[Enhancing effects of celecoxib on the growth inhibition of pancreatic carcinoma by gemcitabine treatment].
OBJECTIVE
To investigate the effect and the mechanisms of selective cyclooxygenase-2 (COX-2) inhibitor celecoxib in the growth inhibition of pancreatic cancer by gemcitabine.


METHODS
Effects of gemcitabine combined with celecoxib on the proliferation in xenograft pancreatic carcinoma induced by SW1990 were investigated by immunohistochemistry of proliferating cell nuclear antigen (PCNA) and cyclin D1. Gemcitabine was administered intraperitoneally twice a week, and celecoxib was given via water daily. Effects of celecoxib and/or gemcitabine in pancreatic carcinoma cell SW1990 with different dose and time were investigated by MTT assay and soft agar assay. Effects on apoptosis and cell cycle were studied by flow cytometry. Effects on the protein expression of cyclin A, B(1) and D(1) were assessed by Western Blot.


RESULTS
The mean volume of xenograft tumor was significantly reduced in gemcitabine group, celecoxib group and combination group (0.41 cm(3) +/- 0.12 cm(3), 1.56 cm(3) +/- 0.17 cm(3), 0.05 cm(3) +/- 0.04 cm(3) vs 2.31 cm(3) +/- 0.41 cm(3), P < 0.05). The expression of PCNA and cyclin D(1) was significantly reduced in gemcitabine group and can hardly be detected in combination group, but without significant change in celecoxib group. Celecoxib and gemcitabine inhibited pancreatic carcinoma cell growth dose-dependently, and the combination of celecoxib with gemcitabine inhibited cell growth to a greater degree than either compound alone. Apoptosis were induced in SW1990 by celecoxib alone or in combined with gemcitabine. Treatment with celecoxib only or combined with gemcitabine altered the cell cycle phase distribution in SW1990, cells were mainly arrested in G(0)/G(1) phase, S phase and G(2)/M phase development were greatly inhibited. Expression of Cyclin A, B(1) and D(1) were closely related with the cell cycle distribution induced by different drug.


CONCLUSIONS
Selective COX-2 inhibitor celecoxib enhances the growth inhibition of pancreatic cancer induced by gemcitabine, which may be realized partly through the arrest of cell cycle and induction of cell apoptosis.
Xu
Gang
G
Department of Gastroenterology, Shanghai First People's Hospital, Shanghai 200080, China.
Wu
Kai
K
Wang
Xing-peng
XP
Zhao
Song
S
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D000068579:Celecoxib; D002453:Cell Cycle / Q000187:drug effects; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D011720:Pyrazoles / Q000008:administration & dosage* / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D003841:Deoxycytidine; D000068579:Celecoxib; D000093542:Gemcitabine