TY - JOUR T1 - Drug Efflux Transporters and Multidrug Resistance in Acute Leukemia: Therapeutic Impact and Novel Approaches to Mediation JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.112.079129 SP - mol.112.079129 AU - Cindy Xia AU - Peter G Smith Y1 - 2012/07/23 UR - http://molpharm.aspetjournals.org/content/early/2012/07/23/mol.112.079129.abstract N2 - Multidrug resistance (MDR), mediated by multiple drug efflux ATP-binding cassette (ABC) transporters, is a critical issue in the treatment of acute leukemia, with permeability (P)-glycoprotein (P-gp), multidrug resistance-associated protein 1 (MRP1), and breast cancer resistance protein (BCRP, or ABCG2) consistently shown to be the key effectors of MDR in cell line studies. Studies have demonstrated that intrinsic MDR can arise due to specific gene expression profiles, and that drug-induced overexpression of P-gp and other MDR proteins can result in acquired resistance, with multiple ABC transporters having been shown to be overexpressed in cell lines selected for resistance to multiple drugs for acute leukemia. Further, numerous anticancer drugs, including agents commonly used in the treatment of acute leukemia, such as doxorubicin, vincristine, mitoxantrone, and methotrexate, have been shown to be P-gp substrates or to be susceptible to efflux via other MDR proteins, and multiple clinical studies have demonstrated associations between P-gp or other MDR protein expression and response to therapy or survival in acute leukemia. Here we review the importance of MDR in cancer, with a focus on acute leukemia, and highlight the need for rapid, accurate assessment of MDR status for determining optimal treatment selection. We also address the latest research into overcoming MDR, from inhibition of P-gp and other MDR proteins via various approaches including direct antagonism and gene silencing, to designing novel agents or novel delivery systems for existing therapeutic agents to evade cellular efflux. ER -