzing activities towards substrates of aminopeptidases in tumor cells, but did not directly inhibit gelatinase A. These results suggest that bestatin may inhibit the invasion of uterine cervical carcinoma cells possibly through the inhibitory mechanisms for production and activation of gelatinase A modulated by tumor aminopeptidases.