Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade

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Cancer Letters j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / c a n l e t

Mini-review

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Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade Zhaolin Chen a,b,1, Tianlu Shi a,b,1, Lei Zhang a, Mingying Deng a, Cheng Huang b, Q2 Tingting Hu b, Ling Jiang a,*, Jun Li b,** a

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Department of Pharmacy, Anhui Provincial Hospital, 17 Lujiang Road, Hefei, Anhui 230001, China Institute for Liver Diseases of Anhui Medical University (AMU), Anhui Institute of Innovative Drugs, Anhui Key Laboratory of Bioactivity of Natural Products, School of Pharmacy, Anhui Medical University, Hefei, Anhui 230032, China b

A R T I C L E

I N F O

Article history: Received 30 July 2015 Received in revised form 9 October 2015 Accepted 10 October 2015 Keywords: Multidrug resistance Cancer therapy Inhibitors ABC transporters

A B S T R A C T

Multidrug resistance (MDR) is a serious phenomenon employed by cancer cells which hampers the success of cancer pharmacotherapy. One of the common mechanisms of MDR is the overexpression of ATPbinding cassette (ABC) efflux transporters in cancer cells such as P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) that limits the prolonged and effective use of chemotherapeutic drugs. Researchers have found that developing inhibitors of ABC efflux transporters as chemosensitizers could overcome MDR. But the clinical trials have shown that most of these chemosensitizers are merely toxic and only show limited or no benefits to cancer patients, thus new inhibitors are being explored. Recent findings also suggest that efflux pumps of the ABC transporter family are subject to epigenetic gene regulation. In this review, we summarize recent findings of the role of ABC efflux transporters in MDR. © 2015 Published by Elsevier Ireland Ltd.

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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]. Q3 Chemoresistance, or multidrug resistance (MDR), describes a phenomenon whereby cancer cell’s resistance to one drug is

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Q1

Abbreviations: 3′-UTR, 3′-untranslated region; ABC, ATP-binding cassette; ATP, adenosine triphosphate; BCR-ABL, breakpoint cluster region-Abelson; BCRP/ ABCG2, breast cancer resistance protein; BMP4, bone morphogenetic protein 4; BrTet, 5-bromotetrandrine; cMOAT, canalicular multispecific organic anion transporter; COX2, cyclo-oxygenase-2; DNMT, DNA methyltransferase; DVL1, dishevelled-1; EGCG, (−)-epigallocatechin-3-gallate; EGFR, epidermal growth factor receptor; EZH2, histonelysine N-methyltransferase; FZD1, Frizzled-1; FZD7, Frizzled-7; HDAC, histone deacetylase; lncRNAs, long non-coding RNAs; MDR, multidrug resistance; miRNAs, microRNAs; MRP2/ABCC2, multidrug resistance-associated protein 2; NBDs, nucleotide-binding domains; NRF2, NF-E2-related factor 2; PDT, photodynamic therapy; P-gp/ABCB1, P-glycoprotein; RNAi, RNA interference; RUNX3, Runtrelated transcription factor 3; SFRP5, secreted frizzle-related protein 5; shRNA, short hairpin RNA; siRNA, small interfering RNA; TKIs, tyrosine kinase inhibitors; TMD0, terminal transmembrane domain; TMDs, transmembrane domains; VEGFR, vascular endothelial growth factor receptor; YC-1, 3-(5′-hydroxymethyl-2′-furyl)-1benzylindazole. * Corresponding author. E-mail address: [email protected] (L. Jiang). ** Corresponding author. E-mail addresses: [email protected], [email protected] (J. Li). 1 The authors contributed equally to this work.

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 [4–8]. 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 [9–11]. 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.

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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

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The physicochemical interactions responsible for substrate binding and mechanisms of ABC efflux transporter-mediated substrate translocation are still incompletely understood. Yet, it is widely assumed that the ATP switch plays an important role in the extraction of their substrates [26]. Generally, binding of two ATPs at the dimer interface could induce changes in TMD conformation, thus leading to the dimerization and configuration of a sandwich-like NBD. When a substrate binds to the TMD, it could induce a decrease in the activation energy for NBD dimerization. The bound ATP Q6 molecule is hydrolyzed to ADP and Pi, which separates the NBDs, then substrate is released into the extracellular space and restores the stable conformational state of the NBD which is ready for binding and transporting of another substrate (Fig. 2). Moreover, ABC transport systems can be viewed as catalytic systems or enzymes [27]. Then subsequently, a very recent article stated by Brian H. Shilton shows that active transport can use the well-established energetic framework consisting of low-energy and high-energy conformation for enzyme-mediated catalysis. The transport process involves binding interactions that selectively stabilize the higher-energy intermediate conformations, and thus promote conformational changes in the system that are coupled to decreases in free energy and substrate translocation [28].

classified into seven subfamilies from ABC-A through to ABC-G based

Q4 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 superfamily transporters involved in MDR development are P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) [14,15]. Structurally, all ABC transporters have two transmembrane domains (TMDs) and two nucleotide-binding domains (NBDs) [16]. Q5 They show a common structural fold that is composed of a core of six TM helices per TMD. The hydrophobic TMDs are structurally diverse, which alternately recognize and translocate various substrates upon conformational changes. So the TMDs which span the membrane and form channels could determine the transport characteristics of substrates [17,18]. ABC transporters can be classified on the basis of the structure and sequence of the NBDs, also known as ABC domains [19,20]. The NBDs are highly conserved proteins consisting of conserved ABC that is responsible for binding and hydrolyzing ATP via an ATPase, thus providing energy for translocation or efflux of physiological and xenobiotic substrates from the cytoplasm to the extracellular space. In addition, the NBDs also contain Walker A and B motifs as well as a signature motif which play a vital role in the hydrolysis of ATP to ADP + P and energy collecting [16,21]. A functional ABC transporter often requires two core units, forming a TMD1–NBD1–TMD2–NBD2 single polypeptide assembly such as ABCB1 (Fig. 1A), but there will be quite a bit difference in the molecular structure of other MDR proteins [22]. ABCC2 protein contains an N-terminal extension consisting of five helical transmembrane fragments as so called terminal transmembrane domain (TMD0), which linked to the core of the molecule by a L0 loop (Fig. 1B) [23]. By contrast, ABCG2 protein is a half-transporter, composed of one TMD and one NBD domain, but in reverse order (i.e. TMD is the C-terminal domain; see Fig. 1C) [24]. Unlike the above-mentioned transports, which function as monomers, ABCG2 forms a homodimer through the disulfide bonds thereby extruding its substrates [25]. Although changes of the transporter structures at different stages are not elucidated exclusively, substrates seem to be bound at the high-affinity site within the TMDs.

