Nature of the interaction of growth factors with suramin

Abstract

Suramin inhibits the binding of a variety of growth factors to their cell surface receptors. The direct interaction of suramin with acidic fibroblast growth factor has been detected by the enhancement of the drug's fluorescence in the presence of the protein with the maximum effect occurring at a molar ratio of suramin to aFGF of 2:1. This interaction stabilizes aFGF to thermal denaturation and partially protects a free thiol in its polyanion binding site from oxidation. The binding of suramin to aFGF also induces aggregation of the growth factor to at least a hexameric state as detected by static and dynamic light scattering as well as by gel filtration studies. Both CD and amide I' FTIR spectra of aFGF in the presence and absence of suramin suggest that the drug may also be causing a small conformational change in the growth factor. Suramin produces an even greater aggregation of bFGF and PDGF but not of EGF or IGF-1. Evidence for a suramin-induced conformational change in IGF-1 but not EGF is found by CD, however. It is concluded that suramin binds to many growth factors and that this induces microaggregation and, in some cases, conformational changes. In the case of aFGF, suramin interacts at or near its heparin binding site. The relationship between these phenomena and the anti-growth factor activity of suramin remains to be clearly elucidated.

A structure-activity analysis of antagonism of the growth factor and angiogenic activity of basic fibroblast growth factor by suramin and related polyanions

“…Similar effects have recently been reported with antibodies that block the activity of VEGF (Kim et al, 1993). The strong interaction of suramin with heparinbinding growth factors (Middaugh et al, 1992) suggests that the analogues may also be effective against other heparinbinding growth factors. It is notable that all of the bestcharacterised angiogenic factors are also heparin binding (e.g.…”

“…A recent, detailed study of the interaction of suramin with growth factors has shown that it blocks acidic FGF (aFGF) activity by aggregation of the growth factor into suramin aFGF multimers, with an aFGF to suramin ratio of 2:1 (Middaugh et al, 1992 itself, e.g. FGF and PDGF (Hosang, 1985;Middaugh et al, 1992), or possibly to the growth factor receptor, it has other diverse activities that probably contribute to its antiproliferative and antimetastatic activities. These include, in the context of antiproliferation, inhibition of key enzymes involved in the intracellular transduction of mitogenic signals, e.g.…”

Leads for Development of New Naphthalenesulfonate Derivatives with Enhanced Antiangiogenic Activity

“…Protein aggregation has been suggested to be a key process in the inhibition of FGFs mitogenic activity by suramins (27). In addition, these compounds have been proposed to block the interaction of aFGF with heparin, because it has been demonstrated that their anti-mitogenic activity can be reverted by this glycosaminoglycan (25,26).…”

“…The antiangiogenic activity of suramins is based, at least in part, on their ability to disrupt the interaction of many growth factors with their membrane receptors, such as in the case of FGFs and their tyrosine kinase receptors (19, 24 -26). Because it has been shown that heparin disrupts aFGF⅐suramin complexes (27) and counteracts the antiangiogenic effect of these polysulfonated ureas (25,26), suramins are considered to act by blocking the heparin-binding sites of FGFs (28). Another group of antiangiogenic and antitumoral compounds is comprised by suradistas, a type of noncytotoxic synthetic binaphthalene sulfonic distamycin-A derivatives.…”

“…Knowledge of the molecular structure of these complexes could be used to improve their pharmacological properties and lead to the design of better angiogenesis inhibitors. A major reason for the lack of data is that these two inhibitors promote the appearance of heterogeneous aggregates of the complexes (23,27). Of outstanding interest was the finding that 1,3,6-naphthalenetrisulfonate (NTS) constitutes a minimal model for the inhibition of aFGF mitogenic activity by suramins and suradistas (32).…”