Pharmacological inhibition of gelatinase B induction and tumor cell invasion

The 92 kDa matrix metalloproteinase (gelatinase B, MMP‐9) plays a major role in the facilitation of tumor metastasis and in inflammatory disorders characterized by excessive matrix protein destruction. MMP‐9 is transcriptionally induced in multiple cell types by exposure to the inflammatory mediators bacterial endotoxin, interleukin‐1 (IL‐1) or tumor necrosis factor‐α (TNF‐α). CT‐2519, (1‐(5‐isothiocyanatohexyl)‐3,7‐dimethylxanthine), a synthetic small molecule from an anti‐inflammatory compound library, was evaluated for its effect on endotoxin and cytokine‐induced MMP‐9 synthesis by a monocytic leukemic cell line, THP‐1, and a monocyte/macrophage line, RAW 264.7. CT‐2519 dose‐dependently inhibited endotoxin and cytokine‐induced synthesis of MMP‐9 by these cells. Furthermore, both MMP‐9 secretion and matrix invasion by cells of a human fibrosarcoma cell line, HT‐1080, were inhibited by CT‐2519 in a dose‐dependent manner. Northern blot analyses and studies utilizing MMP‐9 promoter constructs indicated that the inhibitory action of CT‐2519 occurs at the level of transcriptional suppression. Given the observation that cellular activation by endotoxin, IL‐1 and TNF‐α may be mediated, at least in part, through induction of certain species of phosphatidic acid (PA), the effect of CT‐2519 on lipid levels was analyzed. CT‐2519 effectively reduced endotoxin‐mediated increases, in particular cellular lipid levels. Pharmacologic modulation of cytokine‐dependent gene products, such as MMP‐9, may offer an important therapeutic approach to the treatment of neoplastic and inflammatory disorders. © 1996 Wiley‐Liss, Inc.