Mini-reviewMammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade
Graphical Abstract
Introduction
Despite significant advances in the area of chemotherapy which have led to decreased mortality rate in cancer patients, 5-year survival rates remain dismal, largely due to the resistance to antineoplastic drugs by either intrinsic or acquired mechanisms [1], [2]. Chemoresistance, or multidrug resistance (MDR), describes a phenomenon whereby cancer cell's resistance to one drug is accompanied by resistance to pharmacologically and structurally distinct class of drugs [3].
Even the mechanisms of anticancer drug resistance appear to be complex; the most common mechanisms are categorized into drug dependent, target-dependent and drug/target-independent. Drug dependent MDR is mainly attributable to the overexpression of efflux drug transporters and detoxifying enzymes which reduced uptake or enhanced efflux of drugs in cancer cells. Target-dependent MDR is caused by factors influencing drug targeting such as translocation, deletion, mutation, and amplification of the target. Drug/target-independent MDR is due to the desensitization of drug targeting by alternation of cell signaling pathways genetically or epigenetically [4], [5], [6], [7], [8]. Among these, one of the most important mechanisms underlying MDR is the overexpression of adenosine triphosphate (ATP)-binding cassette (ABC) super-family of transporters, which efflux both cytotoxic agents and targeted anticancer drugs using ATP driven energy [9], [10], [11].
The purpose of this review is to discuss and highlight the role of the ABC transporters in mediating MDR in cancer cells and the development of ABC efflux transporter inhibitors which could restore the sensitivity of chemotherapy, as well as the epigenetic gene regulation in the control of MDR.
Section snippets
General properties of ABC transporters
The human ATP-binding cassette (ABC) transporters, a large group of membrane protein complexes, consist of 48 members that are classified into seven subfamilies from ABC-A through to ABC-G based on their sequence similarities [12]. Among the 48 ABC transporters identified in humans, those primarily located on the plasma membrane significantly reduced the intracellular concentration of a variety of diverse drugs, drug conjugates and metabolites by export [12], [13]. Of them the major ABC
Multidrug resistance and major mechanisms
The resistance of cancer cells to a broad variety of structurally and mechanistically anticancer drugs is known as multidrug resistance (MDR) [59]. Either intrinsic resistant or acquired resistant could produce chemotherapeutic failure and malignant tumor progression in cancer pharmacotherapy [60]. The major mechanisms of MDR may be grouped into several categories as follows: activation of DNA repair, altered drug targets, metabolic modification and detoxification, inhibition of apoptosis
Conclusion
During the past decades, research has shown that one of the major obstacles in the successful chemotherapy of cancer is related to the overexpression of ABC transporters such as MDR1/P-gp, MRP2 and BCRP, therefore leading to multidrug resistance (MDR). ABC efflux transporters are expressed ubiquitously in normal human tissues which interact with drug-metabolizing enzymes and other transporters in the intestine, liver and kidney, thus obviously affecting the overall pharmacokinetic properties of
Conflict of interest
None declared.
Acknowledgements
This project was supported by the National Science Foundation of China (Nos. 81072686, 81273526, and 81202978).
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The authors contributed equally to this work.