Reversal of P-Glycoprotein-mediated multidrug resistance by anthraquinones through cyclooxygenase-2 inhibition

We assessed the effects of anthraquinone derivatives from Rhubarb on LPS-induced RAW 264.7 macrophages in order to determine their anti-inflammatory potential. Also, the derivatives were tested in Caco-2 cell lines to evaluate the inhibition of P-gp expression. Among them, emodin significantly inhibited NO production, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression, and prostaglandin E2 (PGE₂) secretion. Furthermore, emodin reduced paw swelling in the carrageenan-induced paw edema mice model. In Caco-2 cells, emodin elevated the accumulation of R-123 and decreased the efflux ratio of R-123, which indicates P-gp inhibition. The inhibition of COX-2 protein by emodin paralleled the decrease in P-gp expression. In addition, MAPK expression was decreased through the prevention of AP-1 DNA binding, which leads to down-regulation in the expression of P-gp. Our data indicate that the inhibition of P-gp function is caused by the decreased expression of COX-2 through the MAPK/AP-1 pathway. In addition to its anti-inflammatory potential, emodin is a novel P-gp inhibitor.