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COX‐2 independent induction of cell cycle arrest and apoptosis in colon cancer cells by the selective COX‐2 inhibitor celecoxib
Author(s) -
Grösch Sabine,
Tegeder Irmgard,
Niederberger Ellen,
Bräutigam Lutz,
Geisslinger Gerd
Publication year - 2001
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.01-0299fje
Subject(s) - celecoxib , apoptosis , cox 2 inhibitor , cell cycle , cancer research , colorectal cancer , in vivo , cyclooxygenase , cancer , medicine , pharmacology , chemistry , biology , biochemistry , enzyme , microbiology and biotechnology
The regular use of various nonsteroidal anti‐inflammatory drugs (NSAIDs) was shown to decrease the incidence of colorectal cancer. This effect is thought to be caused predominantly by inhibition of cyclooxygenase‐2 (COX‐2) and, subsequently, prostaglandin synthesis. However, recent studies have suggested that COX‐independent pathways may contribute considerably to these antiproliferative effects. To evaluate the involvement of COX‐dependent and COX‐independent mechanisms further, we assessed the effects of celecoxib (selective COX‐2 inhibitor) and SC560 (selective COX‐1 inhibitor) on cell survival, cell cycle distribution, and apoptosis in three colon cancer cell lines, which differ in their expression of COX‐2. Both drugs induced a G0/G1 phase block and reduced cell survival independent of whether or not the cells expressed COX‐2. Celecoxib was more potent than SC560. The G0/G1 block caused by celecoxib could be attributed to a decreased expression of cyclin A, cyclin B1, and cyclin‐dependent kinase‐1 and an increased expression of the cell cycle inhibitory proteins p21 Waf1 and p27 Kip1 . In addition, celecoxib, but not SC560, induced apoptosis, which was also independent of the COX‐2 expression of the cells. In vivo , celecoxib as well as SC560 reduced the proliferation of HCT‐15 (COX‐2 deficient) colon cancer xenografts in nude mice, but both substances had no significant effect on HT‐29 tumors, which express COX‐2 constitutively. Thus, our in vitro and in vivo data indicate that the antitumor effects of celecoxib probably are mediated through COX‐2 independent mechanisms and are not restricted to COX‐2 over‐expressing tumors.