Reversal of ABC Drug Transporter-Mediated Multidrug Resistance in Cancer Cells: Evaluation of Current Strategies

Abstract

Overexpression of ATP-binding cassette (ABC) drug transporters that actively efflux a variety of amphipathic compounds can cause multidrug resistance (MDR) in cancer cells, which is a major obstacle in the success of cancer chemotherapy. The development of synthetic small molecule compounds or the identification of natural products that block ABC transporter-mediated efflux has been the conventional approach used to combat MDR. The strategy of using chemosensitizers, however, has not been successful in clinical cancer chemotherapy. Therefore, alternative approaches to identify or to synthesize compounds that can induce selective toxicity in cancer cells overexpressing one or more ABC transporters have been undertaken. This review summarizes the recent advances in identifying strategies to restore sensitivity to chemotherapeutics in multidrug resistant cancer cells. THE FUNCTION AND SIGNIFICANCE OF ATP-BINDING CASSETTE TRANSPORTERS IN THE DEVELOPMENT OF MULTIDRUG RESISTANCE IN CANCER CELLSMultidrug resistance (MDR) in cancer is a phenomenon that occurs when cancer cells become simultaneously resistant to structurally unrelated chemotherapeutic agents. MDR in cancer patients will eventually lead to the failure of cancer treatment. Several cellular mechanisms can be responsible for MDR, such as reduced apoptosis, advanced DNA damage repair mechanisms or altered drug metabolism. However, the most common mechanism of resistance is the active efflux of drugs by ATP-binding cassette (ABC) transporters. These transporters have important physiological roles in mammalian cells, which have been extensively reviewed [1][2][3][4]. ABC drug transportersABC transporters are membrane proteins consisting of both transmembrane domains (TMDs) and distinctive nucleotide-binding domains (NBDs), which generate energy from ATP hydrolysis to actively transport a variety of compounds across the membrane [4]. These * To whom correspondence should be addressed: Suresh V. Ambudkar, P-glycoprotein (ABCB1)-ABCB1 was the first human ABC drug transporter identified and has been studied extensively [8]. It transports a broad variety of compounds, including some of the most popular anticancer drugs such as taxanes, anthracyclines and Vinca alkaloids [8]. Since all attempts to obtain crystals of human ABCB1 suitable for X-ray crystallography have failed thus far, the structure of ABCB1 (and other human ABC drug transporters) is predicted based on biochemical studies, mutational analysis and structural information from bacterial homologs such as Sav1866 [9]. Although a low resolution structure based on electron microscopy has been described [10,11], the predicted structure of human ABCB1 is believed to consist of 2 halves, each with one transmembrane domain (TMD) containing six transmembrane helices and 1 NBD, with helices 4, 5 and 6 in the N-terminal half and helices 10, 11 and 12 in the C-terminal half to form the transport substrate site(s) [12][13][14].ABCC1 and ABCG2-ABCC1 was the first member of the MRP family that was found to be l...

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