Increase of cyclooxygenase-2 inhibition with celecoxib combined with 5-FU enhances tumor cell apoptosis and antitumor efficacy in a subcutaneous implantation tumor model of human colon cancer.
BACKGROUND
The purpose of this study was to investigate the anti-tumor effect and explore the mechanisms of celecoxib (a selective cyclooxygenase-2 inhibitor) combined with 5-fluorouracil (5-FU) on the treatment of human colorectal cancer in a BALB/C nude mouse subcutaneous xenograft model.


METHODS
Effects of celecoxib combined with 5-FU on the proliferation of xenograft carcinoma induced by HT-29 were investigated. The apoptotic cells were detected by electron microscope and TUNEL (terminal deoxynucleotidyl transferase dUTP nick end labeling) assay. Immunohistochemistry and Western blot were used to estimate the expression of cytochrome C, caspase-3 and caspase-9.


RESULTS
Compared with the control group, treatment groups showed significant inhibition of tumor growth. More apoptotic cells existed after treatment with celecoxib combined with 5-FU. Cytochrome C, caspase-3 and caspase-9 were increased in treated groups, and more obviously in the drug combination group. Cyclooxygenase-2 (COX-2) were decreased after treatment with celecoxib only or combined with 5-FU. And the combined group showed a greater decrease.


CONCLUSIONS
Celecoxib combined with 5-FU could inhibit the growth of tumors in vivo by inducing apoptosis and activation of the cytochrome C dependency apoptosis signal pathway. A decrease of COX-2 and an increase of cytochrome C, caspase-3 and caspase-9 may be involved in this process.
Department of Digestion Internal Medicine, The First Affiliated Hospital of Soochow University, Su Zhou, JiangSu 215006, China.
De-Qing
DQ
Zhang
Qiang
Q
Guo
Jian-Hong
JH
Zhu
Wei-Chang
WC
Chen
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D000068579:Celecoxib; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D000964:Antimetabolites, Antineoplastic; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D045304:Cytochromes c; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D020169:Caspases; D000068579:Celecoxib; D005472:Fluorouracil