Celecoxib can induce cell death independently of cyclooxygenase-2, p53, Mdm2, c-Abl and reactive oxygen species.
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.
Haupt
Sue
S
Department of Hematology, Hadassah University Hospital, Jerusalem, Israel. haupt@vms.huji.ac.il
Kleinstern
Jackie
J
Haupt
Ygal
Y
Rubinstein
Abraham
A
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000502:physiology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D016315:Proto-Oncogene Proteins c-abl / Q000235:genetics / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000502:physiology*; D011720:Pyrazoles / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology*
D000975:Antioxidants; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D051546:Cyclooxygenase 2; D051736:Proto-Oncogene Proteins c-mdm2; D016315:Proto-Oncogene Proteins c-abl; D000068579:Celecoxib