Celecoxib attenuates 5-fluorouracil-induced apoptosis in HCT-15 and HT-29 human colon cancer cells.
OBJECTIVE
To investigate the combined chemotherapeutic effects of celecoxib when used with 5-FU in vitro.


METHODS
Two human colon cancer cell lines (HCT-15 and HT-29) were treated with 5-FU and celecoxib, alone and in combination. The effects of each drug were evaluated using the MTT [3- (4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] assay, flow cytometry, and western blotting.


RESULTS
5-FU and celecoxib showed a dose-dependent cytotoxic effect. When treated with 10(-3) mol/L 5-FU (IC(50)) and celecoxib with its concentration ranging from 10(-8) mol/L to 10(-4) mol/L of celecoxib, cells showed reduced cytotoxic effect than 5-FU (10(-3) mol/L) alone. Flow cytometry showed that celecoxib attenuated 5-FU induced accumulation of cells at subG1 phase. Western blot analyses for caspase-3 and poly (ADP-ribose) polymerase (PARP) cleavage showed that celecoxib attenuated 5-FU induced apoptosis. Western blot analyses for cell cycle molecules showed that G2/M arrest might be possible cause of 5-FU induced apoptosis and celecoxib attenuated 5-FU induced apoptosis via blocking of cell cycle progression to the G2/M phase, causing an accumulation of cells at the G1/S phase.


CONCLUSIONS
We found that celecoxib attenuated cytotoxic effect of 5-FU. Celecoxib might act via inhibition of cell cycle progression, thus preventing apoptosis induced by 5-FU.
Lim
Yun-Jeong
YJ
Division of Gastroen-terology, Department of Internal Medicine, Samsung Medical Center, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, Korea.
Rhee
Jong-Chul
JC
Bae
Young-Mee
YM
Chun
Wan-Joo
WJ
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D000068579:Celecoxib; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D019073:HT29 Cells; D006801:Humans; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D013449:Sulfonamides / Q000494:pharmacology* / Q000627:therapeutic use
D000964:Antimetabolites, Antineoplastic; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib; D005472:Fluorouracil