A

P-gp/ABCB1 (P-gp/MDR1) The first member of ABC transporters, ABCB1 (P-gp/MDR1), was identified in 1976 by Ling et al. as a 170-kDa membrane glycoprotein overexpressed in colchicine resistant cell lines and was referred to as a glycoprotein that reduces drug permeability [29]. P-gp is an apical membrane transporter that is abundantly expressed on the intestine mucosal membrane, kidney proximal tubule epithelia, liver, placenta, and luminal blood–brain barrier, where it functions to protect against xenobiotics and cellular toxicants [30]. As seen in Table 1, P-gp has a very wide substrate spectrum mediating the export of a variety of drugs from different drug classes. These substrates include chemotherapeutic drugs, HIV-protease inhibitors, immunosuppressive agents, antiarrhythmics, calcium-channel blockers, analgesics, antihistamines, antibiotics, natural products, fluorescent dyes and pesticides, among many others [31–38]. And most of the substrates are weakly amphipathic and relatively

TMD1

TMD2 COOH

NH2 NBD1

NBD2

NH2 41

B

TMD0

TMD1

TMD2 COOH

L0

NBD1

C

NBD2

TMD NH2

COOH NBD

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Fig. 1. Secondary structure models of drug efflux transporters of the ATP-binding cassette family. (A) P-gp/ABCB1, (B) MRP2/ABCC2, (C) BCRP/ABCG2. TMD – transmembrane domain; NBD – nucleotide-binding domain; L0 – loop 0.

Please cite this article in press as: Zhaolin Chen, et al., Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.10.010

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NBD

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TMD

TMD

TMD

NBD NBD

NBD

TMD

NBD

NBD

ADP

ADP

Pi

Pi

ATP ATP

ATP

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ATP Hydrolysis

Fig. 2. Function of ABC transporters. ABC transporters are energy-dependent transporters; they exhibit a conformational change upon substrate binding and ATP hydrolysis which drives the transport process of the substrate.

3 hydrophobic, often but not always containing aromatic rings and a positively charged nitrogen atom [37]. Due to its wide substrate spectrum and localization, P-gp seems to be an important determinant of pharmacokinetics and an important mediator of transporter-mediated drug–drug interactions.

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MRP2/ABCC2 The ABCC family consists of 13 subfamily members (ABCC1 to ABCC13). MRP2/ABCC2, the second member of the MRP subfamily of ABC transporter, was first cloned from rat liver in 1996 and was known as cMOAT (canalicular multispecific organic anion transporter) [39]. MRP2 is exclusively expressed in the apical hepatocyte plasma membrane, renal proximal tubules and small intestine, where it is particularly well situated to play a role in the elimination, as

53 well as in the oral bioavailability of drugs, xenotoxins and their phase 54 II metabolites [40,41]. Besides, MRP2 mRNA is also expressed in gall55 bladder, placental trophoblasts, and CD4+ lymphocytes [42–45]. 56 Recently, Korita et al. indicated that MRP2 expression determines 57 the efficacy of cisplatin-based chemotherapy in patients with he58 patocellular carcinoma [46]. 59 MRP2 has a transport facility for a wide variety of chemothera60 peutic substrates such as methotrexate, anthracyclines (doxorubicin, 61 epirubicin), mitoxantrone, cisplatin, and etoposide, which are listed 62 in Table 1 [47–50]. MRP2 is primarily an organic anion transport63 er; it seems that weakly basic drugs are co-transported with GSH by MRP2. This was strongly affirmed by Evers et al., suggesting that Q7 64 65 transport of vinblastine in MRP2-transduced polarized cells (MDCKII66 MRP2) occurs stoichiometrically with GSH transport [51]. Other well67 defined substrates of MRP2 embrace lots of amphipathic anionic

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Q16

Table 1 Selected substrates of P-gp/ABCB1, MRP2/ABCC2 and BCRP/ABCG2. P-gp/ABCB1

MRP2/ABCC2

BCRP/ABCG2

Analgesics: asimadoline, fentanyl, morphine, pentazocine Antiarrhythmics: amiodarone, digoxin, lidocaine, propafenone, quinidine, verapamil Antibiotics: cefoperazone, ceftriaxone, clarithromycin, doxycycline, erythromycin, gramicidin A, gramicidin D, grepafloxacin, itraconazole, ketoconazole, levofloxacin, rifampicin, sparfloxacin, tetracycline, valinomycin Anticancer drugs: 5-fluorouracil, actinomycin D, bisantrene, chlorambucil, colchicine, cisplatin, cytarabine, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, gefitinib, hydroxyurea, irinotecan (CPT-11), methotrexate, mitomycin C, mitoxantrone, paclitaxel, tamoxifen, teniposide, topotecan, vinblastine, vincristine Antihistamines: cimetidine, fexofenadine, ranitidine, terfenadine Antilipidemic: lovastatin, simvastatin Calcium channel blockers: azidopine, bepridil, diltiazem, felodipine, nifedipine, nisoldipine, nitrendipine, tiapamil, verapamil Fluorescent dyes: calcein AM (calcein acetoxymethylester), Hoechst 33342, rhodamine 123 HIV-protease inhibitors: amprenavir, indinavir, lopinavir, nelfinavir, saquinavir, ritonavir Immunosuppressive agents: cyclosporin A, cyclosporin H, FK506, sirolimus, tacrolimus, valspodar (PSC-833) Natural products: curcuminoids, flavonoids Neuroleptics: chlorpromazine, phenothiazine Others: BCECF-AM, bepridil, calcein-AM, diltiazem, endosulfan, leupeptin, methyl parathion, paraquat, pepstatin A, trifluoperazine, trans-flupentixol Antibiotics: ampicillin, azithromycin, cefodizime, ceftriaxone, grepafloxacine, irinotecan Anticancer drugs: cisplatin, doxorubicin, epirubicin, etoposide, irinotecan, mitoxantrone, methotrexate, SN-38, vinblastine, vincristine Antihypertensives: olmesartan, temocaprilate HIV drugs: adevovir, cidofovir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir Others: ethinylestradiol-3-O-glucuronide, genistein-7-glucoside, p-Aminohippurate, phloridzin, quercetin 4′-β-glucoside, vinca alkaloids Antibiotics: ciprofloxacin, norfloxacin, ofloxacin Anticancer drugs: daunorubicin, doxorubicin, epirubicin, etoposide, gefitinib, imatinib, irinotecan, mitoxantrone, methotrexate, SN-38, teniposide, topotecan, Antivirals: delavirdine, lopinavir, lamivudine, nelfinavir, zidovudine Antihypertensives: reserpine Calcium channel blockers: nicardipine Lipid lowering drugs: cerivastatin, pravastatin, rosuvastatin Others: azidothymidine, chrysin, cyclosporin A, lamivudine, ortataxel, quercetin

