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Celecoxib: Its non-cox-2 targets and its anti-cancer effects

Lin, Ho-Pi
http://rave.ohiolink.edu/etdc/view?acc_num=osu1124114562

Abstract Details

2005, Doctor of Philosophy, Ohio State University, Pharmacy.
Our previous work showed that celecoxib (Celebrex®), a nonsteroidal anti-inflammatory drug (NSAID, cyclooxygenase-2 inhibitor) was unique among other cyclooxygenase-2 (COX-2) inhibitors in its superior ability to induce prostate cancer cell death, indicating the involvement of non-COX-2 components in the mode of action of celecoxib. To test this hypothesis, we investigated the effect of COX-2 depletion on apoptosis by tetracycline controllable COX-2 antisense constructs and performed a structure-activity analysis of the COX-2 inhibitor celecoxib in PC-3 cells. Both strategies came out with the same conclusion, which is the unique apoptotic inducing activity of celecoxib comes from interfering with other important signaling pathways. We then focused on one of the most promising pathways, PI3K/PDK-1/Akt pathway, which was previously demonstrated in our laboratory to be severely interrupted by celecoxib. Further target identification showed that PDK-1 is one of major targets. Later, we learned that inhibition of PI3K/PDK-1/Akt pathway alone can only induce apoptotic cell death in LNCap cells but not PC3 cells, and further elucidated that the significantly higher level of Bcl-xL in PC3 cells is attributable to this discrepancy. However, the observations of quick apoptotic death in PC3 cells triggered by celecoxib indicate that other yet unidentified targets are also involved. By studying growth inhibitory effects in Human Umbilical Vein Endothelial Cells (HUVECs), we were able to identify cyclin dependent kinases (CDKs), are important targets in addition to PDK-1 for celecoxib. In conclusion, celecoxib trigger its anti-cancer effect through interfering with multiple signaling pathways. This study was used as a fundamental basis in our laboratory for developing novel anti-cancer agents, targeting pathways important for cancer cell survival and growth, based on structural modifications starting from celecoxib.
Ching-Shih Chen (Advisor)
113 p.
Celecoxib; COX-2; Akt; PI3K; PDK1; CDKs; Apoptosis; Cell cycle arrest; HUVECs

Recommended Citations

Citations

  • Lin, H.-P. (2005). Celecoxib: Its non-cox-2 targets and its anti-cancer effects [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1124114562

    APA Style (7th edition)

  • Lin, Ho-Pi. Celecoxib: Its non-cox-2 targets and its anti-cancer effects. 2005. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1124114562.

    MLA Style (8th edition)

  • Lin, Ho-Pi. "Celecoxib: Its non-cox-2 targets and its anti-cancer effects." Doctoral dissertation, Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1124114562

    Chicago Manual of Style (17th edition)

osu1124114562
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© 2005, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.