Pharmacological inhibition of gelatinase B induction and tumor cell invasion

✍ Scribed by James I. McMillan; Reitha Weeks; James W. West; Stuart Bursten; Glenn C. Rice; David H. Lovett

• Publisher: John Wiley and Sons
• Year: 1996
• Tongue: French
• Weight: 935 KB
• Volume: 67
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/(sici)1097-0215(19960807)67:4<523::aid-ijc11>3.0.co;2-8

✦ Synopsis

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-I (IL-I) or tumor necrosis factor-a (TNFa). CT-25 19, (I -(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-I, and a monocyte/macrophage line, RAW 264.7. CT-25 I 9 dose-dependently inhibited endotoxin and cytokineinduced 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-l and TNF-a 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-medizied increases in particular cellular lipid levels. Pharmacologic modulation of cytokinedependent gene products, such as MMP-9, may offer an important therapeutic approach to the treatment of neoplastic and inflammatory disorders. Q 1996 Wiley-Liss, Inc.

M) and 10% fetal bovine serum (FBS). RAW 264.7 cells were cultured in DMEM supplemented as above,