Growth Factor (FGF-2) interacts with high affinity tyrosine-kinase receptors
(FGFRs) and low affinity heparan sulfate proteoglycans (HSPGs) in target
cells. Both interactions are required for FGF-2-mediated biological responses.
We here report the
FGF-2 antagonist activity of novel synthetic sulfonic acid polymers with
distinct chemical structures and molecular weights (MWs). PAMPS [poly(2-acrylamido-2-methyl-1-propanesulfonic
acid)], (MW»7,000-10,000), PAS [poly(anetholesulfonic acid)], (MW»9,000-11,000),
PSS [poly(4-styrenesulfonic acid)], (MW=70,000), and PVS [poly(vinylsulfonic
acid)], (MW=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 CHO cells to wild-type HSPG-bearing cells.
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
(MBE) cells. The anti-proliferative 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 (ERK-1/2), involved in FGF-2 signal
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.
(1999) 56, 204-213.