Lignans and Norlignans Inhibit Multidrug Resistance Protein 1 (MRP1/ABCC1)-mediated Transport

Background: Multidrug resistance protein I (MRP1/ABCC1) is one of the drug efflux pumps mediating multidrug resistance in several cancer types. Efficient nontoxic inhibitors of MRP1-mediated transport are sought to potentially sensitise cancer cells to anticancer drugs. This study examined the potency of a series of plant lignans and norlignans of various structures to inhibit MRP1-mediated transport from human erythrocytes. The occurrence of MRP1 in the human erythrocyte membrane makes this cell a useful model in searching for efficient MRP1inhibitors. Materials and Methods: The inhibition of 2',7'-bis-(carboxypropyl)-5(6)-carboxyfluorescein (BCPCF) transport from human erythrocytes was measured fluorymetrically. In order to study possible membrane-perturbing effects of lignans and norlignans, the potency of these compounds to induce haemolysis, erythrocyte shape change, and phosphatidylserine (PS) exposure in the external layer of the erythrocyte membrane was examined. Results: Nine compounds (six norlignans and three lignans) of the fourteen that were tested inhibited BCPCF transport from human erythrocytes. The most efficient inhibitor, the norlignan coded LI, had IC50=50 mu M. Structure activity relationship analysis showed that the strongest inhibitors were found among lignans and norlignans bearing a carbonyl function at position C-9. The highly oxidised structures and the presence of an ionisable group such as the carboxylic acid function enhance activity. All compounds that significantly decreased BCPCF transport were non-haemolytic, did not cause PS exposure and did not have any effect on erythrocyte shapes up to 200 mu M. Conclusion: Lignans and norlignans can inhibit MRP1-mediated transport from human erythrocytes and should be further investigated as possible agents reversing multidrug resistance.