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.

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.