Data were compiled from Refs. [31–38,40,47–50,53–55].

Please cite this article in press as: Zhaolin Chen, et al., Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.10.010

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drugs and endogenous compounds including sulfate, glucuronide, and GSH conjugates. Furthermore, MRP2 primarily functions to mediate the elimination of bile acids, GSH and conjugated metabolites of numerous drugs and other xenobiotics, which helps in biliary homoeostasis in the liver [40,52]. Additionally, some glucuronide conjugates and food-derived (pre-)carcinogens are also transported by MRP2, at least in vitro [40,53–55]. BCRP/ABCG2 Breast cancer resistance protein (BCRP) is classified as the second member of the G subfamily of the ABC transporter superfamily (ABCG2). This so-called half-size ABC transporter is thought to function as homo- or heterodimers [56]. Although BCRP was discovered last of the ABC drug efflux transporters discussed here, there is already abundant evidence that, similar to MDR1/P-gp and MRP2, it has a multitude of functions in physiology, pathophysiology, pharmacokinetics, and toxicokinetics [57]. The BCRP transporter is widely distributed in the intestine, liver, kidney, and brain, and in addition mainly in the plasma membrane. In human, BCRP is expressed in the apical surface of proximal tubule cells, enterocytes, hepatocytes, and brain capillary endothelial cells, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds as well as tissue protection against toxic xenobiotic exposure [9,58]. Like MDR1/P-gp and MRP2, BCRP transports very broad structurally and functionally diverse substrates such as antivirals, anticancer drugs, antibiotics, etc., as shown in Table 1 Q8 [34,35,56]. Despite that the specificity of BCRP substrates is different from MDR1/P-gp or MRP2, it substantially overlaps with that of MDR1/P-gp or MRP2. ABC efflux transporters in cancer chemotherapy 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 pathways, decreased drug influx, increased drug efflux predominantly via ABC superfamily transporters, and last but not least, elevated expression levels of these drug efflux pumps [60]. As what mentioned before, members of the ABC superfamily including P-glycoprotein (P-gp/ABCB1), multidrug resistance-associated protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) function as ATP-driven drug efflux transporters, which are overexpressed in cancer cells, forming a unique defense against chemotherapeutics and a multitude of endogenous and exogenous cytotoxic agents. These pumps obviously reduce the intracellular concentration of numerous endo- and exotoxins which are structurally and biochemically distinct, accordingly resulting in MDR. Therefore, in MDR cells resistant to many anticancer drugs, ABC superfamily transporters have a suggested role Q9 in resistance. The ability to overcome the actions of ABC superfam-

ily transporters and then restore the sensitivity of chemotherapy has led the researchers to investigate its very involvement in clinical resistance. ABC efflux transporters as targets to overcome multidrug resistance Overview of the inhibitors of ABC transporters One of the common ways to overcome ABC transporter-mediated MDR is to use inhibitors of ABC superfamily transporter to sensitize tumor cells to chemotherapeutic agents. The rationale of the combination identified inhibitors with anticancer drugs toward an improved drug response is clear, and large efforts have been made to develop chemosensitizers [18,49,61–63](Table 2). The combined therapies displayed some encouraging clinical results; however, there is no effective MDR reversing agent approved for an appreciable sensitization of malignant tumors to chemotherapeutic drugs without toxic effects to date. The MDR inhibitors that were initially recognized, such as verapamil and cyclosporine A, are actually substrates for ABC transporters (e.g., P-gp), and they frequently have their own pharmacodynamic effects, so they are not specifically developed for the modulation of ABC transporters. Combined use of these first-generation MDR inhibitors with anticancer drugs (e.g., mitoxantrone and daunorubicin) led to toxic side effects showing only limited function or no benefits [64,65]. Recently, a study of Binkhathlan et al. [66] declared that encapsulation of cyclosporine A in methoxypoly(ethylene oxide)b-poly(ε-caprolactone) (PEO-b-PCL) micelles was shown to reduce its effects on the pharmacokinetics of doxorubicin in rat. Subsequently, the second-generation MDR inhibitors such as PSC-833 and VX-710 were designed to increase the inhibition effects and decrease unwanted toxicities. For instance, a cyclosporin A analog PSC833 not only sensitizes SK-MES-1/DX1000 cells to doxorubicin by enhancing drug accumulation but also inhibits MDR1/P-gp expression by activating JNK/c-Jun/AP-1 and restraining NF-κB [67]. However, in acute myeloid leukemia (AML) patients, use of the PSC833 together with anticancer drugs provided some advantage in therapy, co-administration brought about pharmacokinetic interactions [68]. Especially, concurrent MDR inhibitors aggrandized the systemic exposure to anticarcinogens by means of altering their absorption, distribution, metabolism and excretion (ADME), thereby increasing the toxicity in cancer patients [69,70]. In addition, VX710 could significantly increase the sensitivity of MDR cells but does not alter the pharmacokinetics of doxorubicin [71,72]; when VX- Q10 710 is co-administered with anticancer drugs, it did not distinctly increase the effects, implying the existence of other mechanisms of MDR besides the overexpression of ABC transporters [73]. The third-generation MDR inhibitors were designed to have a high affinity to ABC transporters including GF120918, LY335979, R101933 and XR9576. Compared with the first- or second-generation MDR inhibitors, the third one revealed an enhancement of chemosensitivity in in vitro studies. Nevertheless, the outcomes from clinical trials were clearly not ideal. A study by Cripe et al. [74] stated that zosuquidar (LY335979) may reverse P-gp-mediated resistance in AML without increased toxicity, but did not increase the overall survival rate of older patients. Another study showed that coadministration of tariquidar (XR9576) with docetaxel did not appear to prolong the overall survival of patients with metastatic cancers

