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Clinically-Relevant ABC Transporter for Anti-Cancer Drug Resistance

Huan Xiao, Yongcheng Zheng, Lingling Ma and 2 more

Frontiers in Pharmacology · 2021 · Review · CC BY

doi:10.3389/fphar.2021.648407

Abstract

Multiple drug resistance (MDR), referring to the resistance of cancer cells to a broad spectrum of structurally and mechanistically unrelated drugs across membranes, severely impairs the response to chemotherapy and leads to chemotherapy failure. Overexpression of ATP binding cassette (ABC) transporters is a major contributing factor resulting in MDR, which can recognize and mediate the efflux of diverse drugs from cancer cells, thereby decreasing intracellular drug concentration. Therefore, modulators of ABC transporter could be used in combination with standard chemotherapeutic anticancer drugs to augment the therapeutic efficacy. This review summarizes the recent advances of important cancer-related ABC transporters, focusing on their physiological functions, structures, and the development of new compounds as ABC transporter inhibitors.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Multidrug resistance (MDR) refers to the resistance of a wide spectrum of structurally and mechanistically unrelated drugs across the membrane. This process is among the culprits of failure of cancer chemotherapy, since the cancer cells can efflux chemotherapy agents and therefore reduce the intracellular drug levels. Members of the ATP-binding cassette family have been found to be involved in this process. To be specific, the ABC transporter family can be divided into seven subfamilies according to their genome sequences and TMDs (transmembrane domain) structures. Some of them have been reported to act both as importers and exporters of bacteria, however, in eukaryotic cells, they all efflux pumps. P-glycoprotein (P-gp) was the first identified member within this family and a high-resolution structure of the mouse homolog, which has 87% sequence identity with human has been elucidated. Except for P-gp, ABCC1(also known as MRP1)and ABCG2 (also known as BCRP) have also been extensively studied, confirming their prominent roles in multidrug resistance of cancer cells. During the past few decades, numerous efforts have been made to solve the drug resistance caused by these transporter proteins. However, most of these attempts lead to disappointing results for both the first generation and the second generation of inhibitors, because they exhibit either unacceptable levels of toxicity or less potential inhibiting effects. So far, more inhibitors have been exploited (from nature or synthetic sources ). In addition, researchers have achieved a deeper understanding of the phenomenon of chemotherapy resistance through their concerns to the genes and signaling pathways that modulate the expression of these proteins. In this review, we summarize the recent progress of the most clinically significant ABC transporters ABCB1, ABCG2, and ABCC1 that cause multi-drug resistance during cancer therapy, with the emphasis on novel small molecule compounds that are tested in preclinical and clinical studies, mainly on natural products, synthetic compounds, aiming to provide a wider perspective to understand the multidrug resistance and new strategies targeting ABC transporters in cancer treatment.

ABCB1 (P-gp)

P-gp was the first found human ABC transporter of all known ones and was identified as a glycoprotein responsible for modulating drug permeability. MDR, the gene encoding P-gp, is located in chromosome 7 at q21 and contains 28 exons encoding 1280 amino acids of this 170 kDa protein. P-gp are similarly expressed in human and mouse tissues, with a more biased expression in excretory tissues, including breast, blood-brain barrier, liver, pancreas, and kidney, and in the apical membrane of epithelial cells located at physiological barriers. P-gp exports neutral or positively charged hydrophobic compounds and xenobiotics from cells, thereby protecting them from cytotoxicity. The critical role of P-gp in the blood-brain barrier (also known as BBB), was first illustrated by Schinkel et al.. They found the deletion of Abcb1a and Abcb1b can lead to CNS toxicity from ivermectin, however, despite its defensive role in protecting cells, the overexpression of P-gp mRNA and protein in clinical specimens in breast, kidney, and lung cancers portends a poor response to chemotherapy, resulting in low survival rates. P-gp can efflux chemotherapy agents and reduce intracellular drug levels, which is one of the major causes of chemo-resistance. The major substrates involved in the multidrug resistance of P-gp are structurally and mechanistically unrelated drugs. Moreover, P-gp is preferable to express in poorly differentiated and most invasive cells. In a range of soft tissue sarcomas, P-gp expresses most in the largest and most aggressive tumors. Single-nucleotide polymorphisms (SNP) occurring in ABCB1 genes can result in increased or decreased transporter efficacy, depending on the gene type of the variants, which remains complex so far.

ABCG2

ABCG2 plays a pivotal role in extruding exogenous and endogenous substrates and drugs, which is related to many multidrug resistant cancer cell lines, including acute lymphoblastic leukemia (ALL), retinal progenitors, hepatic metastases, gastric carcinoma, fibrosarcoma, nonsmall cell lung cancer, glioblastoma and myeloma. ABCG2 locates in the plasma membrane of the cell and expresses in normal tissues like placenta, prostate, kidney, blood-brain barrier, liver, ovary, small intestine, and seminal vesicle, which is responsible for regulating the intracellular levels of hormones, lipids, ion and intracellular organelles such as mitochondrion, lysosome, endoplasmic reticulum, Golgi apparatus. ABCG2 also has a wide range of mechanistically and structurally different substrates, such as mitoxantrone, methotrexate, camptothecins, topotecan and irinotecan, SN-38, epipodophyllotoxin, imidazoacridinones, the anthracycline doxorubicin and tyrosine kinase inhibitors. ABCG2 has a less important role in uric acid transport, however, its dysfunction leads to several diseases linked to hyperuricaemia such as gout, kidney disease, and hypertension. What is more, phytoestrogen sulfate conjugates, uremic toxin, and indoxyl sulfate are unique substrates of ABCG2. A genetically engineered mouse model about BRCA1-associated breast cancer (Brca1−/−p53−/− mice) has identified that ABCG2 overexpression is the cause of acquired topotecan resistance, and the genetic ablation of ABCG2 improves the survival rate of topotecan-treated animals. In fact, in some cancer cell lines, more than one ABC transporter is overexpressed. High levels of ABCG2, ABCB1, and ABCC1 have been found within primitive leukemic CD34+/38- cells. The co-expression contributes to multidrug resistance, which requires multi-transporter inhibitors to achieve a better clinical outcome. However, although the ABCG2-involved multidrug resistance mechanisms are basically clear, the clinical trial relevant to ABCG2 inhibitors has received few satisfying results.

ABCC1

ABCC1 was identified in 1992 from human small-cell lung cancer cell lines whose drug resistant behavior occurred without the overexpression of P-gp. ABCC1 expresses in the plasma membrane of some normal tissues and cells including liver, kidney, lung, intestine, blood-brain barrier and peripheral blood monocellular cells. Overexpression of ABCC1 is related to endometria, acute myeloblastic, glioma, lymphoblastic leukemia, head and neck, non-small cell lung cancer, neuroblastoma, melanoma, prostate, breast, renal, thyroid cancer. To be specific, ABCC1 is a lipophilic anion pump, conferring resistance to anti-cancer drugs. Compared with P-gp, the substrates of ABCC1 have more diverse structures and most of them are amphipathic organic acids with large hydrophobic groups. Endogenous substrates are mainly pro-inflammatory molecules such as Leukotrienes C4 (LTC4), hormones such as estrogens and prostaglandins, sphingosine-1-phosphate, antioxidants like glutathione and glutathione disulphide. Noteworthy, Glutathione (GSH) has an impact on ABCC1 transport activities. ABCC1 and GSH are synergistic to some extent. They co-transport anticancer drugs such as doxorubicin, vincristine and etoposide. ABCC1 also transports GS-conjugated anions such as LTC4 and reduced GSH with low affinity and GSSG with a higher affinity. Exogenous substrates include many natural products like flavonoids, vincristine, daunorubicin, doxorubicin, imatinib, methotrexate and organic anions, metabolites of drugs. Importantly, the MYCN oncogene, a driver of tumorigenesis in neuroblastoma, can regulate ABCC1 drug transporter at the level of transcription.

Structure and Function

The ABC transporter family is divided into 7 subfamilies according to their genome sequences and core TMDs (transmembrane domain) structures. The three transporters we discuss here belong to the type III ABC system, for they all consist of 2 × 6 TMs (transmembrane helix), a striking difference between the type I ABC systems with a minimal core of 2 × 5 transmembrane helices (TMs) and type II ABC systems harboring 2 × 10 TMs. Except from ABCC1, ABCB1 and ABCG2 are both half-transporters, working as a homodimer. Two NBDs dimerize to form two ATPase binding sites, which catalyze the ATP hydrolysis following a common mechanism: a glutamate residue interacts with hydrolytic water for the attack of the ATP phosphate. In NBD1 of ABCC1, the corresponding residue is not a glutamate but an aspartate whose side chain is not long enough to interact with the hydrolytic water.

