PURPOSE: Suramin, a polysulfonated naphthylurea, has been shown to be effective in the treatment of several cancers. We have reported that suramin, at dose concentrations higher than 140 microM, exerts growth-stimulatory effects in several non-small-cell lung cancer (NSCLC) cell lines. The purpose of this study was to examine the mechanisms by which suramin exerts this growth-stimulatory effect in NSCLC cells. METHODS: NCI-H596 cells were treated with agarose-immobilized suramin, directly or by addition on cell culture inserts, after which growth was determined by [3H]thymidine incorporation. PPADS, a specific purinergic receptor antagonist, was used to determine whether suramin acts via purinergic receptors. The effect of suramin on epidermal growth factor receptor (EGFR) was determined by analyzing receptor phosphorylation and dimerization. XAMR 0721, a suramin analogue containing only one of the two polysulfonated arms, was also analyzed for its effects on growth and EGFR activation. RESULTS: Agarose-immobilized suramin stimulated NCI-H596 cell growth, but only when added directly to the cells. When the suramin-conjugated beads were added to the cells on cell culture inserts, which preclude an interaction with the cell surface but allow interaction with the culture medium, there was no effect on proliferation. PPADS had no effect on the growth stimulation by suramin; however suramin treatment resulted in rapid phosphorylation and dimerization of EGFR. Treatment with XAMR 0721 did not affect growth or tyrosine phosphorylation and dimerization of EGFR. CONCLUSIONS: Suramin need not enter NCI-H596 cells to exert its growth-stimulatory effect, nor is this effect mediated by an interaction with soluble growth factors. Rather, it appears that suramin acts via an interaction with EGFR, but not with purinergic receptors.
PURPOSE:Suramin, a polysulfonated naphthylurea, has been shown to be effective in the treatment of several cancers. We have reported that suramin, at dose concentrations higher than 140 microM, exerts growth-stimulatory effects in several non-small-cell lung cancer (NSCLC) cell lines. The purpose of this study was to examine the mechanisms by which suramin exerts this growth-stimulatory effect in NSCLC cells. METHODS: NCI-H596 cells were treated with agarose-immobilized suramin, directly or by addition on cell culture inserts, after which growth was determined by [3H]thymidine incorporation. PPADS, a specific purinergic receptor antagonist, was used to determine whether suramin acts via purinergic receptors. The effect of suramin on epidermal growth factor receptor (EGFR) was determined by analyzing receptor phosphorylation and dimerization. XAMR 0721, a suramin analogue containing only one of the two polysulfonated arms, was also analyzed for its effects on growth and EGFR activation. RESULTS:Agarose-immobilized suramin stimulated NCI-H596 cell growth, but only when added directly to the cells. When the suramin-conjugated beads were added to the cells on cell culture inserts, which preclude an interaction with the cell surface but allow interaction with the culture medium, there was no effect on proliferation. PPADS had no effect on the growth stimulation by suramin; however suramin treatment resulted in rapid phosphorylation and dimerization of EGFR. Treatment with XAMR 0721 did not affect growth or tyrosine phosphorylation and dimerization of EGFR. CONCLUSIONS:Suramin need not enter NCI-H596 cells to exert its growth-stimulatory effect, nor is this effect mediated by an interaction with soluble growth factors. Rather, it appears that suramin acts via an interaction with EGFR, but not with purinergic receptors.
Authors: M A Villalona-Calero; G A Otterson; M G Wientjes; F Weber; T Bekaii-Saab; D Young; A J Murgo; R Jensen; T-K Yeh; Y Wei; Y Zhang; C Eng; M Grever; J L-S Au Journal: Ann Oncol Date: 2008-07-15 Impact factor: 32.976