Combinatorial effects of nonsteroidal anti-inflammatory drugs and food constituents on production of prostaglandin E2 and tumor necrosis factor-alpha in RAW264.7 murine macrophages.

Combinatorial chemopreventive strategies, in contrast to those with individual agents, show potential in terms of potentially lower toxicity and higher efficacy. In this study, we combined several agents and examined their suppressive effects on the combined lipopolysaccharide (LPS)- and interferon(IFN)-gamma-induced formation of proinflammatory mediators, including prostaglandin (PG) E2 and tumor necrosis factor (TNF)-alpha, in RAW264.7 murine macrophages. The combinatorial effects of indomethacin/genistein (GEN) and aspirin/GEN were found to be synergistic for PGE2 suppression, while the nimesulide/GEN combination was antagonistic. Further, while (-)-epigallocatechin gallate (EGCG) alone increased LPS/IFM-gamma-induced production of PGE2 and TNF-alpha as well as cyclooxygenase-2 expression, the EGCG/GEN combination markedly suppressed these parameters. Our results suggest that certain chemopreventive agents act complexly and that, when used in combination, they affect the intracellular signaling pathways of the paired agents to exert additive, synergistic, or antagonistic effects.