XR5967, a novel modulator of plasminogen activator inhibitor-1 activity, suppresses tumor cell invasion and angiogenesis in vitro.

Abstract

Recent reports suggest that elevated levels of plasminogen activator inhibitor (PAI)-1 may contribute to tumor progression. We have recently shown that antibodies to PAI-1 block the invasive and migratory potential of human fibrosarcoma cells and suppress angiogenesis in vitro. Here we report the in vitro evaluation of a low-molecular-weight modulator of PAI-1, XR5967, on invasion, migration and angiogenesis. XR5967, a diketopiperazine, dose-dependently inhibited the activity of human and murine PAI-1, towards urokinase plasminogen activator (uPA), with IC50 values of 800 nM and 8.3 microM, respectively. This was confirmed by SDS-PAGE, revealing that XR5967 inhibited complex formation between PAI-1 and uPA. This suppression may be caused by XR5967 promoting insertion of the reactive center loop within PAI-1. XR5967 dose-dependently inhibited the invasion of human HT1080 fibrosarcoma cells through Matrigel. Their invasion was reduced by 57% (p<0.001) at 5 microM. HT1080 cell migration was inhibited in a similar manner, indicating that PAI-1 may play an additional role in invasion, which is distinct to its role in the regulation of proteolysis. The potential of XR5967 to inhibit the invasion/migration of human endothelial cells was investigated in an in vitro model of angiogenesis. In this model XR5967 reduced tubule formation by 77% at 5 microM (p<0.001), highlighting a crucial role for PAI-1 in angiogenesis. These data stress the importance of a balanced proteolysis in the processes of invasion, migration and angiogenesis. Our results support the clinical findings and indicate that modulation of PAI-1 activity, with low-molecular-weight inhibitor of PAI-1 activity, may be of therapeutic benefit for the treatment of cancer.

• Authors: Teresa D Brooks, Shouming W Wang, Nils Brünner, Peter A Charlton
• Journal: Anti-cancer drugs (Anticancer Drugs) Vol. 15 Issue 1 Pg. 37-44 (Jan 2004) ISSN: 0959-4973 [Print] England
• PMID: 15090742 (Publication Type: Journal Article)

Chemical References

• Angiogenesis Inhibitors
• Antineoplastic Agents
• Fluorescent Dyes
• Piperazines
• Plasminogen Activator Inhibitor 1
• Serine Proteinase Inhibitors
• XR 5967
• Urokinase-Type Plasminogen Activator

Topics

• Angiogenesis Inhibitors (pharmacology, therapeutic use)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Coculture Techniques
• Electrophoresis, Polyacrylamide Gel
• Endothelial Cells
• Fluorescent Dyes
• Humans
• Molecular Structure
• Piperazines (pharmacology, therapeutic use)
• Plasminogen Activator Inhibitor 1 (chemistry, metabolism)
• Serine Proteinase Inhibitors (metabolism)
• Urokinase-Type Plasminogen Activator (analysis, chemistry, metabolism)