Multidrug resistance mediated by the multidrug resistance protein ( MRP) gene

Inherent or acquired resistance to multiple natural product drugs is a major obstacle to the success of chemotherapy. Two proteins have been shown to cause this type of multidrug resistance in human tumour cells, the 170 kDa P-glycoprotein and the 190 kDa multidrug resistance protein (MRP). Overexpression of these N-glycosylated phosphoproteins in mammalian cells is associated with reduced drug accumulation. Both MRP and p-glycoprotein belong to the ATP-binding cassette superfamily of transmembrane transport proteins, but they share only 15% amino acid identity. Furthermore, their predicted membrane topologies differ considerably, with MRP containing three multispanning transmembrane domains compared with the two that are present in P-glycoprotein. The drug cross-resistance profiles of cells that overexpress MRP or P-glycoprotein are similar but not identical. For example, lower levels of taxol resistance are associated with overexpression of MRP than with overexpression of P-glycoprotein. There also appear to be fundamental differences in the mechanisms by which the two proteins transport chemotherapeutic drugs. P-glycoprotein-enriched membrane vesicles have been shown to directly transport several chemotherapeutic drugs, whereas vincristine transport by MRP-enriched membrane vesicles is demonstrable only in the presence of reduced glutathione. Several potential physiologic substrates of MRP including leukotriene C 4 and 17β-estradiol-17-(β- d-glucuronide) have been identified. In contrast, these conjugated organic anions are transported poorly, if at all, by P-glycoprotein. Finally, agents that reverse P-glycoprotein-associated resistance are usually much less effective in MRP-associated resistance. Antisense oligonucleotide-mediated suppression of MRP synthesis offers a highly specific alternative approach to circumventing resistance mediated by this novel drug resistance protein.