Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
B-Lymphocytes / drug effects*
-
B-Lymphocytes / metabolism
-
Catalytic Domain / drug effects
-
Catalytic Domain / genetics
-
Cell Proliferation / drug effects
-
Cell Survival / drug effects
-
Cells, Cultured
-
Cyclooxygenase 2 / deficiency
-
Cyclooxygenase 2 / drug effects*
-
Cyclooxygenase 2 / metabolism
-
Cyclooxygenase 2 Inhibitors / pharmacology*
-
Dose-Response Relationship, Drug
-
Glutamate-Cysteine Ligase / drug effects
-
Glutamate-Cysteine Ligase / genetics
-
Glutathione / analogs & derivatives
-
Glutathione / antagonists & inhibitors
-
Glutathione / metabolism*
-
Glutathione / pharmacology
-
Humans
-
Isoxazoles / pharmacology
-
Leukemia, Lymphocytic, Chronic, B-Cell / drug therapy*
-
Leukemia, Lymphocytic, Chronic, B-Cell / metabolism
-
Lymphoma, B-Cell / drug therapy*
-
Lymphoma, B-Cell / metabolism
-
Mice
-
Mice, Knockout
-
Oxidative Stress / drug effects*
-
Pyrazoles / pharmacology
-
RNA, Messenger / drug effects
-
RNA, Messenger / genetics
-
Reactive Oxygen Species / metabolism
-
Reverse Transcriptase Polymerase Chain Reaction / methods
-
Sulfonamides / pharmacology
-
Sulfones / pharmacology
Substances
-
3-(4-methylsulfonylphenyl)-4-phenyl-5-trifluoromethylisoxazole
-
Cyclooxygenase 2 Inhibitors
-
Isoxazoles
-
OSU 03012
-
Pyrazoles
-
RNA, Messenger
-
Reactive Oxygen Species
-
Sulfonamides
-
Sulfones
-
1-((4-methylsulfonyl)phenyl)-3-trifluoromethyl-5-(4-fluorophenyl)pyrazole
-
S-ethyl glutathione
-
Cyclooxygenase 2
-
Glutamate-Cysteine Ligase
-
Glutathione