Targeting the multidrug resistance-1 transporter in AML: molecular regulation and therapeutic strategies.
The multidrug resistance-1 (MDR1) gene product, P-glycoprotein (P-gp), and the multidrug resistance-related proteins (MRPs) are members of the adenosine triphosphate (ATP)-binding cassette (ABC) transporter gene superfamily that regulates the trafficking of drugs, peptides, ions, and xenobiotics across cell membrane barriers. Three-dimensional modeling of human MDR1/P-gp indicates that these glycoproteins function as efficient, ATP-dependent gate-keepers, which scan the plasma membrane and its inner leaflet to flip lipophilic substrates to the outer membrane leaflet. Delineation of the adverse prognostic power of MDR1 in adult acute myeloid leukemia (AML) raised hopes that pharmacologic blockade of P-gp would improve the outcome of conventional cytotoxic therapy, perhaps more so than in any other human malignancy. Phase 3 clinical trials investigating first- and second-generation P-gp antagonists have yielded conflicting results, emphasizing the importance of applying preclinical principals to realistically appraise expectations for clinical benefit. Structure-based design strategies and the delineation of transcriptional regulators of survival gene cassettes promise to yield novel, more-effective strategies to overcome drug resistance. Lessons learned from investigations of these and other mechanisms of cellular defense hold promise for a renaissance in the development of targeted therapeutics in acute leukemia.
Mahadevan
Daruka
D
University of Arizona Cancer Center, Tucson, AZ 85724, USA. dmahadevan@azcc.arizona.edu
List
Alan F
AF
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000737:chemistry; D001667:Binding, Competitive; D002470:Cell Survival; D002986:Clinical Trials as Topic; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins; D008956:Models, Chemical; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D026901:Membrane Transport Proteins; D010455:Peptides; D000255:Adenosine Triphosphate