CI-988 inhibits growth of small cell lung cancer cells.
The effects of cholecystokinin (CCK) antagonists on small cell lung cancer (SCLC) cells were investigated. CI-988, L-365,260, and L-364,718 inhibited specific (125)I-CCK-8 binding to NCI-H209 cells with IC(50) values of 5, 2, and 200 nM. ([R-(R*,R*)]-4[[2-[[3-(1H-Indole-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3.1.1(3,7)]- dec-2-yloxy)carbonyl[amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid) (CI-988; 100 nM) inhibited the ability of 10 nM CCK-8 to elevate cytosolic Ca(2+) in 1-[2-(5-carboxyoxazol-2-yl)-6-aminobenzofuran-5-oxy]-2-(2'-amino-5'-methylphenoxy)-ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester-loaded NCI-H209 cells. By Western blot, CI-988 inhibited tyrosine phosphorylation of focal adhesion kinase and paxillin stimulated by CCK-8. Also, CI-988 inhibited tyrosine phosphorylation of mitogen-activated protein kinase stimulated by CCK-8. By Northern blot, CI-988 antagonized the ability of 10 nM CCK-8 to increase c-fos mRNA in NCI-H209 cells. Also, CI-988 inhibited the ability of CCK-8 to increase vascular endothelial cell growth factor mRNA. Using a [3-(4,5 dimethylthiazol-2-yl)-2.5-diphenyl-2H-tetrazolium bromide] and clonogenic assay, CI-988 inhibited the proliferation of NCI-H209 cells in vitro. Using nude mice, CI-988 inhibited the proliferation of NCI-H209 xenografts. These results suggest that CI-988 is a CCK(2) receptor antagonist that inhibits the proliferation of SCLC cells.
Moody
T W
TW
Department of Cell and Cancer Biology, Medicine Branch, National Cancer Institute, Rockville, Maryland 20850, USA. moodyt@bprb.nci.nih.gov
Jensen
R T
RT
D000970:Antineoplastic Agents / Q000494:pharmacology*; D018288:Carcinoma, Small Cell / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000473:pathology; D008536:Meglumine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000037:antagonists & inhibitors / Q000502:physiology; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007211:Indoles; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; C065599:PD 134308; D008536:Meglumine