Abstract
Cell lines that do not overexpress functional cyclooxygenase-2 are resistant to the normal plasma levels of celecoxib achieved following oral ingestion. Cell growth inhibition was demonstrated after 24 h exposure to 80 micromol/l celecoxib while significant death was not detected at concentrations below 120 micromol/l following 24 h exposure. This growth inhibition and death induction was identified to be independent of p53 and Hdm2 in these cells, despite wild-type p53 stabilization and Hdm2 diminution in some lines. Cell death induced by celecoxib was preceded by the generation of reactive oxygen species within 4 h of drug exposure. The precise mechanism of elicitation of reactive oxygen species in these cells remains to be elucidated, although it was found to be independent of p53 and c-Abl, while in vitro, celecoxib enhanced superoxide radical production by xanthine oxidase. Importantly, the failure of anti-oxidants to protect from death indicates that celecoxib induces death independently of reactive oxygen species and that reactive oxygen species generation may be an insufficient trigger of death in p53-deficient cells.
MeSH terms
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Animals
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Antioxidants / pharmacology
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Apoptosis / drug effects*
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Blotting, Western
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Celecoxib
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Cell Proliferation / drug effects
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Cells, Cultured / drug effects
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Cells, Cultured / metabolism
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Colorectal Neoplasms / metabolism
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Colorectal Neoplasms / pathology
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Cyclooxygenase 2 / genetics
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Cyclooxygenase 2 / physiology*
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Cyclooxygenase Inhibitors / pharmacology*
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Embryo, Mammalian / cytology
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Embryo, Mammalian / drug effects
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Embryo, Mammalian / metabolism
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Humans
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Mice
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Mice, Knockout
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Proto-Oncogene Proteins c-abl / genetics
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Proto-Oncogene Proteins c-abl / physiology*
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Proto-Oncogene Proteins c-mdm2 / genetics
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Proto-Oncogene Proteins c-mdm2 / physiology*
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Pyrazoles / pharmacology*
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Reactive Oxygen Species / metabolism*
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Sulfonamides / pharmacology*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / physiology*
Substances
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Antioxidants
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Cyclooxygenase Inhibitors
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Pyrazoles
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Reactive Oxygen Species
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Sulfonamides
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Tumor Suppressor Protein p53
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Cyclooxygenase 2
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Proto-Oncogene Proteins c-mdm2
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Proto-Oncogene Proteins c-abl
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Celecoxib