Abstract
The multipotent drug suramin, which is currently being studied as an anticancer agent, was found to inhibit the interaction between the urokinase-type plasminogen activator (u-PA) and its cellular receptor. 50% inhibition of binding was obtained with a suramin concentration between 30 and 60 micrograms/ml when using U937 cells and a ligand concentration of 0.3 nM. This concentration of the drug is well below the serum levels found in suramin-treated patients. Inhibition of binding was also demonstrated at the molecular level, using chemical cross-linking or an enzyme-linked immunosorbent assay-type technique based on the ligand interaction. The inhibition was not caused by a mere polyanion effect since polysulfates such as heparin, heparan sulfate, and pentosan polysulfate were non-inhibitory or showed only a very weak inhibition. However, polysulfonated compounds with structures resembling suramin (i.e. trypan blue and Evans blue) did prove inhibitory. The inhibition found with suramin showed a concentration dependence consistent with a mixed competitive and noncompetitive mechanism. The off-rate of prebound ligand was accelerated by the drug. It is speculated that the present effect may contribute to the anti-invasive properties of suramin by destroying the cellular potential for localized plasminogen activation and proteolytic matrix degradation.
| Original language | English |
|---|---|
| Journal | The Journal of Biological Chemistry |
| Volume | 268 |
| Issue number | 8 |
| Pages (from-to) | 5985-9 |
| Number of pages | 5 |
| ISSN | 0021-9258 |
| Publication status | Published - 15 Mar 1993 |
| Externally published | Yes |
Keywords
- Binding, Competitive
- Cell Membrane
- Cells, Cultured
- Cross-Linking Reagents
- Enzyme-Linked Immunosorbent Assay
- Humans
- Receptors, Cell Surface
- Receptors, Urokinase Plasminogen Activator
- Suramin
- Urokinase-Type Plasminogen Activator
- Journal Article
- Research Support, Non-U.S. Gov't