ABCB1

ABCB1 has been viewed as a “hydrophobic vacuum clearer” because most of the substrates transported by this protein are hydrophobic and distributed into the lipid bilayer. Each ABCB1 contains 1 TMD, 1 nucleotide binding domain (NBD), and forms an active transporter through dimerization. The specific binding site is located in the TMDs and the ATP hydrolysis occurs in the intracellular NBDs. In the apo state, the portals open to the cytoplasm and the inner leaflet of the lipid bilayer (Figure 1A). The portals are large enough to accommodate the potential substrates from the lipid bilayer and allow these hydrophobic compounds to pass through. The portals are formed by the proximity TMs (TM4/6, TM10/12). Most of the amino acid residues in the binding pocket are hydrophobic and located in the upper side of the pocket. Only 15 of the 80 residues are polar and located in the lower half of the pocket. Different substrates or inhibitors, due to their different structures, may bind to different residues. Paclitaxel (Taxol) interacts with residues Q725, Q347, Q990 while zosuquidar interacts with M985, F982. The conserved glutamine Q475 in NBD1, Q1118 in NBD2 can coordinate with Mg2+ and gama-phosphate of ATP, thus they play an important role in ATP hydrolysis and drug transport (Figure 1B). In addition, tyrosine residues also play an important role as hydrogen bond donors and acceptors in ABCB1 drug transport activity. To evaluate the importance of the hydrogen bond in ligand-protein interactions, 15 conserved residues interacting with substrates are substituted with tyrosine residues. This so-called 15Y mutants can still transport small and medium size substrates, however, large substrates like Bodipy-Vinblastine cannot be normally transported. This demonstrates that in some cases it is not the hydrogen bond but the physico-chemical properties which affect the transportation.

ABCG2

ABCG2 is a half transporter, with 6 transmembrane helixes and 1 ATP-binding site. The high-resolution structure which was first elucidated in 2017 (; Figure 2A) brings an insight of the molecular mechanisms underlying the transport behavior. ABCG2 has 1 NBD and 1 TMD located on a single polypeptide chain and forms a homodimer as an active transporter. Unlike ABCB1 transporter, the distance between the NBDs and the membrane within the ABCG2 is smaller due to the shorter transmembrane helix and intracellular loops. The interface of TMD is formed by TM2 and TM5a from opposing ABCG2 monomers. ABCG2 has two cavities involved in the transport behavior (Figure 2B). The larger cavity 1 and the smaller cavity 2 are separated by two leucine (L554, L554’) motifs. Cavity 1 opens to the cytoplasm and inner leaflet of the lipid bilayer, and cavity 2 opens to the extracellular, which is located below the EL3 external loop. The function of cavity 1 is to accommodate potential substrates, especially the flat, polycylic and hydrophobic ones, while cavity 2 possesses lower affinity for these substrates because of its less pronounced hydrophobic interface. However, the lower affinity may release substrates more easily. Two critical steps are involved in the process of substrate transport. Firstly, the di-leucine valve regulates the small molecules to enter the upper cavity, which is a key element for the catalytic cycle. Secondly, the essential residue E585 are harbored by the re-entry helix in the roof, making it more accessible to the extracellular. The mutants N436A, F439A decrease both the substrate transport activity and ATPase activity which proves the functions of these two residues in binding and transporting estrone-3-sulfate (E1S) (Figure 2C). Moreover, the hydrogen bond between N436 and the sulfate group of E1S and the stacking interaction between the phenyl ring of F439 and the ring system of E1S are important for binding affinity. Another mutant V546F reduces the transport activity but simultaneously increases the ATPase activity, indicating that the addition of two phenyl rings at this position mimics the binding of a substrate and stimulates the ATPase activity, but can cause “clog” upon binding with E1S.

ABCC1

ABCC1 transporter is encoded by ABCC1 gene, with the weight of 190 kDa and contains 1580 amino acids. Although there is a 23% sequence identity between P-gp and ABCC1, they have an intriguing substrate overlap. ABCC1 is a single polypeptide, containing transmembrane domains (TMDs) and two nucleotide-binding domains (NBDs). Only the one nucleotide-binding domain located on the NBD2 is responsible for hydrolyzing ATP and providing energy for translocation. ABCC1 contains a N-terminal membrane-bound region (TMDo) domain that links to the transporter core through a Lo linker (Figure 3A). The truncation of TMDo behaves like wild-type, whereas the loss or mutation of Lo linker results in false protein folding and defective function. The binding pocket of ABCC1 transporter is formed by two bundles, TM1 and TM2, and the inner-face residues provided by these two bundles are quite different. Positively charged residues locate in TM1 while hydrophobic residues locate in TM2. The positive charged region usually binds with the moiety of GSH and another region rich in hydrophobic residues binds to the substrate. LTC4 can be selectively transported by ABCC1 (Figures 3B,C) and the way in which LTC4-GSH conjugates to pass through ABCC1 has been elucidated by several studies. Amphipathic substrates that contain both negatively charged and hydrophobic residues can be transported without conjugating with GSH. Besides MYCN oncogene regulates the transcription of ABCC1, the transfection of MCF-7/VP-16 breast cancer cells with miR-326 can downregulate ABCC1 expression and increase cancer cell sensitivity to etoposide and doxorubicin.

ABC Transporter Inhibitors

The past few decades have seen numerous efforts made to solve the drug resistance caused by ABC transporter proteins. Many of the first and second-generation ABC transporter inhibitors exhibit either high levels of toxicity or low potential inhibiting effects. Researchers are exploiting more potent inhibitors, mainly focusing on synthetic compounds and chemicals from nature plants. The chemical structures of representative ABC inhibitors are shown in Figures 4–6.

Flavonoids

Majority of flavonoids are inhibitors of P-gp and their inhibitory mechanisms are different, such as blockage of the binding site, interference with ATP hydrolysis, decrease of P-gp expression. Naringenin (1), isolated from the aerial parts of Euphorbia pedroi, exhibits multiple cellular functions such as antioxidant, anti-inflammatory, P-gp inhibitory activities. Upon applying together with felodipine in KB-V1 cells, it can decrease the P-gp expression level in KB-V1cells and increase the concentration of felodipine. Quercetin (2), which is abundant in onions, apples, broccoli and berries, has a wide range of biological activities including antiproliferation and proapoptotic actions with cancer cells. Used in combination with the chemotherapeutic agent daunorubicin in gastric cancer cells, quercetin can down-regulate the ABCB1 gene, reduce the overexpression of P-glycoprotein, and inhibit the efflux of drugs. Finally, quercetin significantly sensitizes cancer cells to action of daunorubicin and increases the percentage of apoptosis. Another study found that methylated EGC and GC derivatives (3) exhibited better inhibitory effects targeting ABCB1 with an EC50 range from 102 to 195 nM, meanwhile they are not the substrates of ABCB1. Chalcones are precursors for the synthesis of flavonoids, which can also reverse multidrug resistance. 2′,4′-Dihydroxy-6′-methoxy-3′,5′-dimethylchalcone modulates the expression of P-gp gene. When combined with 5-fluorouracil (5-FU), it can significantly elevate tumor inhibition rate to 72.2% in BEL-7402/5-FU cell lines. SAR studies demonstrate that the introduction of a basic group on the chalcone moiety could enhance the P-gp inhibition and weaken the BCRP inhibition. The basic chalcones are better P-gp inhibitors, while the non-basic chalcones are better BCRP inhibitors. The good activity of chalcone is mainly related to properly placed electron donor atoms rather than lipophilicity, especially the meta-disubstituted dimethoxy motif on either ring A or B (Figure 7; ).

Alkaloids

Alkaloids are secondary metabolites found in plants, fungi, and bacteria. The main structural feature of alkaloids is a heterocyclic ring bearing one or more basic nitrogen. Such nitrogen atom is necessary for P-gp inhibitory activity. Quinine (4), is reported to reverse doxorubin resistance in 8226/DOX6 myeloma cells and the quinine dimer can reverse the Rh123 efflux in MCF-7/DX1 cells through P-gp inhibition. Further modifications focus on the variations of the linker within the dimer and the introduction of triazole ring systems. Sanguinarine (5) is a benzylisoquinoline that can increase the bax/bcl2 ratio, thereby activating caspases to reverse the P-gp-induced drug resistance. Berberine (6) is a calcium channel blocker, which can inhibit the Wnt signaling pathway and P-gp so as to increase the intracellular accumulation of drugs. Berbamine (7) can downregulate the mRNA of P-gp in imatinib-resistant BCR-ABL-positive human leukemia K562 (K562-r) cells. Tetrandrine (8), a bisbenzyl isoquinoline, can regulate NF-κB signaling pathway and inhibit P-gp in MCF-7/ADR cell lines when synergistically used with paclitaxel as self-assembled nanoparticles. Verapamil (9), a papaverine derivative, is a classic chemosensitizer and the first found P-gp inhibitor. It can competitively inhibit the transport function of P-gp without interrupting ATP hydrolysis, and increase the intracellular accumulation of many anticancer drugs to overcome the P-gp-mediated MDR.

