Macrophage cyclooxygenase-2 (COX-2) plays an important role in prostaglandin E2 and thromboxane A2 production. Statins are inhibitors of HMG CoA (3-Hydroxy-3-methylglutaryl coenzyme A) reductases and cholesterol synthesis, which block the expression of several inflammatory proteins independent of their capacity to lower endogenous cholesterol. In the present study, we investigated the effect of simvastatin and mevastatin on COX-2 induction in human monocytic cell line U937 and analyzed the underlying mechanisms. Pretreatment of U937 cells with simvastatin or mevastatin for 24 h resulted in a significant reduction in the lipopolysaccharide (LPS)-dependent induction of prostaglandin E2, thromboxane A2 synthesis, and COX-2 expression. Mevalonate, the direct metabolite of HMG CoA reductase, and farnesyl pyrophosphate and geranylgeranyl-pyrophosphate, intermediates of the mevalonate pathway, significantly reversed the inhibitory effect of statins on COX-2. An inhibitor of geranylgeranyl transferases, GGTI-286 mimicked the effect of statins on COX-2 expression. Cytonecrotic factor-1 increased LPS-dependent expression of COX-2. Treatment of cells with NSC 23766, an inhibitor of Rac, which we demonstrated to block Rac 2 activation, resulted in an inhibition of the LPS-dependent expression of COX-2. Whereas no effect was obtained with RhoA/C blocker, C3 exoenzyme. Gel retardation experiments and NFkappaB-p65 transcription factor assay showed that simvastatin and NSC 23766 decrease significantly NF-kappaB complex formation. In macrophages, the antiinflammatory effects of statins are mediated in part through the inhibition of COX-2 and prostanoids. Rac GTPase protein is identified as one of the targets of statins in this regulation.

In acute promyelocytic leukemia (APL), all-trans retinoic acid (ATRA) triggers cell differentiation, while arsenic trioxide (As 2 O 3 ) generates partial differentiation and apoptosis. Animal and human studies suggest that newly diagnosed APL patients can be cured using As 2 O 3 combined with ATRA. Cyclooxygenases are involved in prostaglandins and thromboxane synthesis. We have recently demonstrated that ATRA induces cyclooxygenase-1 (COX-1) expression and prostaglandin synthesis in NB4 cells and in blasts from patients with APL. In the present study we investigated the effect of ATRA and As 2 O 3 co-treatment on COX-1 expression and prostaglandin formation and tested the effect of the COX-1/COX-2 nonselective inhibitor indomethacin on cell differentiation. Arsenic treatment of NB4 cells resulted in a partial but significant reduction of ATRA-dependent induction of COX-1 expression and activity. Pretreatment of NB4 cells with indomethacin significantly impaired ATRA/As 2 O 3 -induced differentiation, as assessed by cell morphology, nitroblue tetrazolium test or CD11c expression. PGE 2 reversed the negative effect of indomethacin on differentiation of ATRA/As 2 O 3 -treated NB4 cells. In conclusion, COX-1 contributes to ATRA-dependent maturation of NB4 cells and is affected by As 2 O 3 . These results also suggest that nonsteroidal antiinflammatory drugs should be avoided in APL patients treated with the combination of ATRA and As 2 O 3 .