Abstract. The ATP-binding cassette (ABC) transporters are members of a protein superfamily that are known to translocate various substrates across membranes, including metabolic products, lipids and sterols, and xenobiotic drugs. Multidrug resistance proteins (MRPs) belong to the subfamily C in the ABC transporter superfamily. MRPs have been implicated in mediating multidrug resistance by actively extruding chemotherapeutic substrates. Moreover, some MRPs are known to be essential in physiological excretory or regulatory pathways. The importance of MRPs in cancer therapy is also implied by their clinical insights. Modulating the function of MRPs to re-sensitize chemotherapeutic agents in cancer therapy shows great promise in cancer therapy; thus, multiple MRP inhibitors have been developed recently. This review article summarizes the structure, distribution, and physiological as well as pharmacological function of MRP1-MRP9 in cancer chemotherapy. Several novel modulators targeting MRPs in cancer therapy are also discussed.

Purpose: The third-generation EGFR inhibitor, osimertinib, is the first mutant-selective inhibitor that has received regulatory approval for the treatment of patients with EGFR-mutant lung cancer. Despite the development of highly selective thirdgeneration inhibitors, acquired resistance remains a significant clinical challenge. Recently, we and others have identified a novel osimertinib resistance mutation, G724S, which was not predicted in in vitro screens. Here, we investigate how G724S confers resistance to osimertinib. Experimental Design: We combine structure-based predictive modeling of G724S in combination with the 2 most common EGFR-activating mutations, exon 19 deletion (Ex19Del) and L858R, with in vitro drug-response models and patient genomic profiling. Results: Our simulations suggest that the G724S mutation selectively reduces osimertinib-binding affinity in the context of Ex19Del. Consistent with our simulations, cell lines transduced with Ex19Del/G724S demonstrate resistance to osimertinib, whereas cells transduced with L858R/ G724S are sensitive to osimertinib. Subsequent clinical genomic profiling data further suggest G724S occurs with Ex19Del but not L858R. Furthermore, we demonstrate that Ex19Del/G724S retains sensitivity to afatinib, but not to erlotinib, suggesting a possible therapy for patients at the time of disease relapse. Conclusions: Altogether, these data suggest that G724S is an allele-specific resistance mutation emerging in the context of Ex19Del but not L858R. Our results fundamentally reframe the problem of targeted therapy resistance from one focused on the "drug-resistance mutation" pair to one focused on the "activating mutation-drug-resistance mutation" trio. This has broad implications across clinical oncology.

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ATP binding cassette (ABC) transporters, such as P-gp, BCRP and MRP1, can increase efflux of clinical chemotherapeutic agents and lead to multi-drug resistance (MDR) in cancer cells. While the discovery and development of clinically useful inhibitors has proved elusive to date, this molecular target nevertheless remains a promising strategy for addressing and potentially overcoming MDR. In a search for new classes of inhibitor, we used fluorescent accumulation and efflux assays supported by cell flow cytometry and MDR reversal assays, against a panel of sensitive and MDR human cancer cell lines, to evaluate the marine sponge co-metabolites 1–12 as inhibitors of P-gp, BCRP or MRP1 initiated MDR. These studies identified and characterized lamellarin O (11) as a selective inhibitor of BCRP mediated drug efflux. A structure–activity relationship analysis inclusive of the natural products 1–12 and the synthetic analogues 13–19, supported by in silico docking studies, revealed key structural requirements for the lamellarin O (11) BCRP inhibitory pharmacophore.

The phenomenon of multidrug resistance (MDR) has attenuated the efficacy of anticancer drugs and the possibility of successful cancer chemotherapy. ATP-binding cassette (ABC) transporters play an essential role in mediating MDR in cancer cells by increasing efflux of drugs from cancer cells, hence reducing the intracellular accumulation of chemotherapeutic drugs. Interestingly, small-molecule tyrosine kinase inhibitors (TKIs), such as AST1306, lapatinib, linsitinib, masitinib, motesanib, nilotinib, telatinib and WHI-P154, have been found to have the capability to overcome anticancer drug resistance by inhibiting ABC transporters in recent years. This review will focus on some of the latest and clinical developments with ABC transporters, TKIs and anticancer drug resistance.

