Abstract
Basic fibroblast growth factor (FGF-2) interacts with high-affinity tyrosine-kinase fibroblast growth factor receptors (FGFRs) and low-affinity heparan sulfate proteoglycans (HSPGs) in target cells. Both interactions are required for FGF-2-mediated biological responses. Here we report the FGF-2 antagonist activity of novel synthetic sulfonic acid polymers with distinct chemical structures and molecular masses (MMs). PAMPS [poly(2-acrylamido-2-methyl-1-propanesulfonic acid)], (MM ≈ 7,000–10,000), PAS [poly(anetholesulfonic acid)], (MM ≈ 9,000–11,000), PSS [poly(4-styrenesulfonic acid)], (MM = 70,000), and poly(vinylsulfonic acid) (MM = 2,000), inhibited FGF-2 binding to HSPGs and FGFRs in fetal bovine aortic endothelial GM 7373 cells. They also abrogated the formation of the HSPG/FGF-2/FGFR ternary complex, as evidenced by their capacity to prevent FGF-2-mediated cell-cell attachment of FGFR-1-overexpressing, HSPG-deficient Chinese hamster ovary cells to wild-type HSPG-bearing cells. Direct interaction of the polysulfonates with FGF-2 was demonstrated by their ability to protect the growth factor from proteolytic cleavage. Accordingly, molecular modeling, based on the crystal structure of the interaction of FGF-2 with a heparin hexamer, showed the feasibility of docking PAMPS into the heparin-binding domain of FGF-2. In agreement with their FGF-2-binding capacity, PSS, PAS, and PAMPS inhibited FGF-2-induced cell proliferation in GM 7373 cells and murine brain microvascular endothelial cells. The antiproliferative activity of these compounds was associated with the abrogation of FGF-2-induced tyrosine phosphorylation of FGFR-1. Moreover, the polysulfonates PSS and PAS inhibited FGF-2-induced activation of mitogen-activated protein kinase-1/2, involved in FGF-2 signal transduction. In conclusion, sulfonic acid polymers bind FGF-2 by mimicking heparin interaction. These compounds may provide a tool to inhibit FGF-2-induced endothelial cell proliferation in angiogenesis and tumor growth.
Footnotes
- Received November 30, 1998.
- Accepted March 26, 1999.
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Send reprint requests to: Dr. Sandra Liekens, Rega Institute for Medical Research, Minderbroedersstraat 10, 3000 Leuven, Belgium. E-mail: Sandra.Liekens{at}rega.kuleuven.ac.be
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This work was supported by Ministero dell’ Università e della Ricerca Scientifica e Tecnologica (Project Inflammation: Biology and Clinics), Consiglio Nazionale della Richerche Target Project on Biotechnology (no. 97.01186. PF49), Associazione Italiana per la Ricerca sul Cancro (Special Project Angiogenesis) and Istituto Superiore di Sanità (AIDS Project) (M.P.) and by grant 3.0180.95 from the Belgian Fonds voor Geneeskundig Wetenschappelijk Onderzoek. J.N. is a post-doctoral research assistant from the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen. R.E. is a fellow of the Onderzoeksfonds of the Katholieke Universiteit Leuven.
- The American Society for Pharmacology and Experimental Therapeutics
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