Pharmacological concentrations of suramin inhibit the binding of alpha(2)-macroglobulin to its cell-surface receptor

Suramin is a polysulfated drug used in the treatment of cancer and AIDS. High concentrations (1 mg/ml) of suramin did not affect the ability of native alpha(2)-macroglobulin (alpha(2)M) to inhibit proteinases nor did it prevent conversion of native alpha(2)M to the 'fast' receptor-binding form, Nevertheless, pharmacological concentrations (below 250 mu g/ml) of suramin prevented the interaction between methylamine-activated alpha(2)M and its receptor, the low-density-lipoprotein-receptor-related protein, Inhibition was demonstrated at the molecular level and was not due to calcium sequestration by the drug, irreversible denaturation of the receptor, or a non-specific polyanion effect (since heparin and dextran sulfate did not alter the binding of alpha(2)M). The ability of suramin to accelerate the dissociation of pre-bound alpha(2)M was consistent with a noncompetitive mechanism of inhibition although the possibility of a competitive component cannot be eliminated. I discuss how the inhibition of alpha(2)M-binding by suramin may contribute to the antiproliferative properties of this drug.