Suramin inhibition of growth factor receptor binding and mitogenicity in AKR‐2B cells

Abstract

Suramin, a polyanionic compound, has previously been shown to dissociate platelet-derived growth factor (PDGF) from its receptor. In the present study suramin was found to inhibit the growth of sparse cultures of AKR-2B cells in fetal bovine serum (FBS)-supplemented medium in a dose-dependent, reversible fashion. Suramin also inhibited the ability of FBS, transforming growth factor beta (TGF beta), heparin-binding growth factor type-2 (HBGF-2), and epidermal growth factor (EGF) to stimulate DNA synthesis in density-arrested cultures of AKR-2B cells. The inhibition of growth factor-stimulated mitogenicity was directly correlated to the dose of suramin required to inhibit the binding of 125I-labeled TGF beta, HBGF-2, and EGF to their cell surface receptors. Suramin affected TGF beta and HBGF-2-related events at a 10-15-fold lower dose than that required for EGF-related events. It was also noted that suramin inhibited TGF beta-stimulated soft agar colony formation of AKR-2B (clone 84A) cells as well as the spontaneous colony formation of AKR-MCA cells, a chemically transformed derivative of AKR-2B cells. This demonstrates that suramin's spectrum of action for growth factors and their receptors should be extended to include TGF beta, HBGF-2, and EGF as well as PDGF. The data further suggest that the spontaneous growth of AKR-MCA cells in soft agar is dependent on growth factor binding to cell surface receptors.

Autocrine Growth Factor Regulation of Lysyl Oxidase Expression in Transformed Fibroblasts

“…It is important to realize that suramin "normalizes" the phenotype of some tumor cell lines (25,26,43). Work now in progress is focused on determining the effect of suramin on the phenotype of tumor cells in an effort to understand whether lysyl oxidase mediates normalization of the cell phenotype by suramin, perhaps by somehow regulating phosphatidylinositol 3-kinase localization and activity.…”

“…Moreover, suramin is active against human immunodeficiency virus-1 (40). Suramin inhibits the binding of growth factors to their respective receptors, and this mechanism is believed to primarily contribute to its therapeutic effects (24,34,(41)(42)(43).…”

Suppression of VEGF‐induced angiogenesis by the protein tyrosine kinase inhibitor, lavendustin A

“…It inhibits the activities of several heparin-binding growth factors such as transforming growth factor-beta, fibroblast growth factor and platelet-derived growth factor (Coffey et al, 1987;Kopp & Pfeiffer, 1990;Myers et al, 1990). In a rat brain tumour model, suramin inhibits endothelial and tumour cell proliferation (Takano et al, 1993).…”

Suramin induced ceramide accumulation leads to apoptotic cell death in dorsal root ganglion neurons

“…In spite of major toxicities, suramin has been documented to have significant in vitro and in vivo activity against a variety of solid tumor cell lines at drug concentrations that are clinically achievable (Betscholtz et al, 1986;Coffey et al, 1987;Kim et al, 1991;Gansler et al, 1992). For this reason, there continues to be considerable clinical interest in this drug.…”

“…However, the mechanism of anti-tumor activity and neurotoxicity of the drug remain unknown. Most reports on suramin describe an inhibitory effect on growth factor receptor binding as its cytotoxic mechanism of action (Hosang, 1985;Coffey et al, 1987;Sjo È lund and Thyberg, 1989;Pollack and Richard, 1990). Other studies have reported a stimulatory effect by suramin on growth factor receptors (Mahoney et al, 1990;Cardinali et al, 1992;Sartor et al, 1992;Tsutsumi et al, 1993;Tsutsumi et al, 1994).…”