Cyclooxygenase-2 independent effects of cyclooxygenase-2 inhibitors on oxidative stress and intracellular glutathione content in normal and malignant human B-cells.
We recently reported that inhibition of Cyclooxygenase-2 (Cox-2) reduced human B-CLL proliferation and survival. Herein, we investigated the mechanisms whereby small molecule Cox-2 selective inhibitors, SC-58125 (a Celebrex analog) and CAY10404 blunt survival of human B-cell lymphomas and chronic lymphocytic leukemia B-cells. SC-58125 and OSU03012 (a Celebrex analog that lacks Cox-2 inhibitory activity) both decreased intracellular glutathione (GSH) content in malignant human B-cells, as well as in Cox-2 deficient mouse B-cells. This new finding supports Cox-2 independent effects of SC-58125. Interestingly, SC-58125 also significantly increased B-cell reactive oxygen species (ROS) production, suggesting that ROS are a pathway that reduces malignant cell survival. Addition of GSH ethyl ester protected B lymphomas from the increased mitochondrial membrane permeability and reduced survival induced by SC-58125. Moreover, the SC-58125-mediated GSH depletion resulted in elevated steady-state levels of the glutamate cysteine ligase catalytic subunit mRNA and protein. These new findings of increased ROS and diminished GSH levels following SC-58125 exposure support novel mechanisms whereby a Cox-2 selective inhibitor reduces malignant B-cell survival. These observations also support the concept that certain Cox-2 selective inhibitors may have therapeutic value in combination with other drugs to kill malignant B lineage cells.
Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 850, Rochester, NY 14642, USA.
Elizabeth P
EP
Ryan
Timothy P
TP
Bushnell
Alan E
AE
Friedman
Irfan
I
Rahman
Richard P
RP
Phipps
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D020134:Catalytic Domain / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000187:drug effects* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005721:Glutamate-Cysteine Ligase / Q000187:drug effects / Q000235:genetics; D005978:Glutathione / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects*; D011720:Pyrazoles / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology
C501048:3-(4-methylsulfonylphenyl)-4-phenyl-5-trifluoromethylisoxazole; D052246:Cyclooxygenase 2 Inhibitors; D007555:Isoxazoles; C500894:OSU 03012; D011720:Pyrazoles; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D013450:Sulfones; C090859:1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole; C042431:S-ethyl glutathione; D051546:Cyclooxygenase 2; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione