© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 8, 585-591,
April 17, 2002
© 2002 Oxford University Press
ARTICLE |
Cyclooxygenase-2, Player or Spectator in Cyclooxygenase-2 Inhibitor-Induced Apoptosis in Prostate Cancer Cells
Affiliations of authors: X. Song, A. J. Johnson, Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington; H.-P. Lin, P.-H. Tseng, Y.-T. Yang, S. K. Kulp, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, and The Comprehensive Cancer Center, The Ohio State University, Columbus; C.-S. Chen, Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky and Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, and The Comprehensive Cancer Center, The Ohio State University.
Correspondence to: Ching-Shih Chen, Ph.D., Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, 500 West 12th Ave., Columbus, OH 43210–1291 (e-mail: chen.844{at}osu.edu).
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 IC50 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. 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. 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. 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.
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