© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 23, 1745-1757,
December 4, 2002
© 2002 Oxford University Press
ARTICLE |
Using Cyclooxygenase-2 Inhibitors as Molecular Platforms to Develop a New Class of Apoptosis-Inducing Agents
Affiliations of authors: J. Zhu, H.-P. Lin (Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy), D. C. Young (Biostatistics Core, Comprehensive Cancer Center), The Ohio State University, Columbus; X. Song, Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington; S. Yan, V. E. Marquez, Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD; C.-S. Chen, Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, and Division of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky.
Correspondence to: Ching-Shih Chen, Ph.D., College of Pharmacy, The Ohio State University, 336 Parks Hall, 500 W. 12th Ave., Columbus, OH 43210–1291 (e-mail: chen.844{at}osu.edu).
Background: The cyclooxygenase-2 (COX-2) inhibitor celecoxib is thought to act as a chemopreventive agent by sensitizing cancer cells to apoptotic signals. Other COX-2 inhibitors, such as rofecoxib, are two orders of magnitude less potent than celecoxib at inducing apoptosis. The molecular structures of celecoxib and rofecoxib were used as starting points to examine the structural features that contribute to this discrepancy. Methods: We used a systematic chemical approach to modify the structures of celecoxib and rofecoxib to produce a series of compounds that were tested for their effects on the viability of human prostate cancer PC-3 cells and their ability to induce apoptosis in these cells. Cell viability was measured by the trypan blue dye exclusion assay, and apoptosis was measured by an enzyme-linked immunosorbent assay that quantifies DNA cleavage and by western blot detection of poly(ADP-ribose) polymerase (PARP) cleavage. Western blotting was used to monitor the effects of the compounds on phosphorylation of the serine/threonine kinase Akt and extracellular signal-regulated kinase 2 (ERK2), two components of celecoxib-induced apoptosis signaling. Monte Carlo simulations were used to molecularly model the surface electrostatic potential and electron density of selected compounds. All statistical tests were two-sided. Results: The structural requirements for the induction of apoptosis in PC-3 cells were different from those for COX-2 inhibition. Structure–function analysis indicated that the induction of apoptosis by compounds derived from COX-2 inhibitors required a bulky terminal phenyl ring, a heterocyclic system with negative electrostatic potential, and a benzenesulfonamide or benzenecarboxamide moiety. These derivatives mediated apoptosis by facilitating the dephosphorylation of Akt and ERK2, irrespective of their COX-2 inhibitory activities. Conclusion: A new class of compounds that induce apoptosis by targeting Akt and ERK2 signaling pathways in human prostate cancer cells can be synthesized by modifying existing COX-2 inhibitors.
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