Interactions of human multidrug resistance protein 4 with camptothecins

Abstract

Multidrug resistance protein 4 (MRP4) is an important member of the MRP family. In this study, we reported that MRP4 is involved in drug resistance to camptothecins (CPTs), which are promising antitumor agents that inhibit the enzyme DNA topoisomerase I. Our goal was to elucidate the role of MRP4 in CPT-related resistance using an extensive panel of its analogs. Cytotoxicity assays suggested that MRP4 overexpression conferred significant resistance to CPTs, and this resistance could be reversed by the glutathione (GSH) synthesis inhibitor buthionine sulfoximine and MRP4 inhibitors including MK571, celecoxib, and diclofenac. In drug accumulation assays, MRP4 significantly decreased the intracellular concentration of most CPT analogs, and MRP4 inhibitors were able to restrain MRP4-mediated drug efflux. Lastly, CPT analogs showed no significant effect on GSH efflux with the exception of CPT-11 at a high concentration. All in all, these novel findings may help us better understand CPT resistance in cancer.