Indole alkaloids such as Reserpine (10), Indole-3-carbinol and indole-3-carbaldehyde can inhibit P-gp mediated efflux of drugs like doxorubicin, vincristine. 3,4,5-trimethoxybenzyl leuconicine A (11), a derivative of leuconicine A, is a potent P-gp inhibitor as it decreases the dose of vincristine in a resistant cancer cell lines.

Lamellarin O (12), isolated from southern Australian marine sponge, possesses inhibitory effects on both P-gp and ABCG2. It increases the accumulation of P-gp transporting drugs like DOX in SW620/DOX300 cells through the blockage of the binding site. Cyanogramide bearing a novel spirocyclic pyrrolo [1,2-c]imidazole skeleton, which is isolated from Actinoalloteichus cyanogriseus WH1-2216-6 can reverse the DOX-induced resistance in K562/A02 and MCF-7/DOX cells, the vincristine (VCR)-induced resistance in KB/VCR cells with moderate activities in micro-molar range. A series of 5-halogenated-7-azaindolin-2-onederivatives containing a 2,4-dimethylpyrrole moiety are evaluated for their anticancer effects in MCF-7, HepG2, HT-29, A549, PANC-1, Hela. The most active one (13), IC50s: 4.49–15.39 μM) was proved to be even more potent than Sunitinib (IC50s: 4.70–>30 μM) against all tested cancer cell lines. Another polysubstituted pyrrole, 4-acetyl-3- (4-fluorophenyl)- 1-(p-tolyl)-5-methylpyrrole, was found to reverse digoxin with a IC50 value of 11.2 µM and enhance the pharmacokinetic properties of P-gp substrates. Piperine, a piperidine alkaloid from Indian spice black pepper, can downregulate the expression level of transporter ABCB1, ABCC1, and ABCG2 genes. Piperine mainly inhibits P-gp activity by interacting with its nucleotide binding domain, that is to say, it competes with ATP binding site in P-gp. Take this into consideration, two piperine analogs Pip1 (14) and Pip2 were synthesized and exhibited better interaction with P-gp than piperine. Tertiary alkaloids like stemocurtisine and oxystemokerrine, isolated from Stemona aphylla and Stemofoline burkillii, also can inhibit P-gp to some extent. Stemofoline can inhibit P-gp of human cervical carcinima cell line (KB-V1) in a dose and time-dependent manner.

Terponoids

Terponoids can be divided into several types according to the number of isoprene units within their parent structure like monoterponoids (bearing 10 C), diterponoids (bearing 20 C), sesquiterponoids (bearing 15 C), tetraterpenes (bearing 40 C). Studies have shown that lipophilic substituents at C6 position and the carbonyl group at C2, C3, C8 positions are required to make terponoids ideal P-gp inhibitors.

Sooneuphanone D (15), isolated from Euphorbia soongarica, is a potent P-gp inhibitor with a remarkable MDR reversal activity much higher than verapamil. When sooneuphanone D is applied together with navelbine, it can significantly reduce the IC50 values of navelbine within KBV200 cell lines, indicating its reversal effects in P-gp overexpressed cancer cell lines. In another study, 28 cucurbitane-type triterponoids, isolated from Momordica balsamina and their derivatives were studied for their collateral sensitivity effect on three different human cancer entities. Balsaminol F (16) exhibits collateral sensitivity effect through high anti-proliferative activity in gastrolic cancer cell lines (EPG85-457). Its derivatives such as balsaminagenin C exhibit reversal of multidrug resistance in human MDR1 gene-transfected mouse lymphoma cells. A myrsinol diterpene J196-10-1, isolated from LANGDU, exhibits reversal effects through competitively inhibiting P-gp transporters and increasing intracellular drug accumulation without altering MDR1 gene expression. Sipholenol A (17), isolated from Red Sea Sponge Callyspongia siphonella, mediates drug efflux activities of P-gp without altering the expression level of P-gp. Substitution of the methyl group at C15 and the oxidation of the hyroxyl group to a ketone at C4 can both cause reduced reversal activity.

Flavonoids

Naringenin (1) is a common dietary flavanone which can be found in citrus fruits like oranges, bergamots and lemons. Naringenin and its derivatives were evaluated as multidrug resistance (MDR) reversers in cancer cells. The carbonyl group of naringenin was modified into hydrazones, azines, carbohydrazides which contain nitrogen atom or extra aromatic moieties. Azines and carbohydrazide derivatives exhibit potent efflux inhibition. Among them, the azine derivatives exert high inhibitory activity due to the introduction of C=N-N=C moiety and have dual inhibition on both ABCG2 and ABCC1. Chrysin (18) shows inhibitory activities toward ABCG2 with an IC50 of 4.6 ± 0.5 μM, while tectochrysin and 6-prenylchrysin exhibit inhibitory activities in R482 ABCG2-transfected HEK-293 cells with an IC50 of 3.0 ± 0.9 μM and 0.29 ± 0.06 μM, respectively. In general, flavones inhibit ABCG2 more efficiently than flavonols, isoflavones and flavanones. As mentioned earlier, introducing different groups on the chalcone template can produce corresponding inhibitory effects on P-gp and BCRP. With respect to chalcone derivatives, the replacement of B-ring with a quinoxaline moiety accompanied with different patterns of hydroxy and methoxy substitutions at A-ring can result in higher and obvious BCRP inhibitory effects in HEK293-ABCG2 cells. The quinoxaline contributes the electrostatic interactions between the two nitrogen atoms and the ABCG2 protein. There are four key structural features that improve the ABCG2 inhibition: the ortho-position of the amide linker; the presence of a phenyl or 2-thienyl substitution at the amide linker; 3,4-dimethoxy substitution on ring B.

Terponoids

Guajadial (19), isolated from the leaves of Psidium guajava, is a natural meroterpenoid which has been found to have anti-tumor activity, especially in breast cancer cell lines. Guajadial has reversal effects in MCF-7/ADR and MCF-7/PTX cells by inhibiting both expressions of P-gp and ABCG2. Meanwhile, it suppresses the PI3K/Akt pathway, which is related to cell proliferation, apoptosis, and migration.

Tariquidar Analogs

Tariquidar (20) was an intrinsically the third-generation P-gp inhibitor which can reverse the resistance of doxorubicin, vinblastine in advanced breast cancer. However, due to its high toxicity in a phase III clinical trial for non-small cell lung cancer (NSCLC) and susceptibility to hydrolysis, a large number of tariquidar analogs have been synthesized to optimize its pharmacological properties. In a recent study, researchers synthesized a series of tariquidar derivatives and found that some of them are able to reverse both ABCB1 and ABCG2-mediated drug efflux, respectively. The mechanism may be related to the inhibition of ATP hydrolysis, but needs to be further verified by ATPase assay. The unstable ester moiety was further replaced by ketones, which increase the stability in mouse plasma. UR-MB108 (21) and UR-MB136 (22) are the most effective ABCG2 inhibitors so far with the IC50 value about 80 nM in a Hoechst 33,342 transport assay. The molecular mechanism of their inhibitory effects lies in the depressing of ATPase by locking the inward-facing conformation.

Ko143 Analogs

The fungal toxin fumitremorgin C (23, FTC) is a specific inhibitor targeting ABCG2, however, the neurotoxicity prevents its further use. Later, tetracyclic analogs of FTC were developed, among which Ko143 (24) was found to be the most potent one, but it is unstable in mouse plasma and has nonspecific effects on ABCC1 and ABCB1. These have led to further structural study of ABCG2 and the development of Ko143 analogs as specific ABCG2 inhibitors. Ko143 analogs are as potent as or even superior than Ko143. The modifications at C-9 position with methoxy group forms a hydrogen bond with T435 in cavity 1. The removal of methoxy groups and addition of small hydrophilic groups reduce the binding energy, while small hydrophobic groups do not make any differences. The tert-butyloxycarbonyl group, which can form van der Waals interactions with residues at C-3 position, also leads to decreased inhibitory effects when exchanged with ion-bearing moieties.

Flavonoids

Flavonoids-type compounds can also exert ABCC1 inhibitory activity in MDCKII-MRP1 cells. Chromones bearing substituted amino groups with N-substituted carboxamide moieties in C-2 are synthesized and tested for their inhibitory activities, among which (2- [4-(Benzo [c][1,2,5]oxadiazol-5-ylmethyl)piperazin-1-yl]-5,7-dimethoxy-4H-chromen-4-one (25) is proved to be the most potent ABCC1 inhibitor and stable in mouse plasma (; B et al., 2020). In another study, flavonoid dimers are found to be more potent toward ABCC1 than their counterpart monomers. Three flavono stilbenes isolated from Sophora alopecuroides L were found to have an inhibitory effect toward ABCC1, which can increase the intracellular concentrations of 6-carboxyfluorescein diacetate and doxorubicin in MRP1-transfected U-2 OS cells. Timosaponin A-III (26, TAIII), a saponin isolated from the rhizome of Anemarrhena asphodeloides, were found to reverse both P-gp and ABCC1-induced drug resistance through regulation of PI3K/Akt signaling pathway. Chrysin (18), 3-methoxy-chrysin and 5,7-dihydroxy-4′-fluoro-flavone are more effective and less toxic than verapamil. Hydroxylation at different places of chrysin can alter the activity, for example, hydroxylation at C-5 or C-7 can increase GSH efflux, while hydroxylation at C-6 leads to the opposite results. However, when hydroxylation occurs both at C-5 and C-7, the activity does not increase. In general, structure-activity relationships demonstrated that although the absence of a hydroxyl group at C-3 of flavonoid C ring is absolutely required to induce ABCC1-cell death, but it cannot to stimulate GSH efflux.

