Celecoxib but not rofecoxib inhibits the growth of transformed cells in vitro.
OBJECTIVE
Nonsteroidal anti-inflammatory drugs reduce the risk of colorectal cancer. The cyclooxygenase (COX) pathway of arachidonic acid metabolism is an important target for nonsteroidal anti-inflammatory drugs. Increased expression of COX-2 was recently shown to be an important step in the multistep process of colorectal cancer carcinogenesis. The new COX-2-specific inhibitors offer the benefit of cancer protection without the gastrointestinal toxicity reported for the old drugs. The purpose of this study was to compare the growth effects of two specific COX-2 inhibitors, celecoxib (Pfizer, Inc., New York, NY), and rofecoxib (Merck, White House Station, NJ) in normal and transformed enterocytes.


METHODS
Cultures of normal rat intestinal epithelial cell line, IEC-18, vector control cells, c-K-ras, c-K-ras-bak, and antisense-bak derivatives were treated with different dosages of celecoxib (0-60 micro M) and rofecoxib (0-20 micro M). Cell cycle analysis and apoptosis were assessed by fluorescence-activated cell sorting analysis. Protein expression was assessed by Western blot analysis and caspases 3 and 8 activities by ELISA.


RESULTS
Celecoxib inhibited cell growth and induced apoptosis in a time- and dose-dependent manner. IEC18 parental cells were two to four times more resistant to celecoxib than ras, ras-bak, and antisense bak transformed cells that overexpress the COX-2 protein. The induction of apoptosis by celecoxib involved the caspase pathways. Rofecoxib, up to its maximal concentration of 20 micro M, did not inhibit cell growth or induce apoptosis.


CONCLUSIONS
Celecoxib may prove to be a very efficient component in the prevention and treatment of gastrointestinal tumors because it inhibits the growth of cancerous cells without affecting the growth of normal cells.
Kazanov
Diana
D
Department of Cancer Prevention, Tel Aviv Medical Center, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Dvory-Sobol
Hadas
H
Pick
Marjorie
M
Liberman
Eliezer
E
Strier
Ludmila
L
Choen-Noyman
Efrat
E
Deutsch
Varda
V
Kunik
Talya
T
Arber
Nadir
N
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism; D000068579:Celecoxib; D002453:Cell Cycle / Q000187:drug effects*; D002461:Cell Line, Transformed / Q000187:drug effects* / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D020895:Enterocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D011905:Genes, ras / Q000502:physiology; D066298:In Vitro Techniques; D007783:Lactones / Q000494:pharmacology*; D011720:Pyrazoles; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones
D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; C505410:Casp3 protein, rat; C505528:Casp8 protein, rat; D053148:Caspase 3; D053181:Caspase 8; D020169:Caspases; D000068579:Celecoxib