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Table 2 Inhibitors of P-gp/ABCB1, MRP2/ABCC2 and BCRP/ABCG2 as chemosensitizers. P-gp/ABCB1 MRP2/ABCC2 BCRP/ABCG2

Atorvastatin, amlodipine, cyclosporin A, dexniguldipine, disulfiram, GF120918, LY475776, LY335979, MS-209, nifedipine, OC144-093, pluronic L61, PSC-833, quinidine, R101933, S9788, VX-710, XR-9576, V-104, verapamil Azithromycin, cyclosporin A, furosemide, glibenclamide, MK-571, probenecid Cyclosporin A, dipyridamole, elacridar, fumitremorgin C, GF120918, novobiocin, ortataxel, reserpine, ritonavir, tariquidar, VX-710, XR-9576

Data were compiled from Refs. [18,49,61–75].

Please cite this article in press as: Zhaolin Chen, et al., Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.10.010

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molecular evidence for the assessment of a novel chemotherapeutical strategy using nilotinib and doxorubicin as treatment combination especially in synovial sarcoma [79]. Another example is a small molecule epidermal growth factor receptor (EGFR) TKI, icotinib, which is efficacious in patients with non-small cell lung cancer [80]. Recently, it was reported that icotinib reverses ABCG2mediated MDR by directly inhibiting the drug efflux function of ABCG2, rather than altering the pAKT and ABCG2 protein expression levels or translocation of ABCG2 in vitro [81]. Telatinib, a vascular endothelial growth factor receptor (VEGFR) TKI, is an orally administered drug that inhibits VEGFR-2, VEGFR-3 PDGFR- and c-Kit [82]. In vitro, telatinib (1 μM) could overtly increase the intracellular accumulation of [3H]-mitoxantrone and decrease its efflux from ABCG2overexpressing cells. In addition, the in vivo results exhibited that telatinib in combination with doxorubicin significantly decreased the ABCG2 overexpressing tumor size [83].

even not producing any toxicity [75]. In general, some possible reasons were proposed to be responsible for the failure of three generations of ABC transporter inhibitors in the clinical trials overcoming MDR. The first-generation inhibitors could be restricted by the inherited side effects, the second-generation inhibitors were confined by the unexpected drug–drug interactions, and the third one may be involved in other mechanisms of MDR in cancers. Moreover, the ABC transporters P-gp, MRP2 and BCRP are often co-expressed in tumor cancers which have an overlapped specificity for a broad range of substrates (Table 1). So selective inhibition of one or two ABC efflux transporters could be compensated by the remaining transporters. Nevertheless, the concept that targeting ABC efflux transporters may overcome MDR is still strong. Selected tyrosine kinase inhibitors of ABC transporters as chemosensitizers During development, researchers pay more and more attention to the new chemosensitizers and novel approaches such as targeted downregulation of MDR genes by small molecule inhibitors, natural drugs, RNA interference, epigenetic regulation as well as signal transduction pathways, etc. In recent years, tyrosine kinase inhibitors (TKIs) (Fig. 3) were reported to inhibit the ABC transportermediated MDR, thereby enhancing the efficacy of conventional chemotherapeutic drugs [8,49,58,76]. First of all, many TKIs are both P-gp inhibitors and BCRP inhibitors. For example, it was described that nilotinib (2.5 and 5 μM), a breakpoint cluster region-Abelson (BCR-ABL) TKI, has an inhibitory effect on the efflux of P-gp/ ABCB1 and BCRP/ABCG2 in vitro [77]. Besides, in vivo studies from Tiwari and his partners have shown that nilotinib, in combination with paclitaxel or doxorubicin, could significantly decrease the size of tumors overexpressing the ABCB1 or ABCG2 transporter, respectively [78]. On the other hand, nilotinib reverts P-gp-mediated resistance by inhibiting the activity of the P-gp as well as doxorubicin-induced expression of P-gp in synovial sarcoma, the latter most probably through inhibition of p38 MAPK. It provided

EGFR

VEGFR

PDGF

5

ABC transporter inhibitors of natural origin Contemporarily, an increasing number of Chinese herbal medicines such as flavonoids, coumarins, terpenoids, and alkaloids were indicated to be an effective way in MDR reversal, also according to their low cost and lower toxicity. In herbal medicine, nobiletin showed MDR reversal effects in KB-C2 cells and KB/MRP cells, respectively. The ATPase activities of P-gp and MRP1 were stimulated by nobiletin. It may cause food–drug interactions because of the inhibitory effects on P-gp and/or MRP1 [84,85]. Yet, (−)epigallocatechin-3-gallate (EGCG) downregulated MDR1/P-gp and BCRP but not MRP1 expression in a tamoxifen resistant MCF-7 cell line [86]. Honokiol, also as a potent MDR reversal agent, was reported to down-regulate the expressions of P-gp at mRNA and protein levels in human breast MDR cancer cell line, MCF-7/ADR cell [87–89]. Another recent study from Li et al. [90] demonstrated that treatment with Mulberroside A, one of the main bioactive constituents of Sangbaipi, significantly decreased P-gp expression and function in vitro and in vivo. Simultaneously,

