Multidrug resistance proteins (MRPs): Structure, function and the overcoming of cancer multidrug resistance

ATP-binding cassette (ABC) transporters mediate the ATP-driven translocation of structurally and mechanistically distinct substrates against steep concentration gradients. Among the seven human ABC subfamilies namely ABCA-ABCG, ABCC is the largest subfamily with 13 members. In this respect, 9 of the ABCC members are termed multidrug resistance proteins (MRPs1-9) due to their ability to mediate cancer multidrug resistance (MDR) by extruding various chemotherapeutic agents or their metabolites from tumor cells. Furthermore, MRPs are also responsible for the ATP-driven efflux of physiologically important organic anions such as leukotriene C-4, folic acid, bile acids and cAMP. Thus, MRPs are involved in important regulatory pathways. Blocking the anticancer drug efflux function of MRPs has shown promising results in overcoming cancer MDR. As a result, many novel MRP modulators have been developed in the past decade. In the current review, we summarize the structure, tissue distribution, biological and pharmacological functions as well as clinical insights of MRPs. Furthermore, recent updates in MRP modulators and their therapeutic applications in clinical trials are also discussed.

Automated summary

ABC transporters mediate the translocation of structurally and mechanistically distinct substrates against steep concentration gradients using ATP energy. The ABCC subfamily is the largest in humans, with 13 members, including 9 multidrug resistance proteins that can extrude chemotherapeutic agents from tumor cells. Additionally, MRPs are also involved in the efflux of physiologically important organic anions and are potential targets for overcoming cancer multidrug resistance.