title: Down-regulation of PGE2 by physiologic levels of celecoxib is not sufficient to induce apoptosis or inhibit cell proliferation in human colon carcinoma cell lines.
abstract: This study was performed to evaluate whether down-regulation of prostaglandin E(2) (PGE(2)) synthesis by celecoxib treatment is associated with inhibition of cell growth in human colon carcinoma cell lines. Physiologic concentrations of celecoxib (5-10 microM) inhibited 80% to 90% of PGE(2) production in HT-29 cells that express high levels of COX-2 protein. In these concentrations, celecoxib had a minor inhibitory effect (20-30%) on cell growth. There was a significant change in induction of apoptosis only at higher concentrations of celecoxib (>20 microM). Treatment by low concentrations of celecoxib did not alter the levels of COX-1, beta-catenin, P(27), Bcl-2, and Bcl-x proteins. The effect of celecoxib on cell growth inhibition was higher on the COX-2-positive HT-29 cell line (IC(50)=20 microM) than on the COX-2 deficient SW-480 cell line (IC(50)=35 microM). In conclusion, inhibition of PGE(2) synthesis is an early, but not sufficient, step in the mechanism of celecoxib-mediated cell growth inhibition. These results support the need for additional evaluation of independent COX-2 pathways of celecoxib in chemoprevention of CRC.
authors.affiliation: Integrated Cancer Prevention Center, Tel Aviv Sourasky Medical Center, Tel Aviv University, 6 Weizmann Street, Tel Aviv 64239, Israel.
authors.forename: Shahar
authors.initials: S
authors.lastname: Lev-Ari
authors.forename: Dina
authors.initials: D
authors.lastname: Kazanov
authors.forename: Eliezer
authors.initials: E
authors.lastname: Liberman
authors.forename: Rami
authors.initials: R
authors.lastname: Ben-Yosef
authors.forename: Nadir
authors.initials: N
authors.lastname: Arber
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology*; D000068579:Celecoxib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis*; D015536:Down-Regulation; D019073:HT29 Cells; D006801:Humans; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib; D015232:Dinoprostone