IGF-1R/IR

P-gp

BCRP

Cell Membrane

36

Icotinib Gefitinib, Erlotinib, Lapatinib, Canertinib, AST1306

BCR- ABL 37 38 39 40

Telatinib, Sunitinib, Motesanib, Vandetanib

Masitinib

Nilotinib, Imatinib, Dasatinib, Ponatinib

Linsitinib

Anticancer drugs

Fig. 3. Overview of TKIs as antagonists in the regulation of ABC transporters. BRAF TKI, breakpoint cluster region-Abelson (BCR-ABL) TKIs, epidermal growth factor receptor (EGFR) TKIs, vascular endothelial growth factor receptor (VEGFR) TKIs, platelet-derived growth factor (PDGF) inhibitors, insulin-like growth factor 1 (IGF-1R)/insulin receptor (IR) TKI either block the function of or down-regulate MDR-ABC transporters such as P-gp/ABCB1 and BCRP/ABCG2. Black solid arrows indicate a reduction on the efflux of various anticancer drugs. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Please cite this article in press as: Zhaolin Chen, et al., Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.10.010

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Mulberroside A treatment increased PKC activity in the membrane microsomes of Caco-2 cells and IκB-α degradation and p65 translocation to nucleus, stating that PKC and NF-κB activations might play an important role in Mulberroside A-induced suppression of P-gp. More recently, it has been shown that sinomenine could enhance the sensitivity of a multidrug-resistant Caco-2 (MDR-Caco2) cell line toward doxorubicin by downregulating MDR-1 and COX-2 expression via inhibition of the NF-κB pathway [91]. Furthermore, novel derivatives of tetrandrine H1, 3-(5′-hydroxymethyl-2′-furyl)1-benzylindazole (YC-1), Grape Seed Procyanidin and anthraquinone have been shown to effectively reduce the transport function and expression of P-gp by inhibiting the MEK-ERK signaling pathway [92–94]. Strikingly, calebin-A, a natural compound present in perennial herb Curcuma longa, enhances the cytotoxicity of vincristine in SGC7901/vincristine cells, inhibits the drug efflux function but not the expression level of P-gp and activates p38 MAPK [95]. Curcumin, also the major active principal of C. longa, used for breast cancer, colon cancer and prostate cancer, suppressed MRPs in cancer cells. It enhanced PhIP-induced apoptosis and inhibited PhIPinduced tumorigenesis in the proximal small intestine of Apc (min) mice [96]. And curcumin could increase the sensitivity of mitoxantrone, topotecan, SN-38 and doxorubicin, which are substrates for ABCG2, in overexpressing ABCG2 cells [97]. Furthermore, curcumin inhibited the expression of COX-2 in the peripheral blood mononuclear cells from pancreatic cancer; the combination therapy of curcumin and docetaxel effectively decreased proliferation and microvessel density, while increasing tumor cell apoptosis in ovarian tumors, strongly suggesting the potential of curcumin as a MDR reversal agent [98]. Additionally, Zhang et al. [99] discovered that using 5-Bromotetrandrine (BrTet) in combination with other anticancer agents (e.g. daunorubicin and paclitaxel) and pharmacological inhibitors of JNK (e.g. SP600125 or siRNA oligonucleotides) can reduce the P-gp-induced MDR in adriamycin-resistant K562 cells which would overcome the difficulty in clinical situation for chemotherapeutic-resistant human leukemia. Illustrative examples of RNAi in blocking the expressions of ABC transporters As previously mentioned, up-regulation of ABC efflux transporters, which results in MDR, has been described in several types of human tumors. Silencing the expression of gene encoding ABC efflux transporters through RNA interference (RNAi) or small interfering RNA (siRNA) could be an effective therapeutic approach against human tumors. Transient RNAi mediated silencing can be achieved by siRNA or stable RNAi-mediated gene silencing through short hairpin RNA (shRNA) transfection. The first study which was reported in 2003 displayed that using the RNAi technology could reverse the MDR phenotype of human cancer cells by knocking down the MDR1/P-gp encoding mRNA. To further increase the efficacy of silencing, several studies have designed stable anti-ABC transporter shRNA expression vectors to overcome the MDR. One direct example is that MDR1/P-gp knockdown using shRNA could distinctly increase the sensitivity to ADR treatment in drug resistant gastric cancer SGC7901-MDR1 cells [100]. In an in vivo model, treatment of the shRNA expressing tumors with vincristine inhibited tumor growth by 42%, showing the efficiency of RNAi to overcome MDR. And compared to the controls, the tumor growth inhibition by 80-fold was observed in cells transfected with anti-MDR1/P-gp shRNA plasmids that were implanted into nude mice [101]. Furthermore, another group designed and synthesized a poly-siRNA for P-gp suppression (psi-P-gp) to overcome MDR in cancers. Contemporary psi-P-gp and thiolated glycol chitosan polymers (tGC) formed stable nanoparticles (psi-P-gp-tGC NPs), thus proving a clear evidence for reversing MDR in vivo [102]. As for MRP2, Materna et al. have been designed two specific anti-ABCC2 small interfering RNAs (siRNAs) as well as a stable shRNA-encoding expression vector to

