Cyclooxygenase Inhibitors Down Regulate P-glycoprotein in Human Colorectal Caco-2 Cell Line

Purpose. Elevated expression of the ABC transporters P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) seems to correlate with multidrug resistance of cancer cells. In this study we investigated the effect of COX inhibitors in modulating P-gp and BCRP expression and P-gp activity in Caco-2 cells. Methods. mRNA and protein expression of MDR1 and BCRP were evaluated by real time PCR and western blot respectively. The activity of P-gp was measured by intracellular accumulation of rhodamine123 or H-3-Digoxin. Results. The chronic exposure of Caco-2 to indomethacin heptyl ester (indo HE) (0.4 mu M) or nimesulide (10 mu M) (selective COX-2 inhibitors) and naproxen (6 mu M) (non selective inhibitor COX-1/COX-2) significantly decreased the expression and activity of P-gp. In contrast, the acute treatment by nimesulide and naproxen did not modify these parameters while indo HE treatment (48-72 h) caused a protein decrease and a functional inhibition of P-gp. Unexpectedly, the short-term treatment with naproxen induced an important increase of BCRP expression, but this induction was lost after long-term treatment. No modification of BCRP expression was observed after indo HE or nimesulide treatment. Conclusion. Our observations suggest a possible down regulation of P-gp by COX inhibitors, which may enhance the accumulation of chemotherapy agents.