Dimethylcelecoxib inhibits prostaglandin E2 production.

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-1beta and TNFalpha. 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.