reverse the resistance against cisplatin and paclitaxel in human ovarian carcinoma cell line A2780RCIS [103]. Moreover, shRNA expression vectors effectively reduce MRP2 expression by Western blot and immunocytochemistry, and it can restore the sensitivity of a MDR human ovarian cancer cell (A2780/cp70) to chemotherapeutic agent cisplatinum [104]. Several papers also reported a role of RNAi in the control of BCRP in the MDR. The results from Aliabadi et al. [105] revealed that silencing of BCRP was associated to siRNA delivery efficiency of the polymers; BCRP down-regulation increased sensitivity of the drug-resistant cells to cytotoxic effect of mitoxantrone by an ~14-fold reduction in the IC50 value. Moreover, a recent research elaborated that BCRP inhibition by siRNA significantly sensitizes human MCF7 breast cancer cells against mitoxantrone chemotherapy. Combination of siRNA with mitoxantrone could distinctly overcome MDR in breast cancer cells [106]. Meanwhile, disruption of BCRP with siRNA in the glioblastoma LN229 cell line further increased the cytotoxicity of mitoxantrone [107]. Besides, pLenti6/BCRPsi shRNA (V-BCRPi) recombinant retroviruses were constructed and packaged, conferring significant knockdown effects of BCRP. The in vivo and in vitro studies brought out the results that V-BCRPi could improve the BCRP/ ABCG2-mediated drug-resistant phenotype in human choriocarcinoma cell line JAR and increase the sensitivity of the tumor histiocytes to 5-FU [108]. Indirectly, for example, Wang et al. [109] presented that CIAPIN1 gene silencing by lentivirus-vector-based RNA interference (RNAi) in nude mice could attenuate P-gp expression, increase P53 expression and reinstate the chemotherapy sensitivity of MDR breast cancer in vivo. In the K562 and K562/VCR cells, knockdown of WNT1 and β-catenin using a siRNA approach and overexpression of nuclear β-catenin, combined with TCF binding site activation indicated that the canonical pathway of Wnt signaling positively regulates the ABCB1 [110]. Meanwhile, Zhang et al. [111] demonstrated that MDR1/P-gp as well as FZD1 expression is also upregulated in the multidrug resistant breast cancer cell line MCF-7/ADM. Silencing FZD1 decreased the MDR1/P-gp expression, improved the cell sensitivity to chemotherapy drugs, and obviously decreased the levels of cytoplasmic and nuclear β-catenin. Moreover, inhibition of Wnt/ β-catenin pathway by β-catenin siRNA reversed the MDR of a human MDR cholangiocarcinoma cell line QBC939/5-FU to chemotherapeutics [112]. Lim and his companions investigated that the inhibitor of GSK-3 and Wnt agonist enhanced β-catenin expression and increased the transcript and protein levels of P-gp in endothelial cells which were derived from brain vasculature; on the other hand, blocking the Wnt signaling using Dickkopf-1 or quercetin could attenuate the P-gp expression, also suggesting the involvement of Wnt/βcatenin signaling pathway in the regulation of P-gp expression [113]. Silencing dishevelled-1 (DVL1) by applying siRNA in human ovarian cancer cell line A2780 (A2780/Taxol line) decreased the protein expression levels of P-gp, BCRP and Bcl-2, and restored the sensitivity of MDR cells to paclitaxel, via restraining AKT/GSK-3β/β-catenin signaling. These consequences provide a novel strategy for chemosensitization of ovarian cancer to paclitaxel-induced cytotoxicity [114]. In addition, knockdown of histone-lysine N-methyltransferase (EZH2) gene by RNAi strongly reduced the expressions of EZH2, MDR, MRP and BCRP mRNA and protein levels, therefore resulting in apoptosis and a cell cycle arrest in the G1/S phase in human glioblastoma cell lines U251/TMZ and U87/TMZ [115]. Runt-related transcription factor 3 (RUNX3) is a tumor suppressor gene and its protein expression is absent in 72% of pancreatic cancer patients. Loss of RUNX3 expression may contribute to gemcitabine resistance by upregulating the MRP2 expression, thereby resulting in poor patient survival and shorter time to recurrence. Therefore, transfection with RUNX3 siRNA in pancreatic cancer cells SUIT-2 and KLM-1 could increase the MRP2 expression and improve the chemosensitivity to gemcitabine [116]. Furthermore, Yamaguchi

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et al. [117] reported that inhibition of BAF57 using specific siRNA could decrease the BCRP protein expression, accrue cell cycle arrest at G1 phase and increase the sensitivities to cisplatin, doxorubicin, 5-fluorouracil and paclitaxel in A2780 ovarian cancer cells, implying that BAF57 may be a target for ovarian cancer therapy. Particularly, therapy combined BAF57-targeting agents with anticancer agents such as doxorubicin, etoposide and gefitinib, which are substrates for BCRP, might be an effective treatment strategy for ovarian cancer. NF-E2-related factor 2 (NRF2), a redox-sensing transcription factor, is known to upregulate a wide spectrum of genes involved in redox balance, glutathione metabolism, and drug detoxification, which confers chemoresistance in cancer cells. Down-regulation of NRF2 expression by NRF2 shRNA can decrease the expression of ABCG2 transcript and protein in A549 and H460 lung cells, and dramatically sensitize these cells to mitoxantrone and topotecaninduced cytotoxicity [118]. Similarly, stable NRF2 knockdown by transfecting with shRNA increases intracellular accumulation of Pba, which is a fluorogenic substance, and enhances photodynamic therapy (PDT) sensitivity because of the reduction of BCRP expression in multiple cancer cells [119]. Epigenetic regulators Nowadays, epigenetic mechanisms play an important role in the regulation of gene expression, and different epigenetic processes are Q11 associated with gene silencing (Fig. 4) [120]. MicroRNAs (miRNAs) are evolutionarily conserved, endogenous, nonprotein-coding RNAs of 20–22 nucleotides in length, which have been shown to function as posttranscriptional regulation of target gene expression. Functionally, they are closely related to play roles in the malignant phenotypes of cancers such as embryogenesis, cell development, proliferation, and apoptosis [121,122]. Considerable researchers showed that dysregulation of miRNA may influence the expressions of many target proteins which result in variations of sensitivity of cells to chemotherapeutic drugs [123,124]. In the work of Feng et al. [125], in leukemia K562 cells resistant to doxorubicin, a direct regulation was found in MDR1 through a putative miR-331-5p site. And another example of direct regulation was miR-451, which controls P-gp expression through a unique binding site located at nt

