Mechanisms and strategies to overcome multiple drug resistance in cancer

Abstract 

One of the major problems in chemotherapy is multidrug resistance (MDR) against anticancer drugs. ATP-binding cassette (ABC) transporters are a family of proteins that mediate MDR via ATP-dependent drug efflux pumps. Many MDR inhibitors have been identified, but none of them have been proven clinically useful without side effects. Efforts continue to discover not toxic MDR inhibitors which lack pharmacokinetic interactions with anticancer drugs. Novel approaches have also been designed to inhibit or circumvent MDR. In this review, the structure and function of ABC transporters and development of MDR inhibitors are described briefly including various approaches to suppress MDR mechanisms.

Abbreviations: MDR, multidrug resistance, MRP, multidrug resistance protein, ATP, adenosinetriphosphate, ABC, ATP-binding cassette, TMD, transmembrane domains, P-gp, P-glycoprotein, MRP1, MDR related protein, BCRP, breast cancer resistance protein, ABC-P, ABC transporter in placenta, LRP, lung resistance-related protein, MVP, major vault protein, CMOAT, canalicular multi-organic anion transporter, CYP3A4, Cytochrome p450 3A4, SXR, steroid and xenobiotic receptor, GC, glucosylceramide, GCS, glucosylceramide synthase, GSH, glutathione, NAC, N-acetylcysteine, BSO, dl-buthionine (S,R)-sulfoximine, HEK, human embryonic kidney, ROS, reactive oxygen species

Keywords: Multidrug resistance, ATP-binding cassette transporters, Cancer chemotherapy, Multidrug resistance inhibitors