ABC Efflux Pump-Based Resistance to Chemotherapy Drugs

Chemotherapeutic treatment of cancers can fail due to the development of tumor cell resistance to multiple drugs, a phenomenon called multidrug resistance (MDR), which is mediated by the efflux pump proteins belonging to the ATP-Binding Cassette (ABC) superfamily of proteins. Cultured cell lines subjected to increasing concentrations of varied cytotoxic or chemotherapeutic drugs in vitro can develop resistance due to upregulation of cytochrome P450-based degradation of drugs; sequestration of the compound from its target nucleic acid; increased DNA repair activity; and insensitivity to drug-induced apoptosis. Substrates must bind to the drug-binding pocket of efflux pumps before the transport process starts, powered by ATP binding/hydrolysis at the NBDs of the protein. Binding occurs with variable affinity, which is characteristic of each drug.