Modulators of Multidrug Resistance Proteins in the Management of Anticancer and Antimicrobial Drug Resistance and the Treatment of Inflammatory Diseases

Human multidrug resistance protein (MRP/ABCC) family contains 9 members (MRP1-9) which transport a structurally diverse array of anticancer and antimicrobial drugs and several important endogenous substances including prostaglandins (PGs) and leukotrienes (LTs) with different substrate specificity. MRP1-5 can collectively confer resistance to natural product anticancer drugs and their conjugated metabolites, platinum compounds, folate antimetabolites, nucleoside and nucleotide analogs, and alkylating agents. MRP1-3 are often associated with tumor resistance which is often caused by an increased efflux and decreased intracellular accumulation of natural product anticancer drugs and other anticancer agents. Both PGE(1) and PGE(2) are known high-affinity substrates of MRP4, but not MRP1, MRP2, MRP3 and MRP5. LTC4 is a substrate of MRP1, MRP2, MRP3, and MRP6-8. MRP2 is also able to transport LTD4 and LTE4. Experimental studies in Abcc1-defficient mice have demonstrated a role of MRP1 in inflammation process in vivo. Abcc3-deficcient mice have normal bile salt transport, however, they have decreased blood bilirubin glucuronide levels. Abcc6-deficient mice show remarkable mineralization of the connective tissues, including skin, arterial blood vessels, and retina. Most MRP/ABCC transporters are subject to inhibition by a variety of compounds. Drug targeting of these transporters to overcome MRP/ABCC-mediated multidrug resistance may play a role in cancer and infection (e. g. HIV infection) chemotherapy. Some modulators of MRPs have shown reversing effects on MDR phenotype in preliminary clinical studies and some modulators of MRPs may modify the inflammatory process and consequently ameliorate the inflammatory symptoms. A better understanding of the interactions of these modulators with MRPs has important implications in development of novel drugs for treatment of cancer, infection and inflammation.