title: 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.affiliation: Department of Medicine, Box Hill Hospital, Monash University, Melbourne, Victoria, Australia.
authors.forename: Kristina
authors.initials: K
authors.lastname: Cakarovski
authors.forename: Jenny Y
authors.initials: JY
authors.lastname: Leung
authors.forename: Christina
authors.initials: C
authors.lastname: Restall
authors.forename: Anna
authors.initials: A
authors.lastname: Carin-Carlson
authors.forename: Eunice
authors.initials: E
authors.lastname: Yang
authors.forename: Patrick
authors.initials: P
authors.lastname: Perlmutter
authors.forename: Robin
authors.initials: R
authors.lastname: Anderson
authors.forename: Robert
authors.initials: R
authors.lastname: Medcalf
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Dear
mesh_terms: D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D013449:Sulfonamides / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D013449:Sulfonamides; C527236:metacept-1; C100692:oxamflatin; D014568:Urokinase-Type Plasminogen Activator