Inhibitory effect of the reversal agents V-104, GF120918 and pluronic L61 on MDR1 Pgp-, MRP1- and MRP2-mediated transport

The human multidrug transporter MDR1 P-glycoprotein and the multidrug resis tance proteins MRP1 and MRP2 transport a range of cytotoxic drugs, resultin g in multidrug resistance in tumour cells. To overcome this form of drug re sistance in patients, several inhibitors (reversal agents) of these transpo rters have been isolated. Using polarized cell lines stably expressing huma n MDR1, MRP1 or MRP2 cDNA, and 2008 ovarian carcinoma cells stably expressi ng MRP1 cDNA, we have investigated in this study the specificity of the rev ersal agents V-104 (a pipecolinate derivative), GF120918 (an acridone carbo xamide derivative also known as GG918), and Pluronic L61 (a (poly)oxypropet hylene and (poly)oxypropylene block copolymer). Transport experiments with cytotoxic drugs with polarized cell lines indicate that all three compounds efficiently inhibit MDR1 Pgp. Furthermore, V-104 partially inhibits daunor ubicin transport by MRP1 but not vinblastine transport by MRP2. V-104 rever ses etoposide resistance of 2008/MRP1 cells, whereas GF120918 does not reve rse resistance due to MRP1. V-104 partially inhibits the export of the orga nic anion dinitrophenyl S-glutathione by MDCKII-MRP1 but not by MDCKII-MRP2 cells. Unexpectedly export of the organic anion calcein by MDCKII-MRP1 and MDCKII-MRP2 cells is stimulated by Pluronic L61, probably because it relie ves the block on entry of calcein AM into the eel by endogenous MDR1 Pgp, ( C) 2000 Cancer Research Campaign.