Pharmacological concentrations of suramin inhibit the binding of alpha2-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 alpha2-macroglobulin (alpha2M) to inhibit proteinases nor did it prevent conversion of native alpha2M to the 'fast' receptor-binding form. Nevertheless, pharmacological concentrations (below 250 microg/ml) of suramin prevented the interaction between methylamine-activated alpha2M 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 alpha2M). The ability of suramin to accelerate the dissociation of pre-bound alpha2M was consistent with a non-competitive mechanism of inhibition although the possibility of a competitive component cannot be eliminated. I discuss how the inhibition of alpha2M-binding by suramin may contribute to the antiproliferative properties of this drug.
Vassiliou
G
G
Heart Research Institute, Camperdown, Sydney, Australia. gerard.vassiliou@anu.edu.au
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002118:Calcium / Q000494:pharmacology; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011487:Protein Conformation; D011489:Protein Denaturation; D011971:Receptors, Immunologic / Q000378:metabolism*; D013498:Suramin / Q000494:pharmacology*; D000511:alpha-Macroglobulins / Q000378:metabolism*
D000970:Antineoplastic Agents; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011971:Receptors, Immunologic; D000511:alpha-Macroglobulins; D013498:Suramin; D002118:Calcium