Novel inhibitors of urokinase-type plasminogen activator and matrix metalloproteinase expression in metastatic cancer cell lines.

Abstract

The plasminogen-activating (PA) and matrix metalloproteinase (MMP) enzyme systems are implicated in proteolytic turnover of the extracellular matrix (ECM) associated with biologic processes including wound healing, inflammation and angiogenesis. Aberrant expression of components of the PA and MMP enzyme systems occurs in the pathogenesis of metastatic cancer. Oxamflatin (Ox), a novel hydroxamic acid derivative, inhibits u-PA mRNA expression and proteolytic activity while simultaneously upregulating the expression of the natural inhibitor of u-PA, plasminogen activator inhibitor type 2 (PAI-2) in metastatic cancer cells. We have characterized the effects of Ox and a novel derivative, Metacept-1 (MCT-1), on PA and MMP-mediated proteolysis and invasion in several metastatic tumor lines. Both compounds are able to inhibit u-PA-, MMP-2- and MMP-9-mediated gene expression at low micromolar concentrations as well as u-PA- and MMP-mediated proteolysis as assessed by zymography, with MCT-1 being the more effective of the 2 agents in some assays. Cellular invasion assays correlate with gene expression and zymography experiments identifying both Ox and MCT-1 as able to inhibit invasion of metastatic cancer cell lines through matrigel at nanomolar concentrations, with MCT-1 more effective than Ox in 2 of the 3 cancer cell lines assessed.

• Authors: Kristina Cakarovski, Jenny Y Leung, Christina Restall, Anna Carin-Carlson, Eunice Yang, Patrick Perlmutter, Robin Anderson, Robert Medcalf, Anthony E Dear
• Journal: International journal of cancer (Int J Cancer) Vol. 110 Issue 4 Pg. 610-6 (Jul 01 2004) ISSN: 0020-7136 [Print] United States
• PMID: 15122596 (Publication Type: Journal Article)
• Copyright: Copyright 2004 Wiley-Liss, Inc.

Chemical References

• Enzyme Inhibitors
• Hydroxamic Acids
• Matrix Metalloproteinase Inhibitors
• RNA, Messenger
• Sulfonamides
• metacept-1
• oxamflatin
• Urokinase-Type Plasminogen Activator

Topics

• Cell Line, Tumor
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hydroxamic Acids (pharmacology)
• Matrix Metalloproteinase Inhibitors
• Neoplasm Invasiveness
• Neoplasm Metastasis (drug therapy, pathology)
• RNA, Messenger (analysis)
• Sulfonamides (pharmacology)
• Urokinase-Type Plasminogen Activator (antagonists & inhibitors, genetics)