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 I-125-CCK-8 binding to NCI-H209 cells with IC50 values of 5, 2, an d 200 nM. ([R-(R*,R*)]-4[[2-[[3-(1H-Indole-3-yl)-2-methyl-1-oxo-2-[[tricycl o[3.3.1.1(3,7)]-dec-2-yloxy)carbonyl[amino]propyl]amino]-1-phenylethyl-]ami no]-4-oxobutanoic acid) (CI-988; 100 nM) inhibited the ability of 10 nM CCK -8 to elevate cytosolic Ca2+ in 1-[2-(5-carboxyoxazol-2-yl)-6-aminobenzofur an-5-oxy]-2-(2'-amino-5'-methylphenoxy)-ethane-N,N,N',N'-tetraacetic acid a cetoxymethyl 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-activa ted protein kinase stimulated by CCK-8. By Northern blot, CI-988 antagonize d 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 ce ll growth factor mRNA. Using a [3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-2 H-tetrazolium bromide] and clonogenic assay, CI-988 inhibited the prolifera tion of NCI-H209 cells in vitro. Using nude mice, CI-988 inhibited the prol iferation of NCI-H209 xenografts. These results suggest that CI-988 is a CC K2 receptor antagonist that inhibits the proliferation of SCLC cells.