CI-988 Inhibits Growth of Small Cell Lung Cancer Cells
- 1Department of Cell and Cancer Biology, Medicine Branch, National Cancer Institute, Rockville, Maryland (T.W.M.); and 2Digestive Disease Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland (R.T.J.).
- Dr. Terry W. Moody, National Cancer Institute, Medicine Branch, Bldg. KWC, Rm. 300, 9610 Medical Center Dr., Rockville, MD 20850. E-mail:moodyt{at}bprb.nci.nih.gov
Abstract
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 125I-CCK-8 binding to NCI-H209 cells with IC50 values of 5, 2, and 200 nM. ([R-(R*,R*)]-4[[2-[[3-(1H-Indole-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3.1.13,7]- 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 Ca2+ 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 CCK2 receptor antagonist that inhibits the proliferation of SCLC cells.
Footnotes
- Abbreviations:
- CCK
- cholecystokinin
- SCLC
- small cell lung cancer
- CI-988
- ([R-(R*,R*)]-4[[2-[[3-(1H-indole-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3.1.13,7]dec-2-yloxy)carbonyl[amino]propyl]amino]-1-phenylethyl]amino]-4-oxobutanoic acid)
- VEGF
- vascular endothelial cell growth factor
- FBS
- fetal bovine serum
- Fura-2 AM
- 1-[2-(5-carboxyoxazol-2-yl)-6-aminobenzofuran-5-oxy]-2-(2′-amino-5′-methylphenoxy)-ethane-N,N,N′,N′-tetraacetic acid acetoxymethyl ester
- MTT
- [3-(4,5 dimethylthiazol-2-yl)-2.5-diphenyl-2H-tetrazolium bromide]
- L-364,718
- 3S(−)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-yl)-1H-indole-2 carboxamide
- L-365,260
- 3R-(+)-2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1,4-benzodiazepin-3-yl)-N′-(3-methylphenyl) urea
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- Received June 19, 2001.
- Accepted September 5, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
