Dimethylcelecoxib inhibits prostaglandin E2 production.

Abstract Dimethylcelecoxib (DMC), a derivative of celecoxib, has been developed to distinguish between the COX-dependent and COX-independent anti-carcinogenic effects of celecoxib. Although DMC has been shown to have no COX-inhibitory activity, it is important to ensure that DMC has no other influence on prostaglandin production. Interestingly, in this study we show that DMC inhibits PGE 2 production in vitro in the low micromolar range in different cancer cell lines. This effect can be at least partly explained by our findings that DMC inhibits microsomal prostaglandin E synthase-1 (mPGES-1) activity in a cell-free assay. Moreover, it prevents mPGES-1 up-regulation after stimulation of HeLa cells with IL-1β and TNFα. Conversely, DMC has no effect on the expression levels of COX-1, COX-2, cytosolic PGES (cPGES) or mPGES-2 in these cells. However, in the cell-free assay DMC inhibits mPGES-1 to a maximum of 65% only and concentrations needed for inhibition of mPGES-1 activity are about 10-fold higher than needed for inhibition of PGE 2 production in cell culture. This suggests that DMC also has an impact on other proteins involved in PGE 2 production. In cell culture experiments the anti-proliferative effect of DMC, measured by the WST-1 assay, seems not to be dependent on PGE 2 inhibition, as DMC was equally effective in unstimulated HeLa cells as well as in stimulated HeLa cells, and the addition of external PGE 2 did not reverse the anti-proliferative effect of DMC in HCA-7 cells. We conclude that DMC is not a suitable non-prostaglandin-inhibiting control substance for research purposes.