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Cyclooxygenase-2, player or spectator in cyclooxygenase-2 inhibitor-induced apoptosis in prostate cancer cells.
- Source :
-
Journal of the National Cancer Institute [J Natl Cancer Inst] 2002 Apr 17; Vol. 94 (8), pp. 585-91. - Publication Year :
- 2002
-
Abstract
- Background: The antitumor activity of cyclooxygenase-2 (COX-2) inhibitors is thought to involve COX-2 enzyme inhibition and apoptosis induction, but it is unclear whether COX-2 inhibition is required for apoptosis. Different COX-2 inhibitors have similar IC(50) values (concentration for 50% inhibition) for COX-2 inhibition but differ considerably in their abilities to induce apoptosis, suggesting the involvement of a COX-2-independent pathway in apoptosis. To test this hypothesis, we investigated the effect of COX-2 depletion on apoptosis and performed a structure-activity analysis of the COX-2 inhibitor celecoxib in the androgen-independent prostate cancer cell line PC-3.<br />Methods: Tetracycline-inducible (Tet-On) COX-2 antisense clones were isolated to assess the effect of COX-2 expression on cell viability and sensitivity to apoptosis induced by COX-2 inhibitors. Untreated Tet-On clones differentially expressed COX-2, and doxycycline-treated clones were depleted of COX-2. We synthesized and characterized various celecoxib derivatives with various COX-2 inhibitory activities and determined their apoptotic activity in PC-3 cells. Apoptosis was assessed with four tests.<br />Results: In contrast to the effect of COX-2 inhibitors, which induced apoptosis, COX-2 depletion did not induce cell death. Susceptibility to COX-2 inhibitor-induced apoptosis was independent of the level of COX-2 expression. Structure-activity analysis found no correlation between apoptosis induction and COX-2 inhibition. Some celecoxib derivatives that lacked COX-2 inhibitory activity facilitated apoptosis and vice versa. Moreover, celecoxib and apoptosis-active celecoxib derivatives mediated cell death by inhibiting the same pathway.<br />Conclusion: We have dissociated the apoptosis-inducing activity from the COX-2 inhibitory activity by structural modifications of the COX-2 inhibitor celecoxib. This separation of activities may provide a molecular basis for the development of new classes of apoptosis-inducing agents.
- Subjects :
- Antineoplastic Agents pharmacology
Blotting, Western
Celecoxib
Cyclooxygenase 2
Cyclooxygenase 2 Inhibitors
Cyclooxygenase Inhibitors pharmacology
Dinoprostone metabolism
Dose-Response Relationship, Drug
Doxycycline pharmacology
Enzyme-Linked Immunosorbent Assay
Humans
Immunoblotting
Indoles pharmacology
Inhibitory Concentration 50
Lactones pharmacology
Male
Membrane Proteins
Models, Chemical
Oligonucleotides, Antisense pharmacology
Phosphorylation
Pyrazoles
Structure-Activity Relationship
Sulfonamides pharmacology
Sulfones
Time Factors
Tumor Cells, Cultured
Apoptosis
Isoenzymes antagonists & inhibitors
Isoenzymes physiology
Prostaglandin-Endoperoxide Synthases physiology
Prostatic Neoplasms enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8874
- Volume :
- 94
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Journal of the National Cancer Institute
- Publication Type :
- Academic Journal
- Accession number :
- 11959891
- Full Text :
- https://doi.org/10.1093/jnci/94.8.585