The inhibitory effect of celecoxib on mouse hepatoma H22 cell line on the arachidonic acid metabolic pathway.
Celecoxib is a selective inhibitor of cyclooxygenase-2 (COX-2). It may reduce the risk of cancer formation by affecting the metabolism of arachidonic acid (AA), which has been implicated in the development of cancer. Accordingly, this study was designed to determine the effects of celecoxib on the AA pathway in mouse hepatoma H22 cells. Celecoxib was found to inhibit the proliferation of H22 cells in a dose- and time-dependent manner. Low doses (50 and 100 micromol.L-1) of celecoxib caused an increase in the expression of cytosolic phospholipase A2 (cPLA2), but did not affect the expression of COX-2 in terms of the mRNA and protein levels. Surprisingly, the amount of AA was elevated and the level of prostaglandin E2 (PGE2) was unaltered in the culture supernatant. At higher celecoxib doses (200 and 400 micromol.L-1), the mRNA and protein of both COX-2 and cPLA2 were inhibited. The concentration of AA was increased, and PGE2 level was depressed in H22 cells. The ratio of AA to PGE2 was increased in a dose-dependent manner. Our findings suggest that the imbalance between AA and PGE2, characterized by increased AA at a low dosage and decreased PGE2 at a high dosage of celecoxib, was an important indicator of cytotoxicity of celecoxib on H22 cells.
Xu
Zhigang
Z
Department of Pharmacology, Norman Bethune College of Medicine, Jilin University, Changchun, Jilin, China.
Zhang
Ming
M
Lv
Xiaoyan
X
Xiang
Dan
D
Zhang
Xuewen
X
Chen
Li
L
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000032:analysis / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D000068579:Celecoxib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D053858:Metabolic Networks and Pathways / Q000187:drug effects*; D051379:Mice; D054467:Phospholipases A2 / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D016718:Arachidonic Acid; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D054467:Phospholipases A2; D000068579:Celecoxib; D015232:Dinoprostone