In various tumour cell lines the peptide bradykinin B(2) receptor antagonist, Hoe 140 (Icatibant), may act as mitogenic agonist.
This study examined the mitogenic effects of bradykinin (BK, Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg), the peptide bradykinin B(2) receptor antagonist Hoe 140 (D-Arg(0)[Hyp(3)-Thi(6)-D-Tic(7)-Oic(8)]BK, and the orally active, nonpeptide B(2) receptor antagonist FR 173657 ((E)-3-(6-acetamido-3-pyridyl)-N-[N-2-4-dichloro-3-[(2-methyl-8-quino linyl) oxymethyl]phenyl]-N-methylaminocarbonyl-methyl]acrylamide) in three different human tumour cell lines: the small cell lung carcinoma (SCLC) cell line H-69, the breast carcinoma cell line EFM-192A, and the colon carcinoma cell line SW-480. In these cell lines activation of mitogen-activated protein kinase (MAPK) is involved in BK-induced stimulation of cell proliferation and may be mediated by both G(q) proteins (SW-480) and G(i) proteins (EFM-192A; H-69). In these cells BK as well as Hoe 140 increased the rate of DNA synthesis measured with the [(3)H]-thymidine uptake assay. Hoe 140 did neither antagonize nor potentiate the effect of BK. FR 173657 did not stimulate [(3)H]-thymidine incorporation but clearly antagonized the mitogenic effects of BK as well as Hoe 140. In H-69 cells, FR 173657 induced a decrease in the basal rate of DNA synthesis. In all three cell lines BK and Hoe 140 stimulated the activity of MAPK. Their effect on MAPK activity was completely abolished by FR 173657 which itself did not increase the activity of MAPK. In H-69 cells, the basal activity of MAPK was slightly inhibited by FR 173657. In the cell lines SW-480 and H-69 both BK and Hoe 140 but not FR 173657 stimulated phosphatidylinositol hydrolysis. In H-69 cells, FR 173657 decreased basal inositol phosphate formation. Our results show that in certain tumour cell lines the classical peptide B(2) receptor antagonist, Hoe 140, may act as mitogenic B(2) receptor agonist whereas the nonpeptide B(2) receptor antagonist, FR 173657, does not. In H-69 cells FR 173657 was found to exhibit properties of an inverse agonist.
Drube
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Institute of Biochemistry & Biophysics, Biological and Phamaceutical Faculty, Friedrich-Schiller-University Jena, Philosophenweg 12, D-07743 Jena, Germany.
Liebmann
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D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D065168:Bradykinin Receptor Antagonists; D004247:DNA / Q000096:biosynthesis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin / Q000819:agonists / Q000502:physiology; D015398:Signal Transduction; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
D065168:Bradykinin Receptor Antagonists; D004791:Enzyme Inhibitors; C105311:FR 173657; D005419:Flavonoids; D007295:Inositol Phosphates; D008934:Mitogens; D011804:Quinolines; D043782:Receptor, Bradykinin B2; D018002:Receptors, Bradykinin; C065679:icatibant; D004247:DNA; D020928:Mitogen-Activated Protein Kinases; D001920:Bradykinin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one