Suramin blocks the binding of interleukin-1 to its receptor and neutralizes IL-1 biological activities.
This report demonstrates the ability of the anti-cancer drug suramin to interfere with the binding of interleukin (IL)-1 to its receptor and to inhibit IL-1-induced biological activities. In a radioreceptor cell based assay, suramin inhibits the binding of IL-1 alpha to several murine cell lines expressing predominantly type I and type II IL-1 receptors. Affinity cross-linking experiments using IL-1 alpha and EL-4.6.1 cells confirms that suramin inhibits the binding of the ligand to the 80 kDa IL-1 type I receptor. In contrast, suramin fails to displace significantly prebound IL-1. In a cell-free system, suramin prevents the binding of IL-1 alpha and IL-1 beta to murine and human recombinant soluble type I IL-1 receptors. For example, the IC50 for suramin inhibiting IL-1 alpha and IL-1 beta binding to soluble human IL-1 receptor were 204 microM and 186 microM, respectively. The suramin analogues, NF-058 and NF-103 (which bear the same number of sulfate groups as suramin), are between three- and ten-fold less active than suramin in inhibiting IL-1 binding to EL-4.6.1 cells, and to recombinant soluble IL-1 receptor. Furthermore, in a dose-dependent manner suramin prevents several IL-1 mediated biological responses, including thymocyte proliferation, PGE-2 synthesis and IL-6 production. The inhibitory effect of the drug can be significantly reversed by the addition of excess cytokine. Taken together, the results indicate that suramin is a competitive IL-1 receptor antagonist. Because IL-1 participates in a broad range of immunological and inflammatory functions, the data suggest that suramin administration may influence important activities beyond those associated strictly with tumor inhibition.
Strassmann
G
G
Department of Immunology, Otsuka America Pharmaceutical Co. Inc., Rockville, MD 20850.
D'Alessandro
F
F
Fong
M
M
Nordan
R P
RP
Nickel
P
P
Chizzonite
R
R
D000818:Animals; D001667:Binding, Competitive; D001681:Biological Assay / Q000379:methods; D002460:Cell Line; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis; D051379:Mice; D011869:Radioligand Assay; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D013498:Suramin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D007375:Interleukin-1; D015850:Interleukin-6; D017472:Receptors, Interleukin-1; D013498:Suramin