ATP-Binding Cassette transporters are involved in the efflux of xenobiotic compounds and are responsible for decreasing drug accumulation in multidrug resistant (MDR) cells. Discovered by structure-based virtual screening algorithms, bafetinib, a Bcr-Abl/Lyn tyrosine kinase inhibitor, was found to have inhibitory effects on both ABCB1- and ABCG2-mediated MDR in this in-vitro investigation. Bafetinib significantly sensitized ABCB1 and ABCG2 overexpressing MDR cells to their anticancer substrates and increased the intracellular accumulation of anticancer drugs, particularly doxorubicin and [3H]-paclitaxel in ABCB1 overexpressing cells; mitoxantrone and [3H]-mitoxantrone in ABCG2 overexpressing cells, respectively. Bafetinib stimulated ABCB1 ATPase activities while inhibited ABCG2 ATPase activities. There were no significant changes in the expression level or the subcellular distribution of ABCB1 and ABCG2 in the cells exposed to 3 μM of bafetinib. Overall, our study indicated that bafetinib reversed ABCB1- and ABCG2-mediated MDR by blocking the drug efflux function of these transporters. These findings might be useful in developing combination therapy for MDR cancer treatment.

The cytotoxicity of the natural ent-kaurene diterpenoid, oridonin, has been extensively studied. However, the application of oridonin for cancer therapy was hampered primarily by its moderate potency. In this study, a series of oridonin A-ring modified analogues, and their derivatives bearing various substituents on 14-OH position, were designed, synthesized, and evaluated for anticancer efficacy. Some of the derivatives were significantly more potent than oridonin against both drug-sensitive and drug-resistant cancer cells. The most potent compound, 13p, was 200-fold more efficacious than oridonin in MCF-7 cancer cells. Furthermore, 13p induced apoptosis and cell cycle arrest at the G2/M phase. A decrease in mitochondrial membrane potential and an increase in Bax/Bcl-2 ratio, accompanied by activated caspase-3 cleavage, were observed in MCF-7 cells after treatment with 13p, suggesting that the mitochondrial pathway was involved in the 13p-mediated apoptosis. Moreover, 13p significantly inhibited tumor growth in mouse xenograft models and had no observable toxic effect.

In the present in vitro study, we examined the effect of the compound β-elemene on the response of KB-C2 cells overexpressing the ABCB1 transporter to specific antineoplastic compounds. The MTT assay was used to determine the effects of β-elemene in combination with other anticancer drugs on ABCB1-overexpressing cancer cell lines. Furthermore, we used [3H]-paclitaxel accumulation, efflux assay, immunofluorescence experiments, western blot assays and docking analysis to ascertain the mechanism of action of β-elemene. The incubation of KB-C2 cells overexpressing ABCB1 transporter with β-elemene (100 µM) significantly augmented the antineoplastic efficacy of colchicine, vinblastine and paclitaxel when compared to KB-C2 cells incubated with these drugs alone. In HEK293 cells overexpressing the ABCB1 transporter, β-elemene significantly increased the cytotoxicity of paclitaxel. In addition, 100 µM of β-elemene significantly increased the accumulation of [3H]-paclitaxel and this was due to a decrease in [3H]-paclitaxel efflux when compared to controls. The incubation of KB-C2 cells with β-elemene (100 µM) for 72 h did not significantly alter the expression of ABCB1 protein levels. Immunofluorescence experiments indicated that β-elemene did not significantly alter the subcellular localization of the ABCB1 transporter. Docking analysis indicated that β-elemene binds to the drug-binding site of ABCB1 transporter. Finally, β-elemene at 100 µM partially (~50%) increased the sensitivity of the BCRP-overexpressing cell line, NCI-H460/MX20, to mitoxantrone, but β-elemene did not significantly alter the resistance of MRP1-transfected HEK293/MRP1 cells to vincristine. Overall, our in vitro findings indicated that β-elemene potentiates the cytotoxic effects of various antineoplastic drugs in cell lines overexpressing the ABCB1 transporter and that this is due to the inhibition of the efflux component of the ABCB1 transporter.