Alkaloids

The inhibitory effects of pyrrolo [3,2-d]pyrimidines toward ABCC1 show that piperazine, which bears large phenylalkyl side chains at C-4 position, can increase the inhibitory activities, whereas when piperazine is replaced with an amino group, the activity decreases. Moreover, the aliphatic and aliphatic aromatic variations in C-5 and C-6, especially the large aliphatic side chain at position 5, can inhibit ABCC1 effectively with IC50 value in the nanomolar range (Figure 8; ). A novel triazolonaphthalimide derivative named LSS-11 (9-amino-6-(2-dimethylamino)propyl]-1-(3-(dimethylamino)-propyl)benzo [de] [1,2,3]triazolo [5,4-g]isoquinoline-5,7(1H, 6H)-dione (27) acts as a potent inhibitor toward ABCC1 through DR5/PARP1 pathway and STAT3/MDR1/MRP1 STAT3 inhibition. Recently, a series of 9-deazapurines are synthesized (Figure 8), among which the 4-(4-(2-(1H-Indol-3-yl)ethyl)piperazin-1-yl)-5-(3-phenylpropyl)-5H-pyrrolo [3,2-d]pyrimidine-7-carbonitrile (28), has been identified to be a broad-spectrum inhibitors which regulate P-gp-mediated efflux of Calcein AM, ABCC1-mediated efflux of daunorubicin, and ABCG2-mediated efflux of pheophorbide A.

Other Inhibitors

3β-Acetyl tormentic acid (29) can reverse the resistance of doxorubicin and vincristine by mediating intracellular levels of GSH and inhibition of glutathione-s-transferase (GST) activity, instead of modulating the expression of ABCC1.

Tyrosine Kinase Inhibitors

TKIs bind to the catalytic domain of tyrosine kinases and inhibit cross-phosphoralation and thereby interfere downstream signaling pathways, subsequently impairing cell proliferation and survival. The mechanism underlying the inhibitory effects of TKIs on ABC transporters may be similar to that of tyrosine kinase, that is, they compete with ATP and bind to the ATP-binding sites. Whether TKIs are substrates or inhibitors of ABC transporters depends on their concentrations and the cancer cells they target (Figure 9).

Imatinib and Nilotinib

Imatinib (30) is a kinase inhibitor which targets BCR-ABL (BCR, break point cluster region; ABL, Abelson virus tyrosine kinase). Studies revealed that imatinib could reverse the drug resistance to doxorubicin by downregulating expression level of ABCB1 and subsequently resulting in accumulation of doxorubicin. Imatinib also exhibits inhibitory effects toward ABCG2 even at low concentration and the expression level of ABCG2 did not affect the efflux and accumulation of imatinib, which indicates that imatinib may have a higher affinity for ABCG2 than ABCB1. Nilotinib (31), an aminopyrimidine ATP-competitive second-generation TKI, was designed to overcome resistance to imatinib in many BCR-ABL mutants. It exhibits reversal effects in the doxorubicin-resistant MG63/DOX cell line. Moreover, it specifically reverses mitoxantrone efflux caused by ABCG2 and increases the intracellular accumulation of mitoxantrone in over-expressing ABCG2 cells.

Gefitinib, Erlotinib and Lapatinib

Gefinitib (32), one of the most famous EGFR inhibitors, has been used to treat NSCLC. However, enhanced ABCG2 expression has been detected within gefinitib-resistant cancer cells. Inhibition of EGFR by erlotinib (33) can also induce the alteration in ABCG2 gene and protein expression level, supporting the fact that EGFR/AKT pathway is involved in the regulation of ABCG2 expression. What is more, a synergistic effect of lapatinib (34) and doxorubicin was also found in tumorspheres which generates from human breast cancer cells and exhibits drug resistance due to the overexpression of ABCB1 and increased EGFR/HER2 signaling.

Sunitinib

Recently, a study has shown that in doxorubicin-resistant endothelial cell lines, the over-expression of ABCG2 and ABCB1 has a cross-resistant effect on sunitinib (35). The blockage of ABCG2 can result in a restored sunitinib cytotoxic effect. In another study, RCC cells with ABCG2 overexpression due to the treatment of sunitinib, were treated with elacridar, a dual inhibitor of ABCG2 and ABCB1, resulting in the restored cytotoxicity of sunitinib. This indicates that sunitinib is mainly transported by ABCG2 and efficient inhibition of ABCG2 is needed in sunitinib-resistant cancer cells.

Other TKIs

There are dozens of newly found TKIs which efficiently targeted ABC transporters. For example, osimeritinib (36), a third-generation EGFR inhibitor, have been found to reverse the drug resistance within ABCB1-overexpressed bone marrow cells collected from AML patients. Evidences show that osimeritinib can increase the accumulation of Rhodamine 123. Ibrutinib (37), an inhibitor of Bruton’s tyrosine kinase, can increase the accumulation of ABCC1 substrates within ABCC1-overexpressed HEK293/MRP1 and HL60/Adr cells. Dinaciclib (38), a cyclin-dependent tyrosine kinase inhibitor, can decrease the daunorubicin efflux of MDCKII-ABCC1 and human cancer T47D cells, thus exhibit a synergistic effect when co-administrated with other anti-cancer drugs. GSK1904529A (39), an IGF-IR inhibitor, can also increase the intracellular concentration thus enhancing the cytotoxicity of ABCC1 substrate vinblastine in HEK293/MRP1 cells by inhibiting its efflux. In general, TKIs have been deeply implicated in counteracting ABC-induced multidrug resistance through ways like inhibiting efflux activity, co-administration with drugs, which provides new opportunities for clinical treatment of multidrug resistance.

Conclusion and Perspective

In recent years, many efforts have been made to modulate these ABC transporters, thus increase the intracellular concentration of drugs and reverse multidrug resistance. Several chemo-sensitizers were tested in clinical trials, like cyclosporine A, tariquidar, however, they did not show satisfying therapeutic effects due to their high toxicity, drug-drug interactions and clinical trial design problems. However, there are also novel strategies that can reverse multidrug resistance such as using DNA methyltransferase inhibitors (DNMTi), hypomethylating agents (HMAs) and histone deacetylase inhibitors (HDACi). A DNA methyltransferase (DNMT), 5-AC (5-azacytidine) can reverse irinotecan resistance in metastatic CRC patients when combined with irinotecan. In a phase II clinical trial, 17 pretreated and platinum-resistant patients with ovarian cancer were re-sensitized to carboplatin after being treated with HDACi. Expression of ABC transporters can also be regulated by miRNAs. For example, ABCB1/MDR1 encoding for P-gp can be downregulated by miR-30a in advanced gastric cancer and miR-9-3p in CML to reverse drug resistance. miR-145 can decrease the level of ABCC1/MRP1 and increase cisplatin toxicity in gallbladder cancer. miR-490-3p regulates ABCC2/MRP2 in ovarian cancer and possibly increases response to cisplatin. This provides us with an insight for finding other ways to reduce the mortality caused by multidrug resistance. More importantly, efflux of drugs has recently been found not to be the only role for ABC transporters in the failure of cancer therapy. They may also release signaling molecules, hormones, and metabolites andregulate cellular redox status, membrane lipid composition and tumor microenvironment. Additionally, MAPK, WNT, VEGF, and p53 and other signaling pathways involved in cell differentiation and proliferation should also be concerned, because they also regulate the expression and membrane localization of ABC transporters. Conclusively, the clinical failure of the ABC inhibitors makes it urgent to discover a more effective strategy.

Regarding further research on multidrug resistance, three main aspects could be focused on in future: 1) Develop a more precise drug delivery system, especially target cancer stem cells and other poorly differentiated cells. From the previous studies on cancer and multidrug resistance, we know that ABC transporters mainly over-express in poorly differentiated cells and lead to multidrug resistance. However, when drugs are delivered, they also nonspecifically target the ABC transporters of normal cells, causing many side effects. Therefore, precise delivery systems are necessary to ensure alleviation of side effects. 2) Find more about the signaling pathways related to ABC transporters. Researchers have found that signaling pathways like MAPK, WNT, VEGF, and p53 are deeply involved in regulating the expression, location of ABC transporters. Proper inhibition or activation of these signaling pathways can also reduce multidrug resistance. 3) Further investigate the molecular mechanism of ABC transporters in complex with different substrates in details by using structural biology, which provides insights in drug design and development.

