Leik CE, Su EJ, Nambi P, Crandall DL, Lawrence DA
Effect of pharmacologic PAI-1 inhibition on cell motility and tumor angiogenesis. [JOURNAL ARTICLE]
J Thromb Haemost 2006 Oct 2.
Background: Plasminogen activator inhibitor (PAI-1) is integrally involved in tumorigenesis by impacting both proteolytic activity and cell migration during angiogenesis.
Objective: We hypothesized that an orally active small molecule inhibitor of PAI-1 (PAI-039; tiplaxtinin) could affect smooth muscle cell (SMC) attachment and migration in vitro on a vitronectin matrix, and exhibit antiangiogenic activity in vivo.
Methods: In vitro assays were used to assess the mechanism of inhibition of PAI-1 by PAI-039 using wild type PAI-1 in the presence or absence of vitronectin and wild type PAI-1 and specific PAI-1 mutants in SMC adhesion and migration assays. An in vivo tumor angiogenesis model was used to assess the effect of PAI-039 administration on neovascularization in a Matrigel implant.
Results: PAI-039 dose-dependently inhibited soluble, but not vitronectin-bound PAI-1. Cell adhesion assays using PAI-1 mutants unable to bind vitronectin (PAI-1(K)) or inactivate proteases (PAI-1(R)) further suggested that PAI-039 inactivated PAI-1 by binding near its vitronectin domain. In a tumor angiogenesis model, PAI-039 treatment of wild type mice dose-dependently decreased hemoglobin concentration and endothelial cell staining within the Matrigel implant, indicative of reduced angiogenesis, but exhibited no in vivo efficacy in PAI-1 null mice.
Conclusion: Administration of an orally active PAI-1 inhibitor prevented angiogenesis in a Matrigel implant. The lack of activity of PAI-039 against wild type PAI-1 bound to vitronectin and PAI-1(K) suggests PAI-039 binding near the vitronectin binding site. Our studies further substantiate a role for PAI-1 in cellular motility and tumor angiogenesis, and suggest for the first time that these effects can be modulated pharmacologically.
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