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dc.contributor.authorBrooks, TD
dc.contributor.authorWang, SMW
dc.contributor.authorBrunner, N
dc.contributor.authorCharlton, PA
dc.identifier.citationANTI-CANCER DRUGS, 2004, 15 pp. 37 - 44
dc.description.abstractRecent 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 muM, 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 muM. 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 muM (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. (C) 2004 Lippincott Williams Wilkins.
dc.format.extent37 - 44
dc.titleXR5967, a novel modulator of plasminogen activator inhibitor-1 activity, suppresses tumor cell invasion and angiogenesis in vitro
dc.typeJournal Article
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfANTI-CANCER DRUGS
pubs.notesunique-id: ISI:000188970800007
pubs.notesNot known
pubs.embargo.termsNot known
dc.contributor.icrauthorBrooks, Teresa

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