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    Kashiwayama Y. Seki M. Yasui A. Murasaki Y. Morita M. Yamashita Y. (2009 ). 70-kDa peroxisomal membrane protein related protein (P70R/ABCD4) localizes to endoplasmic reticulum not peroxisomes, and NH2-terminal hydrophobic property determines the subcellular localization of ABC subfamily D proteins. Exp. Cell. Res. 315 (2), 190–205.

    Not in our library10.1016/j.yexcr.2008.10.031

  79. 79.

    Kathawala R. J. Gupta P. Ashby C. R. Jr. Chen Z.-S. (2015 ). The modulation of ABC transporter-mediated multidrug resistance in cancer: a review of the past decade. Drug Resist. Updates 18, 1–17.

    Not in our library10.1016/j.drup.2014.11.002

  80. 80.

    Khunweeraphong N. Stockner T. Kuchler K. (2017 ). The structure of the human ABC transporter ABCG2 reveals a novel mechanism for drug extrusion. Sci. Rep. 7 (1), 13767.

    Not in our library10.1038/s41598-017-11794-w

  81. 81.

    Khunweeraphong N. Szöllősi D. Stockner T. Kuchler K. (2019 ). The ABCG2 multidrug transporter is a pump gated by a valve and an extracellular lid. Nat. Commun. 10 (1), 5433.

    Not in our library10.1038/s41467-019-13302-2

  82. 82.

    Kim Y. Chen J. (2018 ). Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation. Science 359 (6378), 915–919.

    Not in our library10.1126/science.aar7389

  83. 83.

    Kraege S. Köhler S. C. Wiese M. (2016a ). Acryloylphenylcarboxamides: a new class of breast cancer resistance protein (ABCG2) modulators. ChemMedChem 11 (21), 2422–2435.

    Not in our library10.1002/cmdc.201600341

  84. 84.

    Kraege S. Stefan K. Juvale K. Ross T. Willmes T. Wiese M. (2016b ). The combination of quinazoline and chalcone moieties leads to novel potent heterodimeric modulators of breast cancer resistance protein (BCRP/ABCG2). Eur. J. Med. Chem. 117, 212–229.

    Not in our library10.1016/j.ejmech.2016.03.067

  85. 85.

    Kraege S. Stefan K. Köhler S. C. Wiese M. (2016c ). Optimization of acryloylphenylcarboxamides as inhibitors of ABCG2 and comparison with acryloylphenylcarboxylates. ChemMedChem 11 (22), 2547–2558.

    Not in our library10.1002/cmdc.201600455

  86. 86.

    Kumar A. Jaitak V. (2019 ). Natural products as multidrug resistance modulators in cancer. Eur. J. Med. Chem. 176, 268–291.

    Not in our library10.1016/j.ejmech.2019.05.027

  87. 87.

    Lainey E. Sébert M. Thépot S. Scoazec M. Bouteloup C. Leroy C. (2012 ). Erlotinib antagonizes ABC transporters in acute myeloid leukemia. Cell Cycle 11 (21), 4079–4092.

    Not in our library10.4161/cc.22382

  88. 88.

    Lainey E. Wolfromm A. Marie N. Enot D. Scoazec M. Bouteloup C. (2013 ). Azacytidine and erlotinib exert synergistic effects against acute myeloid leukemia. Oncogene 32 (37), 4331–4342.

    Not in our library10.1038/onc.2012.469

  89. 89.

    Leier I. Jedlitschky G. Buchholz U. Cole S. P. Deeley R. G. Keppler D. (1994 ). The MRP gene encodes an ATP-dependent export pump for leukotriene C4 and structurally related conjugates. J. Biol. Chem. 269 (45), 27807–27810.

    Not in our library10.1016/s0021-9258(18)46856-1

  90. 90.

    Li C. Zou J. Zheng G. Chu J. (2016 ). MiR-30a decreases multidrug resistance (MDR) of gastric cancer cells. Med. Sci. Monit. 22, 4505–4515.

    Not in our library10.12659/msm.898415

  91. 91.

    Li Y. Liu Y. Ren J. Deng S. Yi G. Guo M. (2018 ). miR-1268a regulates ABCC1 expression to mediate temozolomide resistance in glioblastoma. J. Neurooncol. 138 (3), 499–508.

    Not in our library10.1007/s11060-018-2835-3

  92. 92.

    Li Y. Zhai Z. Li H. Wang X. Huang Y. Su X. (2019 ). Guajadial reverses multidrug resistance by inhibiting ABC transporter expression and suppressing the PI3K/Akt pathway in drug-resistant breast cancer cells. Chemico-Biol. Interact 305, 98–104.

    Not in our library10.1016/j.cbi.2019.03.032

  93. 93.

    Li Y. Zhao L. Li N. Miao Y. Zhou H. Jia L. (2017 ). miR-9 regulates the multidrug resistance of chronic myelogenous leukemia by targeting ABCB1. Oncol. Rep. 37 (4), 2193–2200.

    Not in our library10.3892/or.2017.5464

  94. 94.

    Liang Z. Wu H. Xia J. Li Y. Zhang Y. Huang K. (2010 ). Involvement of miR-326 in chemotherapy resistance of breast cancer through modulating expression of multidrug resistance-associated protein 1. Biochem. Pharmacol. 79 (6), 817–824.

    Not in our library10.1016/j.bcp.2009.10.017

  95. 95.

    Liening S. Scriba G. K. Rummler S. Weinigel C. Kleinschmidt T. K. Haeggström J. Z. (2016 ). Development of smart cell-free and cell-based assay systems for investigation of leukotriene C 4 synthase activity and evaluation of inhibitors. Biochim. Biophys. Acta 1861 (11), 1605–1613.

    Not in our library10.1016/j.bbalip.2016.07.011

  96. 96.

    Liu X. L. Tee H. W. Go M. L. (2008 ). Functionalized chalcones as selective inhibitors of P-glycoprotein and breast cancer resistance protein. Bioorg. Med. Chem. 16 (1), 171–180.

    Not in our library10.1016/j.bmc.2007.10.006

  97. 97.

    Locher K. P. Lee A. T. Rees D. C. (2002 ). The E. coli BtuCD structure: a framework for ABC transporter architecture and mechanism. Science 296 (5570), 1091–1098.

    Not in our library10.1126/science.1071142

  98. 98.

    Loe D. W. Almquist K. C. Deeley R. G. Cole S. P. C. (1996 ). Multidrug resistance protein (MRP)-mediated transport of leukotriene C4 and chemotherapeutic agents in membrane vesicles. J. Biol. Chem. 271 (16), 9675–9682.

    Not in our library10.1074/jbc.271.16.9675

  99. 99.

    Lorendeau D. Dury L. Genoux-Bastide E. Lecerf-Schmidt F. Simões-Pires C. Carrupt P. A. (2014 ). Collateral sensitivity of resistant MRP1-overexpressing cells to flavonoids and derivatives through GSH efflux. Biochem. Pharmacol. 90 (3), 235–245.

    Not in our library10.1016/j.bcp.2014.05.017

  100. 100.

    Lu C. Shan Z. Li C. Yang L. (2017 ). MiR-129 regulates cisplatin-resistance in human gastric cancer cells by targeting P-gp. Biomed. Pharmacother. 86, 450–456.

    Not in our library10.1016/j.biopha.2016.11.139

  101. 101.

    Manayi A. Nabavi S. M. Setzer W. N. Jafari S. (2019 ). Piperine as a potential anti-cancer agent: a review on preclinical studies. Curr Med Chem. 25 (37), 4918–4928.

    Not in our library10.2174/0929867324666170523120656

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    Manolaridis I. Jackson S. M. Taylor N. M. I. Kowal J. Stahlberg H. Locher K. P. (2018 ). Cryo-EM structures of a human ABCG2 mutant trapped in ATP-bound and substrate-bound states. Nature 563 (7731), 426–430.

    Not in our library10.1038/s41586-018-0680-3

  103. 103.

    Mao Q. Unadkat J. D. (2015 ). Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport-an update. Aaps J. 17 (1), 65–82.

    Not in our library10.1208/s12248-014-9668-6

  104. 104.

    Mares L. Vilchis F. Chávez B. Ramos L. (2019 ). Expression and regulation of ABCG2/BCRP1 by sex steroids in the Harderian gland of the Syrian hamster (Mesocricetus auratus). C. R. Biol. 342 (9–10), 279–289.

    Not in our library10.1016/j.crvi.2019.11.003

  105. 105.

    Matei D. Fang F. Shen C. Schilder J. Arnold A. Zeng Y. (2012 ). Epigenetic resensitization to platinum in ovarian cancer. Cancer Res. 72 (9), 2197–2205.

    Not in our library10.1158/0008-5472.can-11-3909

  106. 106.

    Mesraoua B. Deleu D. Kullmann D. M. Shetty A. K. Boon P. Perucca E. (2019 ). Novel therapies for epilepsy in the pipeline. Epilepsy Behav. 97, 282–290.

    Not in our library10.1016/j.yebeh.2019.04.042

  107. 107.