Calebin-A

Procyanidi, anthraquinone, H1, YC1,

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4742–4763 within the MDR1 3′-untranslated region (3′-UTR) [126]. MiR-451 and miR-298 were both reported to decrease doxorubicin chemoresistance of the breast cancer cells by regulating the expression of MDR1/P-gp [126,127]. Furthermore, Zhu et al. [128] indicated that aberrant expressions of miR-451 and miR-27a were related to the activation of MDR1/P-gp and led to drug resistance in human cancer cell lines A2780DX5 and KB-V1. We previously highlighted a novel miRNA-mediated regulation mechanism in which miR-27a positively reverses the MDR1/P-gp-mediated MDR by repressing FZD7/β-catenin pathway through the down-regulation of FZD7 (Frizzled-7). It was also confirmed that reduction of FZD7 by RNA interference induced inhibitory effects on the expression of MDR1/P-glycoprotein and β-catenin, similar to miR-27a [129]. Xu et al. [130] also found that overexpression of miR-122 could improve the sensitivity of the HCC cells to chemotherapeutic drugs by suppressing MDR-related genes including MDR1, MRP and GST-p. In addition, miR-19a and miR-19b were found to be overexpressed in MDR cell lines and modulated MDR in gastric cancer cells by targeting PTEN [131]. Recently, Zhu et al. [132] elaborated the role of miR-145 as a key regulator of chemoresistance in ovarian cancer by targeting both Sp1 and Cdk6. They confirmed that miR-145 was frequently decreased and Sp1 and Cdk6 were increased in MDR ovarian cancer cells or tissues; introducing miR-145 into MDR ovarian cancer cells (SKOV3/PTX and A2780/PTX cells) could cause a reduction in Cdk6 and Sp1 along with downregulation of P-gp and pRb. More interesting, demethylation with 5-aza-dC resulted in the enhancement of miR-145 expression, which also led to increased sensitivity to paclitaxel in MDR ovarian cancer cells. A more recent study presented that hypermethylation of the miR-137 promoter contributed in part to reduced miR-137 expression and increased MDR1 expression in doxorubicin-resistant neuroblastoma cells, indicating that miR-137 is a crucial regulator of cancer response to doxorubicin treatment [133]. Moreover, the role of MRP2 and miR379 was lately uncovered by Werk et al. [134], revealing that MRP2/ ABCC2 was suppressed through miR-379 in a haplotype-dependent manner, and efflux of glutathione-methylfluorescein was obviously declined in miR-379-transfected peripheral blood monocytic cells. And Loeser et al. [135] illuminated a direct interaction between

Nobiletin, 5-BrTet, Sinomenine, Mulberroside A Curcumin

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Fig. 4. RNAi technology and epigenetic regulators involved in the control of MDR. Black solid arrow indicates a reduction on the efflux of various anticancer drugs. Red solid arrows indicate a reduction on the expression level of P-gp/ABCB1, BCRP/ABCG2 or MRP2/ABCC2. Light blue bars indicate RNA interference between miRNA or lncRNA and target mRNA. Red forks indicate RNA interference on the expression of target genes, thus inhibiting the expression level of P-gp/ABCB1, BCRP/ABCG2 or MRP2/ABCC2. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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1 the miR-133a and the 3′UTR of MRP2; however, there is no ample 2 evidence showing its connections with MDR. As for the post3 transcriptional regulation of BCRP/ABCG2, miR-328 might readily 4 target the 3′-UTR of ABCG2. In drug-resistant breast cancer MCF7/MX100 (mitoxantrone-selected) cells, overexpression of miR5 328 by transfecting with pS-miR-328 plasmid apparently restrained 6 the level of ABCG2 protein. Besides, miR-328-directed down7 regulation of ABCG2 expression clearly increased the sensitivity to 8 mitoxantrone by a significantly lower IC50 value (2.46 ± 1.64 μM) com9 pared with the vehicle control [136]. Contemporarily, another study 10 showed that miR-181a could inhibit BCRP expression via target11 ing the 3′-UTR of BCRP mRNA, and sensitized the MCF-7/MX cells 12 to mitoxantrone; in vivo study presents the similar consequence that 13 intratumoral injection of miR-181a mimics suppressed BCRP ex14 pression, and fortifies the antitumor activity of mitoxantrone [137]. 15 Consistently, a more recent research by Ma et al. [138] also ob16 served that miR-487a directly bound to the 3′UTR of BCRP, exhibiting 17 the parallel outcomes as aforementioned. These findings provide 18 experimental evidence for the use of miRNA as a potential target 19 for preventing and reversing drug resistance in breast cancer. 20 DNA methylation and histone modifications are two signifi21 cant reversible mechanisms of epigenetic regulation of gene 22 expression and play a role in cancer development. Many recent 23 studies have suggested a direct role for epigenetic inactivation of 24 genes in determining tumor chemo-sensitivity. Wang et al. [139] 25 identified secreted frizzle-related protein 5 (SFRP5) gene methyla26 tion in cultured bone mononuclear cells from 7/12 patients with 27 acute leukemia and in HL-60, Raji, U937 and KG1a human leuke28 mia cell lines by methylation-specific PCR. SFRP5 gene methylation 29 in leukemia cells activates Wnt/β-catenin signaling to upregulate 30 MDR1/P-gp expression and cause MDR. What is more, epigenetic 31 analysis identified bone morphogenetic protein 4 (BMP4) as an epi32 genetically regulated gene that is upregulated in cisplatin-resistant 33 gastric cancer cell lines. In primary tumors, methylation levels of 34 BMP4 promoter were inversely associated with BMP4 expression, 35 and patients with high BMP4-expressing tumors exhibited signifi36 cantly poorer prognosis. Therapeutically, the targeted genetic 37 inhibition of BMP4 caused a significant sensitization of gastric cancer 38 cells to cisplatin [140]. It was found that epigenetic silencing of most 39 cancer suppressor and osteoblast differentiation genes yields clonal 40 selection of the MDR phenotype. Treatments with the inhibition of 41 DNA methyltransferase (DNMT) 5-Aza-dC and histone deacetylase 42 (HDAC) Trichostatin A were shown to reverse the epigenetic aber43 rations and led to the reprogramming of MDR osteosarcoma (OS) 44 cells toward osteoblast differentiation [141]. Furthermore, DNA meth45 ylation and histone H3 acetylation were shown to be involved in 46 ABCB1 gene expression and were associated with an MDR pheno47 type in canine lymphoid tumor cell lines UL-1 and Ema [142]. One 48 study demonstrated that the ABCB1/MDR1 and ABCG2/BCRP pro49 moters were hypomethylated in gemcitabine-resistant pancreatic 50 cancer cells, which may contribute to pancreatic cancer tumori51 genesis and drug resistance [143]. Another study from Turner et al. 52 [144] illustrated that ABCG2 is expressed and functional in human 53 myeloma cell lines and patient plasma cells, regulated by promot54 er methylation, up-regulated in response to chemotherapy, and may 55 bring about intrinsic drug resistance. Further studies confirmed that 56 melatonin increased the methylation levels of the ABCG2/BCRP pro57 moter; the effects on ABCG2/BCRP expression and function were 58 prevented by preincubation with a DNA methyl-transferase inhib59 itor. Thus combination of melatonin and chemotherapeutic drugs 60 (including temozolomide) has a synergistic toxic effect on brain 61 tumor stem cells (BTSCs) and A172 malignant glioma cells [145]. 62 63 Q12 Very interesting, Saito et al. [146] claimed that DNA methylation in the miR-328 5′-flanking region is suggested to be connected to 64 an increased expression of BCRP, resulting in drug resistance in 65 human placenta. 66

