INHIBITION OF INVASION, GELATINASE ACTIVITY, TUMOR TAKE AND METASTASIS OF MALIGNANT-CELLS BY N-ACETYLCYSTEINE

The thiol N-acetylcysteine (NAG) is currently considered one of the mo st promising cancer chemopreventive agents by virtue of its multiple a nd coordinated mechanisms affecting the process of chemical carcinogen esis. Recent studies have shown that an unpaired cysteine residue in t he propeptide plays a key role in inactivation of latent metastasis-as sociated metalloproteinases: the present study was designed to assess whether NAC could also affect tumor take, invasion and metastasis of m alignant cells. As assessed by zymographic analysis, NAC completely in hibited the gelatinolytic activity of type-IV collagenases in the cell s tested (gelatinases A and B). Moreover, NAC was efficient in inhibit ing the chemotactic and invasive activities of tumor cells of human (A 2058 melanoma) and murine origin (K1735 and B16-F10 melanoma cells as well as C87 Lewis lung carcinoma cells) in Boyden-chamber assays, whic h are predictive of the invasive and metastatic properties. Reduced gl utathione (GSH) had a similar, although less effective activity. The n umber of lung metastases decreased sharply when B16-F10 murine melanom a cells, injected i.v. into nude mice, were pre-treated with NAC and r esuspended in medium supplemented with 10 mM NAG. In other experiments NAC was given in drinking water, starting 48-72 hr before subcutaneou s inoculation of either B16-F10 cells or of their highly metastatic va riant B16-BL6, or intramuscular injection of LLC cells. In all experim ents NAC treatment decreased the weight of the locally formed primary tumor and produced a dose-related delay in tumor formation. Spontaneou s metastasis formation by B16-F10 and B16-BL6 tumors was slightly yet significantly reduced by oral administration of NAG. However, this was not observed for Lewis lung tumors. These data indicate that NAC affe cts the process of tumor-cell invasion and metastasis, probably due to inhibition of gelatinases by its sulfhydryl group, with the possible contribution of other mechanisms, including the potent antioxidant act ivity of this thiol. (C) 1995 Wiley-Liss, Inc.