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
- Received June 19, 2001.
- Accepted September 5, 2001.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|