Antiproliferative activity to vascular smooth muscle cells and receptor binding of heparin-mimicking polyaromatic anionic compounds.
Proliferation of bovine aortic smooth muscle cells (SMCs) induced by thrombin, basic fibroblast growth factor, or serum is inhibited by anionic, nonsulfated aromatic compounds that mimic many of the effects of heparin. Among these compounds are aurintricarboxylic acid (ATA) and a newly synthesized polymer of 4-hydroxyphenoxy acetic acid (compound RG-13577). Iodinated- or 14C-labeled compound RG-13577 binds to cultured SMCs in a highly specific and saturable manner. Scatchard analysis of the binding data revealed the presence of an estimated 1 x 10(7) binding sites per cell with an apparent dissociation constant of 3 x 10(-6) mol/L. Binding of radiolabeled RG-13577 was efficiently competed for by related aromatic anionic compounds and by apolipoprotein E, but not by heparin, heparan sulfate, suramin, or various purified growth factors and extracellular matrix proteins. Receptor cross-linking of SMC-bound 125I-RG-13577 revealed a single species of high M(r) (approximately 280 kD) cell surface receptors detected in the absence but not the presence of excess unlabeled compound RG-13577. Binding was susceptible to downregulation and restoration of receptor levels in a manner similar to that of hormone and growth factor receptors. We suggest that the antiproliferative activity of compound RG-13577 and related compounds is initiated by binding to specific growth-inhibiting cell surface receptors. Heparin-mimicking compounds may be applied to inhibit SMC proliferation associated with atherosclerosis and restenosis.
Benezra
M
M
Department of Oncology, Hadassah University Hospital, Jerusalem, Israel.
Ben-Sasson
S A
SA
Regan
J
J
Chang
M
M
Bar-Shavit
R
R
Vlodavsky
I
I
D000818:Animals; D001312:Aurintricarboxylic Acid / Q000494:pharmacology; D001665:Binding Sites; D002417:Cattle; D002452:Cell Count; D005109:Extracellular Matrix / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006497:Heparan Sulfate / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism*; D010642:Phenoxyacetates / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011108:Polymers / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011956:Receptors, Cell Surface / Q000187:drug effects / Q000378:metabolism*; D013917:Thrombin / Q000037:antagonists & inhibitors
D001312:Aurintricarboxylic Acid; D016222:Fibroblast Growth Factor 2; D006497:Heparan Sulfate; D010642:Phenoxyacetates; D011108:Polymers; D011956:Receptors, Cell Surface; D013917:Thrombin; C090697:2-(4-hydroxyphenoxy)acetic acid-formaldehyde polymer