Antagonist, partial agonist and antiproliferative actions of B-9870 (CU201) as a function of the expression and density of the bradykinin B1 and B2 receptors.

BACKGROUND AND PURPOSE: A bradykinin (BK) B2 receptor (B2R) antagonist, B-9870 (CU201), has been proposed to behave as a 'biased agonist' at B2Rs and to exert anti-neoplasic effects. It was unclear whether these effects were determined by the activation of B2Rs by the drug. B-9870 was evaluated for antagonism or stimulation of several responses mediated by the rabbit B2R or B1 receptor (B1R); its anti-proliferative activity was also characterized. EXPERIMENTAL APPROACH AND KEY RESULTS: B-9870 was an insurmountable B2R antagonist in the rabbit jugular vein contractility assay, but a partial agonist in HEK 293 cells expressing the rabbit B2R or a green fluorescent protein (GFP) conjugate of the latter (ERK1/2 phosphorylation, [Ca2+]i, [3H]-arachidonate release, endocytosis). The agonist-like effects of B-9870 were inhibited by the B2R antagonist LF 16.0687 and absent in untransfected cells. In addition, B-9870 was a surmontable antagonist of the rabbit B1R in the aorta contractility assay, and blocked Lys-des-Arg9-BK-induced ERK1/2 phosphorylation in HEK 293 cells expressing a fluorescent B1R conjugate. B-9870 inhibited the growth of MDA-MB-231 cells. The latter effect was not influenced by B1R or B2R antagonists and was not apoptotic. MDA-MB-231 cells expressed a small population of B2Rs but no B1Rs; they responded to BK (small calcium transients) and B-9870 behaved as an antagonist. CONCLUSION AND IMPLICATIONS: B-9870 is a dual B1R and B2R antagonist with confirmed stimulating effects at the B2R in high expression systems only. Its cell type-specific anti-proliferative effect occurs at a high concentration, independently from kinin receptors and apoptosis.