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-alpha (TNF-alpha). 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-alpha 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.
McMillan
J I
JI
Department of Medicine, San Francisco VAMC/UCSF 94121, USA.
Weeks
R
R
West
J W
JW
Bursten
S
S
Rice
G C
GC
Lovett
D H
DH
D000818:Animals; D002460:Cell Line; D017364:Collagenases / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005354:Fibrosarcoma; D006801:Humans; D007249:Inflammation; D007375:Interleukin-1 / Q000494:pharmacology*; D017879:Isothiocyanates / Q000494:pharmacology*; D007700:Kinetics; D007951:Leukemia, Myeloid; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008264:Macrophages; D020780:Matrix Metalloproteinase 9; D051379:Mice; D009000:Monocytes; D009361:Neoplasm Invasiveness; D010712:Phosphatidic Acids / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D012475:Salmonella; D014158:Transcription, Genetic / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014970:Xanthines / Q000494:pharmacology*
C100851:1-(5-isothiocyanatohexyl)-3,7-dimethylxanthine; D007375:Interleukin-1; D017879:Isothiocyanates; D008070:Lipopolysaccharides; D010712:Phosphatidic Acids; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D014970:Xanthines; D017364:Collagenases; D020780:Matrix Metalloproteinase 9