Recently, many researchers have investigated the relationship between histone deacetylases (HDACs) and multidrug resistance. It has been reported that HDAC1 was upregulated in multidrug resistant neuroblastoma cells and siRNA knockdown sensitized cells for etoposide treatment [147]. Oehme et al. [148] provided in vivo and in vitro evidence that HDAC10 could promote the autophagymediated survival of neuroblastoma cells. They revealed that both the knockdown and inhibition of HDAC10 effectively disrupted the autophagy associated with the sensitization to cytotoxic drug treatment in a panel of highly malignant V-MYC myelocytomatosis viralrelated oncogene, neuroblastoma derived-amplified neuroblastoma cell lines, in contrast to nontransformed cells. Meanwhile, accumulating evidence showed that HDAC inhibitors can induce MDR through increasing the expression of ABC transporters, thus contributing to a poor prognosis in cancer treatment [149–152]. However, there are also controversial reports suggesting that HDAC inhibitors can overcome MDR through reducing the expression of ABC transporters [153]. So for instance, vorinostat (SAHA) is a novel hydroxamate structure HDAC inhibitor which was found to be a potential inducer of HDAC inhibitor resistance. It was demonstrated that SAHA induced drug resistance following continuous treatment in a MDR1-independent manner, which is noteworthy as SAHA is not a substrate for MDR1 [154]. Trichostatin A (TSA), another natural hydroxamate HDAC-inhibitor with a structure similar to SAHA, induced an enhancement in the level of acetylated H4 and sequentially promoted the gene expression of MDR1, thus resulting in MDR [155]. Yet, another study by Kim et al. [156] assumed that MRP2 but not MDR1 or BCRP expression is attenuated by SAHA and TSA, in MDR positive cancer cell KBV20C. Therefore, the declined levels of MRP2 contribute to an increase in paclitaxelinduced G2/M arrest and apoptosis. Interestingly, a new class of transcripts, long non-coding RNAs (lncRNAs), has recently been found to be responsible for at least 80% of all genome transcripts. In cancer, lncRNAs can function as oncogenes or tumor suppressors through silencing or activating the expression of protein-coding genes; they play important roles in regulating transcriptional processes, splicing, mRNA translation and cell development [157–159]. Some of the studies in gastric cancer showed that lncRNA MRUL increases P-gp/ABCB1 expression. MRUL knockdown using siRNA markedly reduced the levels of ABCB1 mRNA in vitro and in vivo, thus resulting in increased rates of ADRinduced apoptosis and ADR accumulation in two MDR gastric cancer cell sublines, SGC7901/ADR and SGC7901/VCR [158]. Subsequently, another analogous study carried out by Zhang et al. [160] reported that lncRNA PVT-1 enhances the mRNA and protein expression levels of MDR1/P-gp and MRP1 in two cisplatin resistance gastric cancer cell lines (BGC823/DDP and SGC7901/DDP), too. Transfection with PVT-1 siRNA could reverse the cisplatin resistance. As Q13 noted above, a summary of these two independent studies provided convincing evidence showing that lncRNA MRUL or PVT-1 might be a promising therapeutic target in the treatment of MDR-gastric cancer. 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 drugs. Hence, researchers pay more attention to the approaches inversing the MDR. Although many chemosensitizers have been used in clinical trials, most of them are demonstrated to be unbeneficial for cancer

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Fig. 5. Selected natural drugs as potential reversing agents of MDR. Black solid arrow indicates a reduction on the efflux of various anticancer drugs. Red solid arrow indicates a reduction on the expression of P-gp/ABCB1. Orange solid arrows indicate a reduction on the expression of P-gp/ABCB1 and BCRP/ABCG2. Black dashed arrows indicate a reduction on the drug efflux function but not the expression level of P-gp/ABCB1 or BCRP/ABCG2. Light blue bars indicate inhibiting effect between natural drugs and target pathway. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

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patients due to the inherited toxicities or pharmacokinetic interactions. However, the enthusiasm is still high for targeting ABC efflux transporters to overcome MDR, which includes the development of new chemosensitizers and novel ways such as RNA interferQ14 ence and epigenetic regulation (see Figs. 3 and 4). Moreover, it will benefit for the development of novel anticancer drugs that wound bypass ABC transporter-mediated efflux by the lessons learned from Q15 previous MDR modulators (see Fig. 5). Accordingly, further preclinical and clinical investigations are required to determine the impact of ABC transporters on multidrug resistance in various cancers. Acknowledgements This project was supported by the National Science Foundation of China (Nos. 81072686, 81273526, and 81202978). Conflict of interest None declared. References [1] A.K. Tiwari, K. Sodani, C.L. Dai, C.R. Ashby Jr., Z.S. Chen, Revisiting the ABCs of multidrug resistance in cancer chemotherapy, Curr. Pharm. Biotechnol. 12 (2011) 570–594. [2] Z. Binkhathlan, A. Lavasanifar, P-glycoprotein inhibition as a therapeutic approach for overcoming multidrug resistance in cancer: current status and future perspectives, Curr. Cancer Drug Targets 13 (2013) 326–346. [3] B.C. Baguley, Multiple drug resistance mechanisms in cancer, Mol. Biotechnol. 46 (2010) 308–316. [4] T. Fojo, M. Menefee, Mechanisms of multidrug resistance: the potential role of microtubule-stabilizing agents, Ann. Oncol. 18 (Suppl. 5) (2007) v3–v8. [5] H. Lage, An overview of cancer multidrug resistance: a still unsolved problem, Cell. Mol. Life Sci. 65 (2008) 3145–3167. [6] J.P. Gillet, M.M. Gottesman, Mechanisms of multidrug resistance in cancer, Methods Mol. Biol. 596 (2010) 47–76.

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Please cite this article in press as: Zhaolin Chen, et al., Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade, Cancer Letters (2015), doi: 10.1016/j.canlet.2015.10.010

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