Suramin alters phosphoinositide synthesis and inhibits growth factor receptor binding in HT-29 cells.
Initiation of cell growth frequently involves activation of growth factor receptor-coupled tyrosine kinases and stimulation of the phosphoinositide second messenger system. The antitrypanosomal and antifiliarial drug suramin has been shown to exert antiproliferative activities by inhibition of growth factor receptor binding. We therefore investigated the effect of suramin on epidermal growth factor receptor-binding characteristics and, additionally, searched for effects on basal or cholinergically stimulated phospholipid metabolism in HT-29 cells. Suramin caused a dose-dependent and noncompetitive inhibition of 125I-epidermal growth factor binding (concentration producing 50% inhibition, 44.2 micrograms/ml) but did not alter muscarinic receptor binding. Suramin did not affect the basal 32P incorporation into phosphoinositides at concentrations of less than 200 micrograms/ml suramin. In contrast, the carbachol-stimulated enhancement of 32P incorporation into phosphatidic acid, phosphatidylinositol, and polyphosphoinositides was reduced by 48-95% in the presence of 100 micrograms/ml suramin. Thus, phosphoinositide and diacylglycerol kinases involved in basal and receptor-stimulated phosphoinositide metabolism may be localized in different subcellular compartments, which can be dissociated by the use of suramin. Direct measurements of phosphatidylinositol kinase and diacylglycerol kinase activities showed a potent inhibition when treated with suramin. Suramin did not affect the stimulation of phospholipase C by carbachol, determined by release of [3H]inositol phosphates in [3H]myoinositol-prelabeled cells. Our data indicate that suramin potently inhibits phosphoinositide resynthesis under stimulated conditions. Additionally, we confirm the inhibitory effects of suramin on epidermal growth factor receptor binding in a human intestinal cell line. The inhibitory effects of suramin on phospholipid metabolism may play a role in the antiproliferative actions of this drug.
Kopp
R
R
Department of Surgery, University of Munich, West Germany.
Pfeiffer
A
A
D019870:1-Phosphatidylinositol 4-Kinase; D002217:Carbachol / Q000494:pharmacology; D019852:Diacylglycerol Kinase; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D010716:Phosphatidylinositols / Q000096:biosynthesis*; D010743:Phospholipids / Q000378:metabolism; D010770:Phosphotransferases / Q000032:analysis; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D013498:Suramin / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D010716:Phosphatidylinositols; D010743:Phospholipids; D011976:Receptors, Muscarinic; D013498:Suramin; D004815:Epidermal Growth Factor; D002217:Carbachol; D010770:Phosphotransferases; D019852:Diacylglycerol Kinase; D019870:1-Phosphatidylinositol 4-Kinase; D066246:ErbB Receptors