    Moody J. E. Millen L. Binns D. Hunt J. F. Thomas P. J. (2002 ). Cooperative, ATP-dependent association of the nucleotide binding cassettes during the catalytic cycle of ATP-binding cassette transporters. J. Biol. Chem. 277 (24), 21111–21114.

    Not in our library10.1074/jbc.c200228200

  108. 108.

    Munagala S. Sirasani G. Kokkonda P. Phadke M. Krynetskaia N. Lu P. (2014 ). Synthesis and evaluation of Strychnos alkaloids as MDR reversal agents for cancer cell eradication. Bioorg. Med. Chem. 22 (3), 1148–1155.

    Not in our library10.1016/j.bmc.2013.12.022

  109. 109.

    Nabekura T. Yamaki T. Kitagawa S. (2008 ). Effects of chemopreventive citrus phytochemicals on human P-glycoprotein and multidrug resistance protein 1. Eur. J. Pharmacol. 600 (1–3), 45–49.

    Not in our library10.1016/j.ejphar.2008.10.025

  110. 110.

    Nasr R. Lorendeau D. Khonkarn R. Dury L. Pérès B. Boumendjel A. (2020 ). Molecular analysis of the massive GSH transport mechanism mediated by the human Multidrug Resistant Protein 1/ABCC1. Sci. Rep. 10 (1), 7616.

    Not in our library10.1038/s41598-020-64400-x

  111. 111.

    Natarajan K. Xie Y. Baer M. R. Ross D. D. (2012 ). Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance. Biochem. Pharmacol. 83 (8), 1084–1103.

    Not in our library10.1016/j.bcp.2012.01.002

  112. 112.

    Ni K. Yang L. Wan C. Xia Y. Kong L. (2014 ). Flavonostilbenes from Sophora alopecuroides L. as multidrug resistance associated protein 1 (MRP1) inhibitors. Nat. Product. Res. 28 (23), 2195–2198.

    Not in our library10.1080/14786419.2014.930856

  113. 113.

    Nobili S. Landini I. Giglioni B. Mini E. (2006 ). Pharmacological strategies for overcoming multidrug resistance. Cdt 7 (7), 861–879.

    Not in our library10.2174/138945006777709593

  114. 114.

    Obreque-Balboa J. E. Sun Q. Bernhardt G. König B. Buschauer A. (2016 ). Flavonoid derivatives as selective ABCC1 modulators: synthesis and functional characterization. Eur. J. Med. Chem. 109, 124–133.

    Not in our library10.1016/j.ejmech.2015.12.010

  115. 115.

    Oda Y. Saito T. Tateishi N. Ohishi Y. Tamiya S. Yamamoto H. (2005 ). ATP-binding cassette superfamily transporter gene expression in human soft tissue sarcomas. Int. J. Cancer 114 (6), 854–862.

    Not in our library10.1002/ijc.20589

  116. 116.

    Ohtsuki S. Kamoi M. Watanabe Y. Suzuki H. Hori S. Terasaki A. (2007 ). Correlation of induction of ATP binding cassette transporter A5 (ABCA5) and ABCB1 mRNAs with differentiation state of human colon tumor. Biol. Pharm. Bull. 30 (6), 1144–1146.

    Not in our library10.1248/bpb.30.1144

  117. 117.

    Olarte Carrillo I. Ramos Peñafiel C. Miranda Peralta E. Rozen Fuller E. Kassack Ipiña J. J. Centeno Cruz F. (2017 ). Clinical significance of the ABCB1 and ABCG2 gene expression levels in acute lymphoblastic leukemia. Hematology 22 (5), 286–291.

    Not in our library10.1080/10245332.2016.1265780

  118. 118.

    Oldham M. L. Chen J. (2011 ). Snapshots of the maltose transporter during ATP hydrolysis. Proc. Natl. Acad. Sci. U.S.A. 108 (37), 15152–15156.

    Not in our library10.1073/pnas.1108858108

  119. 119.
    ABCG2 transports anticancer drugs via a closed-to-open switch · 2020
    No notice
  120. 120.

    Orlando U. D. Castillo A. F. Medrano M. A. R. Solano A. R. Maloberti P. M. Podesta E. J. (2019 ). Acyl-CoA synthetase-4 is implicated in drug resistance in breast cancer cell lines involving the regulation of energy-dependent transporter expression. Biochem. Pharmacol. 159, 52–63.

    Not in our library10.1016/j.bcp.2018.11.005

  121. 121.

    Özvegy-Laczka C. Hegedűs T. Várady G. Ujhelly O. Schuetz J. D. Váradi A. (2004 ). High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter. Mol. Pharmacol. 65 (6), 1485–1495.

    Not in our library10.1124/mol.65.6.1485

  122. 122.

    Parcej D. Tampé R. (2010 ). ABC proteins in antigen translocation and viral inhibition. Nat. Chem. Biol. 6 (8), 572–580.

    Not in our library10.1038/nchembio.410

  123. 123.

    Pires M. M. Emmert D. Hrycyna C. A. Chmielewski J. (2009 ). Inhibition of P-glycoprotein-mediated paclitaxel resistance by reversibly linked quinine homodimers. Mol. Pharmacol. 75 (1), 92–100.

    Not in our library10.1124/mol.108.050492

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    Porcelli L. Giovannetti E. Assaraf Y. Jansen G. Scheffer G. Kathman I. (2014 ). The EGFR pathway regulates BCRP expression in NSCLC cells: role of erlotinib. Curr. Drug Targets 15 (14), 1322–1330.

    Not in our library10.2174/1389450116666141205145620

  125. 125.

    Porro A. Haber M. Diolaiti D. Iraci N. Henderson M. Gherardi S. (2010 ). Direct and coordinate regulation of ATP-binding cassette transporter genes by myc factors generates specific transcription signatures that significantly affect the chemoresistance phenotype of cancer cells*. J. Biol. Chem. 285 (25), 19532–19543.

    Not in our library10.1074/jbc.m109.078584

  126. 126.

    Qiu S. Sun H. Zhang A. H. Xu H. Y. Yan G. L. Han Y. (2014 ). Natural alkaloids: basic aspects, biological roles, and future perspectives. Chin. J. Nat. Med. 12 (6), 401–406.

    Not in our library10.1016/s1875-5364(14)60063-7

  127. 127.

    Raaijmakers M. H. G. P. de Grouw E. P. L. M. Heuver L. H. H. van der Reijden B. A. Jansen J. H. Scheper R. J. (2005 ). Breast cancer resistance protein in drug resistance of primitive CD34+38− cells in acute myeloid leukemia. Clin. Cancer Res. 11 (6), 2436–2444.

    Not in our library10.1158/1078-0432.ccr-04-0212

  128. 128.

    Ramalhete C. Mulhovo S. Lage H. Ferreira M. J. (2018 ). Triterpenoids from Momordica balsamina with a collateral sensitivity effect for tackling multidrug resistance in cancer cells. Planta Med. 84 (18), 1372–1379.

    Not in our library10.1055/a-0651-8141

  129. 129.

    Ramalhete C. Mulhovo S. Molnar J. Ferreira M. J. U. (2016 ). Triterpenoids from Momordica balsamina: reversal of ABCB1-mediated multidrug resistance. Bioorg. Med. Chem. 24 (21), 5061–5067.

    Not in our library10.1016/j.bmc.2016.08.022

  130. 130.

    Reustle A. Fisel P. Renner O. Büttner F. Winter S. Rausch S. (2018 ). Characterization of the breast cancer resistance protein (BCRP/ABCG2 ) in clear cell renal cell carcinoma. Int. J. Cancer 143 (12), 3181–3193.

    Not in our library10.1002/ijc.31741

  131. 131.

    Robey R. W. Massey P. R. Amiri-Kordestani L. Bates S. E. (2010 ). ABC transporters: unvalidated therapeutic targets in cancer and the CNS. Anticancer Agents Med. Chem. 10 (8), 625–633.

    Not in our library10.2174/187152010794473957

  132. 132.

    Robey R. W. Pluchino K. M. Hall M. D. Fojo A. T. Bates S. E. Gottesman M. M. (2018 ). Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat. Rev. Cancer 18 (7), 452–464.

    Not in our library10.1038/s41568-018-0005-8

  133. 133.

    Rocha G. D. G. Oliveira R. R. Kaplan M. A. C. Gattass C. R. (2014 ). 3β-Acetyl tormentic acid reverts MRP1/ABCC1 mediated cancer resistance through modulation of intracellular levels of GSH and inhibition of GST activity. Eur. J. Pharmacol. 741, 140–149.

    Not in our library10.1016/j.ejphar.2014.07.054

  134. 134.

    Sacha T. Saglio G. (2019 ). Nilotinib in the treatment of chronic myeloid leukemia. Future Oncol. 15 (9), 953–965.

    Not in our library10.2217/fon-2018-0468

  135. 135.

