title: Understanding the mechanism of the antimitogenic activity of suramin.
abstract: Fibroblast growth factors (FGFs) play crucial roles in the regulation of key cellular processes such as angiogenesis, differentiation, and tumor growth. Suramin, a polysulfonated naphthylurea, is known to be a potent inhibitor of FGF-induced angiogenesis. Using isothermal titration calorimetry, we demonstrate that human acidic fibroblast growth factor (hFGF-1) binds to suramin with high affinity in the nanomolar range. The suramin:hFGF-1 binding stoichiometry is estimated to be 2:1. Size-exclusion chromatography data reveal that suramin oligomerizes hFGF-1 to form a stable tetramer. Thermal unfolding experiments monitored by steady state fluorescence, and limited trypsin digestion analysis data suggest that suramin-induced oligomerization of hFGF-1 occurs in two steps. The first step involves the binding of suramin at specific sites on the protein. Two molecules of suramin appear to bind simultaneously to one molecule of hFGF-1. Binding of suramin possibly involves formation of solvent-exposed nonpolar surfaces in hFGF-1. In the second step, FGF appears to oligomerize through coalescence of the solvent-accessible nonpolar surfaces. Results of the NMR experiments reveal that suramin binds to residues in the heparin binding pocket as well as to residues involved in FGF receptor binding. On the basis of the results of this study, we propose a model to explain the molecular mechanism(s) underlying the antimitogenic activity of suramin. To our knowledge, this is the first study in which suramin interaction sites on FGF have been characterized.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701, USA.
authors.forename: Karuppanan Muthusamy
authors.initials: KM
authors.lastname: Kathir
authors.forename: Thallapuranam Krishnaswamy S
authors.initials: TK
authors.lastname: Kumar
authors.forename: Chin
authors.initials: C
authors.lastname: Yu
mesh_terms: D050256:Antimitotic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics; D016220:Fibroblast Growth Factor 1 / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation / Q000187:drug effects; D017510:Protein Folding; D013498:Suramin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D050256:Antimitotic Agents; D016220:Fibroblast Growth Factor 1; D013498:Suramin