Suramin binds to platelet‐derived growth factor and inhibits its biological activity

The polyanion suramin was recently found to inhibit binding of 125 I‐PDGF (platelet‐derived growth factor) to Balb/e 3T3 cell membranes. Cultured Swiss 3T3 cells were used to investigate the mode of action of suramin and to monitor its effect on the biological activity of PDGF. Evidence is presented that suramin inhibits cellular binding of PDGF by binding to PDGF itself, thereby preventing it from binding to its cell surface receptor: First, while suramin inhibited I‐PDGF binding with a hail maximum inhibition concentration of ∼60 μM or 90 μg/ml in a simultaneous competition assay, it was inactive in a sequential radioreciptor assay, in which an inhibitor is expected to be active if it interacts with the receptor (even with relatively low affinity) but to be inactive if it interacts with PDGF. Second, suramin prevented immunoprecipitation of 125 I‐PDGF in a dose‐dependent manner, with a half maximum effective concentration of ∼50 μM. Furthermore, suramin efficiently dissociated 125 I‐PDGF bound to its cell surface receptor, whereas unlabeled PDGF even in large excess was virtually inactive. This is also in line with the proposed direct interaction between PDGF and suramin, since such an interaction can he envisaged to induce a conformational change in the PDGF‐receptor complex, resulting in an increased off‐rate of the complex. Reduced 125 I‐PDGF binding in the presence of suramin correlated directly with a suramin dose‐dependent inhibition of PDGF‐induced incorporation of 3 H‐thymidine into quiescent Swiss 3T3 cells and of the proliferation of these cells. These observations suggest that suramin, by complexing with PDGF, renders this mitogen unable to bind to its physiological receptor and, thereby, prevents PDGF‐initiated biological activities.