    Sato H. Siddig S. Uzu M. Suzuki S. Nomura Y. Kashiba T. (2015 ). Elacridar enhances the cytotoxic effects of sunitinib and prevents multidrug resistance in renal carcinoma cells. Eur. J. Pharmacol. 746, 258–266.

    Not in our library10.1016/j.ejphar.2014.11.021

  136. 136.

    Schinkel A. H. Smit J. J. M. van Tellingen O. Beijnen J. H. Wagenaar E. van Deemter L. (1994 ). Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 77 (4), 491–502.

    Not in our library10.1016/0092-8674(94)90212-7

  137. 137.

    Schmitt S. M. Stefan K. Wiese M. (2016 ). Pyrrolopyrimidine derivatives as novel inhibitors of multidrug resistance-associated protein 1 (MRP1, ABCC1). J. Med. Chem. 59 (7), 3018–3033.

    Not in our library10.1021/acs.jmedchem.5b01644

  138. 138.

    Shapiro A. B. Ling V. (1997 ). Effect of quercetin on Hoechst 33342 transport by purified and reconstituted P-glycoprotein. Biochem. Pharmacol. 53 (4), 587–596.

    Not in our library10.1016/s0006-2952(96)00826-x

  139. 139.

    Sharom F.J. (2011 ). The P-glycoprotein multidrug transporter. Essays Biochem. 50 (1), 161–178.

    Not in our library10.1042/bse0500161

  140. 140.

    Sharma A. Vatapalli R. Abdelfatah E. Wyatt McMahon K. Kerner Z. Guzzetta A. A. (2017 ). Hypomethylating agents synergize with irinotecan to improve response to chemotherapy in colorectal cancer cells. PLoS One 12 (4), e0176139.

    Not in our library10.1371/journal.pone.0176139

  141. 141.

    Shi Z. Jain S. Kim I. W. Peng X. X. Abraham I. Youssef D. T. A. (2007 ). Sipholenol A, a marine-derived sipholane triterpene, potently reverses P-glycoprotein (ABCB1)-mediated multidrug resistance in cancer cells. Cancer Sci. 98 (9), 1373–1380.

    Not in our library10.1111/j.1349-7006.2007.00554.x

  142. 142.

    Si X. Gao Z. Xu F. Zheng Y. (2020 ). SOX2 upregulates side population cells and enhances their chemoresistant ability by transactivating ABCC1 expression contributing to intrinsic resistance to paclitaxel in melanoma. Mol. Carcinog. 59 (3), 257–264.

    Not in our library10.1002/mc.23148

  143. 143.

    Silbermann K. Shah C. P. Sahu N. U. Juvale K. Stefan S. M. Kharkar P. S. (2019 ). Novel chalcone and flavone derivatives as selective and dual inhibitors of the transport proteins ABCB1 and ABCG2. Eur. J. Med. Chem. 164, 193–213.

    Not in our library10.1016/j.ejmech.2018.12.019

  144. 144.

    Sims J. T. Ganguly S. S. Bennett H. Friend J. W. Tepe J. Plattner R. (2013 ). Imatinib reverses doxorubicin resistance by affecting activation of STAT3-dependent NF-κB and HSP27/p38/AKT pathways and by inhibiting ABCB1. PLoS One 8 (1), e55509.

    Not in our library10.1371/journal.pone.0055509

  145. 145.

    Singh D. V. Godbole M. M. Misra K. (2013 ). A plausible explanation for enhanced bioavailability of P-gp substrates in presence of piperine: simulation for next generation of P-gp inhibitors. J. Mol. Model 19 (1), 227–238.

    Not in our library10.1007/s00894-012-1535-8

  146. 146.

    Sita G. Hrelia P. Tarozzi A. Morroni F. (2017 ). P-glycoprotein (ABCB1) and oxidative stress: focus on alzheimer’s disease. Oxidative Med. Cell Longevity 2017, 1.

    Not in our library10.1155/2017/7905486

  147. 147.

    Stefan K. Schmitt S. M. Wiese M. (2017 ). 9-deazapurines as broad-spectrum inhibitors of the ABC transport proteins P-glycoprotein, multidrug resistance-associated protein 1, and breast cancer resistance protein. J. Med. Chem. 60 (21), 8758–8780.

    Not in our library10.1021/acs.jmedchem.7b00788

  148. 148.

    Sultan M. Vidovic D. Paine A. S. Huynh T. T. Coyle K. M. Thomas M. L. (2018 ). Epigenetic silencing of TAP1 in Aldefluor+Breast cancer stem cells contributes to their enhanced immune evasion. Stem Cells 36 (5), 641–654.

    Not in our library10.1002/stem.2780

  149. 149.

    Sun L. Chen W. Qu L. Wu J. Si J. (2013 ). Icaritin reverses multidrug resistance of HepG2/ADR human hepatoma cells via downregulation of MDR1 and P-glycoprotein expression. Mol. Med. Rep. 8 (6), 1883–1887.

    Not in our library10.3892/mmr.2013.1742

  150. 150.

    Surya Sandeep M. Sridhar V. Puneeth Y. Ravindra Babu P. Naveen Babu K. (2014 ). Enhanced oral bioavailability of felodipine by naringenin in Wistar rats and inhibition of P-glycoprotein in everted rat gut sacsin vitro. Drug Develop. Ind. Pharm. 40 (10), 1371–1377.

    Not in our library10.3109/03639045.2013.819885

  151. 151.

    Syed S. B. Arya H. Fu I. H. Yeh T. K. Periyasamy L. Hsieh H. P. (2017 ). Targeting P-glycoprotein: investigation of piperine analogs for overcoming drug resistance in cancer. Sci. Rep. 7 (1), 7972.

    Not in our library10.1038/s41598-017-08062-2

  152. 152.

    Takada T. Yamamoto T. Matsuo H. Tan J. K. Ooyama K. Sakiyama M. (2018 ). Identification of ABCG2 as an exporter of uremic toxin indoxyl sulfate in mice and as a crucial factor influencing CKD progression. Sci. Rep. 8 (1), 11147.

    Not in our library10.1038/s41598-018-29208-w

  153. 153.

    Taylor N. M. I. Manolaridis I. Jackson S. M. Kowal J. Stahlberg H. Locher K. P. (2017 ). Structure of the human multidrug transporter ABCG2. Nature 546 (7659), 504–509.

    Not in our library10.1038/nature22345

  154. 154.

    Teodori E. Dei S. Bartolucci G. Perrone M. G. Manetti D. Romanelli M. N. (2017 ). Structure-activity relationship studies on 6,7-Dimethoxy-2-phenethyl-1,2,3,4-tetrahydroisoquinoline derivatives as multidrug resistance reversers. ChemMedChem 12 (16), 1369–1379.

    Not in our library10.1002/cmdc.201700239

  155. 155.

    Tian J. Xu Y. Y. Li L. Hao Q. (2017 ). MiR-490-3p sensitizes ovarian cancer cells to cisplatin by directly targeting ABCC2. Am. J. Transl. Res. 9 (3), 1127–1138.

    Not in our library

  156. 156.
    Inhibitors of Human ABCG2: From Technical Background to Recent Updates With Clinical Implications · 2019
    No notice
  157. 157.

    Traxl A. Mairinger S. Filip T. Sauberer M. Stanek J. Poschner S. (2019 ). Inhibition of ABCB1 and ABCG2 at the mouse blood-brain barrier with marketed drugs to improve brain delivery of the model ABCB1/ABCG2 substrate [11C]erlotinib. Mol. Pharm. 16 (3), 1282–1293.

    Not in our library10.1021/acs.molpharmaceut.8b01217

  158. 158.

    Tsuchida M. Emi Y. Kida Y. Sakaguchi M. (2008 ). Human ABC transporter isoform B6 (ABCB6) localizes primarily in the Golgi apparatus. Biochem. Biophys. Res. Commun. 369 (2), 369–375.

    Not in our library10.1016/j.bbrc.2008.02.027

  159. 159.

    Uhlén M. Fagerberg L. Hallström B. M. Lindskog C. Oksvold P. Mardinoglu A. (2015 ). Tissue-based map of the human proteome. Science 347 (6220), 1260419.

    Not in our library10.1126/science.1260419

  160. 160.

    Vahedi S. Chufan E. E. Ambudkar S. V. (2017 ). Global alteration of the drug-binding pocket of human P-glycoprotein (ABCB1) by substitution of fifteen conserved residues reveals a negative correlation between substrate size and transport efficiency. Biochem. Pharmacol. 143, 53–64.

    Not in our library10.1016/j.bcp.2017.07.014

  161. 161.

    Waghray D. Zhang Q. (2018 ). Inhibit or evade multidrug resistance P-glycoprotein in cancer treatment. J. Med. Chem. 61 (12), 5108–5121.

    Not in our library10.1021/acs.jmedchem.7b01457

  162. 162.

    Wang F. Miao M. X. Sun B. B. Wang Z. J. Tang X. G. Chen Y. (2017 ). Acute liver failure enhances oral plasma exposure of zidovudine in rats by downregulation of hepatic UGT2B7 and intestinal P-gp. Acta Pharmacol. Sin. 38 (11), 1554–1565.

    Not in our library10.1038/aps.2017.54

  163. 163.

    Wang H. Chen X. Li T. Xu J. Ma Y. (2016 ). A myrsinol diterpene isolated from a traditional herbal medicine, LANGDU reverses multidrug resistance in breast cancer cells. J. Ethnopharmacol. 194, 1–5.

    Not in our library10.1016/j.jep.2016.08.041

  164. 164.

    Wang L. Sun Y. (2020 ). Efflux mechanism and pathway of verapamil pumping by human P-glycoprotein. Arch. Biochem. Biophys. 696, 108675.

    Not in our library10.1016/j.abb.2020.108675

  165. 165.

    Wang M. Ye C. Liu M. Wu Z. Li L. Wang C. (2015a ). Synthesis and antitumor activity of 5-(5-halogenated-2-oxo-1H-pyrrolo[2,3-b]pyridin-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxamides. Bioorg. Med. Chem. Lett. 25 (14), 2782–2787.

    Not in our library10.1016/j.bmcl.2015.05.017

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    Wang S. Q. Liu S. T. Zhao B. X. Yang F. H. Wang Y. T. Liang Q. Y. (2015b ). Afatinib reverses multidrug resistance in ovarian cancer via dually inhibiting ATP binding cassette subfamily B member 1. Oncotarget 6 (28), 26142–26160.

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    Wei D. D. Wang J. S. Kong L. Y. (2012 ). Reversal effects of components from the fruits of Illicium simonsii on human Adriamycin-resistant MCF-7 and 5-fluorouracil-resistant Bel7402 cells. Phytother. Res. 26 (4), 562–567.

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    Wei Y. L. Xu L. Liang Y. Xu X. H. Zhao X. Y. (2009 ). Berbamine exhibits potent antitumor effects on imatinib-resistant CML cells in vitro and in vivo. Acta Pharmacol. Sin 30 (4), 451–457.

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    Weidner L. D. Zoghbi S. S. Lu S. Shukla S. Ambudkar S. V. Pike V. W. (2015 ). The inhibitor Ko143 is not specific for ABCG2. J. Pharmacol. Exp. Ther. 354 (3), 384–393.

    Not in our library10.1124/jpet.115.225482

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    Weigl K. E. Conseil G. Rothnie A. J. Arama M. Tsfadia Y. Cole S. P. C. (2018 ). An outward-facing aromatic amino acid is crucial for signaling between the membrane-spanning and nucleotide-binding domains of multidrug resistance protein 1 (MRP1; ABCC1). Mol. Pharmacol. 94 (3), 1069–1078.

    Not in our library10.1124/mol.118.112615

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    Weiss W. A. Aldape K. Mohapatra G. Feuerstein B. G. Bishop J. M. (1997 ). Targeted expression of MYCN causes neuroblastoma in transgenic mice. Embo J. 16 (11), 2985–2995.

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    Wetering K. Sapthu S. (2012 ). ABCG2 functions as a general phytoestrogen sulfate transporter in vivo. FASEB J. 26 (10), 4014–4024.

    Not in our library10.1096/fj.12-210039

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    Whitt J. D. Keeton A. B. Gary B. D. Sklar L. A. Sodani K. Chen Z. S. (2016 ). Sulindac sulfide selectively increases sensitivity of ABCC1 expressing tumor cells to doxorubicin and glutathione depletion. J. Biomed. Res. 30 (2), 120–133.

    Not in our library10.7555/jbr.30.20150108

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    Winter E. Gozzi G. J. Chiaradia-Delatorre L. D. Daflon-Yunes N. Terreux R. Gauthier C. (2014 ). Quinoxaline-substituted chalcones as new inhibitors of breast cancer resistance protein ABCG2: polyspecificity at B-ring position. Drug Des. Devel Ther. 8, 609–619.

    Not in our library10.2147/dddt.s56625

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    Wong I. L. K. Wang B. C. Yuan J. Duan L.-X. Liu Z. Liu T. (2015 ). Potent and nontoxic chemosensitizer of P-glycoprotein-mediated multidrug resistance in cancer: synthesis and evaluation of methylated epigallocatechin, gallocatechin, and dihydromyricetin derivatives. J. Med. Chem. 58 (11), 4529–4549.

    Not in our library10.1021/acs.jmedchem.5b00085

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    Woo J.-S. Zeltina A. Goetz B. A. Locher K. P. (2012 ). X-ray structure of the Yersinia pestis heme transporter HmuUV. Nat. Struct. Mol. Biol. 19 (12), 1310–1315.

    Not in our library10.1038/nsmb.2417

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    Yin H. Dong J. Cai Y. Shi X. Wang H. Liu G. (2019 ). Design, synthesis and biological evaluation of chalcones as reversers of P-glycoprotein-mediated multidrug resistance. Eur. J. Med. Chem. 180, 350–366.

    Not in our library10.1016/j.ejmech.2019.05.053

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    Yu J. Zhou P. Asenso J. Yang X.-D. Wang C. Wei W. (2016 ). Advances in plant-based inhibitors of P-glycoprotein. J. Enzyme Inhib. Med. Chem. 31 (6), 867–881.

    Not in our library10.3109/14756366.2016.1149476

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    Zander S. A. L. Kersbergen A. Van der Burg E. de Water N. van Tellingen O. Gunnarsdottir S. (2010 ). Sensitivity and acquired resistance of BRCA1;p53-deficient mouse mammary tumors to the topoisomerase I inhibitor topotecan. Cancer Res. 70 (4), 1700–1710.

    Not in our library10.1158/0008-5472.can-09-3367

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    Zhan M. Zhao X. Wang H. Chen W. Xu S. Wang W. (2016 ). miR-145 sensitizes gallbladder cancer to cisplatin by regulating multidrug resistance associated protein 1. Tumor Biol. 37 (8), 10553–10562.

    Not in our library10.1007/s13277-016-4957-6

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    Zhang G.-N. Zhang Y.-K. Wang Y.-J. Gupta P. Ashby C. R. Jr. Alqahtani S. (2018 ). Epidermal growth factor receptor (EGFR) inhibitor PD153035 reverses ABCG2-mediated multidrug resistance in non-small cell lung cancer: in vitro and in vivo. Cancer Lett. 424, 19–29.

    Not in our library10.1016/j.canlet.2018.02.040

  182. 182.

    Zhang H. Patel A. Ma S.-L. Li X. J. Zhang Y.-K. Yang P.-Q. (2014 ). In vitro,in vivoandex vivocharacterization of ibrutinib: a potent inhibitor of the efflux function of the transporter MRP1. Br. J. Pharmacol. 171 (24), 5845–5857.

    Not in our library10.1111/bph.12889

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    Zhang L. Mao Y. Gao Z. Chen X. Li X. Liu Y. (2020 ). The nonclinical pharmacokinetics and prediction of human pharmacokinetics of SPH3127, a novel direct renin inhibitor. Eur. J. Drug Metab. Pharmacokinet. 45 (1), 15–26.

    Not in our library10.1007/s13318-019-00573-9

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    Zhang W. St Clair D. Butterfield A. Vore M. (2016 ). Loss of Mrp1 potentiates doxorubicin-induced cytotoxicity in neonatal mouse cardiomyocytes and cardiac fibroblasts. Toxicol. Sci. 151 (1), 44–56.

    Not in our library10.1093/toxsci/kfw021

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    Zhang Y. Guo L. Huang J. Sun Y. He F. Zloh M. (2019 ). Inhibitory effect of berberine on broiler P-glycoprotein expression and function: in situ and in vitro studies. Int. J. Mol. Sci. 20 (8), 1966.

    Not in our library10.3390/ijms20081966

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    Zhou S. F. Wang L. L. Di Y. Xue C. Duan W. Li C. (2008 ). Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development. Curr. Med. Chem. 15 (20), 1981–2039.

    Not in our library10.2174/092986708785132870

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    Zhou X. T. Ding J. Li H. Y. Zuo J. L. Ge S. Y. Jia H. L. (2020 ). Hedgehog signalling mediates drug resistance through targeting TAP1 in hepatocellular carcinoma. J. Cell. Mol. Med. 24 (7), 4298–4311.

    Not in our library10.1111/jcmm.15090

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    Zhou Z.-Y. Wan L. L. Yang Q. J. Han Y. L. Li D. Lu J. (2016 ). Nilotinib reverses ABCB1/P-glycoprotein-mediated multidrug resistance but increases cardiotoxicity of doxorubicin in a MDR xenograft model. Toxicol. Lett. 259, 124–132.

    Not in our library10.1016/j.toxlet.2016.07.710

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    Zu B. Li Y. Wang X. He D. Huang Z. Feng W. (2014 ). MDR1gene polymorphisms and imatinib response in chronic myeloid leukemia: a meta-analysis. Pharmacogenomics 15 (5), 667–677.

    Not in our library10.2217/pgs.13.222

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