Quercetin: A potential drug to reverse multidrug resistance

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Life Sciences 87 (2010) 333–338

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Life Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / l i f e s c i e

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Quercetin: A potential drug to reverse multidrug resistance Chen Chen a, Jane Zhou b, Chunyan Ji a,⁎ a b

Department of Hematology, Qilu Hospital, Shandong University, 107 West Wenhua Road, Jinan, Shandong, 250012, PR China Zenith Diagnostic Consultants, 4035 Silver Lace Lane, Redding, CA 96001, USA

a r t i c l e

i n f o

Article history: Received 14 May 2010 Accepted 7 July 2010 Keyword: Quercetin Multidrug resistance P-glycoprotein Multidrug resistance associated protein Breast cancer resistance protein

a b s t r a c t This review centers on recent findings with respect to modulating cancer multidrug resistance (MDR) with the well-known flavonoid quercetin. After a short introduction of quercetin, major in vitro and in vivo findings are summarized showing that quercetin is a MDR modulator and thus a potential chemosensitizer. Finally, we contemplate future prospects of modulating MDR in the clinic. © 2010 Elsevier Inc. All rights reserved.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chemistry of quercetin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pharmacokinetics of quercetin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anti-cancer properties of quercetin . . . . . . . . . . . . . . . . . . . . . . . . . . Quercetin as a chemosensitizer of the multi-pump category . . . . . . . . . . . . . . . In vitro studies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . In vivo studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Mechanisms for reversion of MDR . . . . . . . . . . . . . . . . . . . . . . . . . . . Interaction between quercetin and P-gp . . . . . . . . . . . . . . . . . . . . . . Quercetin can inhibit its activity or decrease its expression . . . . . . . . . Quercetin can interact with the ATP-binding site or the substrate-binding site Interaction between quercetin and MRP1 . . . . . . . . . . . . . . . . . . . . . Interaction between quercetin and BCRP . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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Introduction Intrinsic or acquired multidrug resistance (MDR) is a major impediment to successful chemotherapy. The phenomenon of MDR is mediated by multiple mechanisms, including tumor vasculariza-

⁎ Corresponding author. Tel./fax: + 86 531 86115887. E-mail address: [email protected] (C. Ji). 0024-3205/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.lfs.2010.07.004

tion, altering activity of specific enzyme systems, deregulation of apoptosis, active extrusion of drugs by ATP-binding cassette (ABC) transporters and so on (Krishna and Mayer 2000). Among the mechanisms proposed to mediate MDR, overexpression of ABC transporters has received extensive investigation (Litman et al. 2001). ABC transporters are a superfamily, with 49 different transporter proteins having been identified in humans so far. These proteins function as ATP-dependent drug efflux pumps, and are usually classified into seven subfamilies based on their characteristics:

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ABCA (12 members), ABCB (11), ABCC (13), ABCD (4), ABCE (1), ABCF (3) and ABCG (5) (Chang 2007). Among these transporters, Pglycoprotein (P-gp, ABCB1), multidrug resistance associated protein 1 (MRP1, ABCC1) and breast cancer resistance protein (BCRP, ABCG2) are found to efflux drugs leading to a decrease in cellular drug accumulation (Ambudkar et al. 2003; Cole and Deeley 1998; Ejendal and Hrycyna 2002). Accordingly, inhibition of ABC transporters may lead to enhanced efficacy of chemotherapy. A number of studies demonstrate that natural products from plants such as flavonoids are potential drugs to overcome MDR in many multidrug resistant cells (Kim et al. 1998; Duraj et al. 2005; Skupien et al. 2006, 2008). Quercetin, 3, 3′, 4′, 5, 7-pentahydroxylflavone (Fig. 1), is a typical flavonol-type flavonoid ubiquitously present in fruits and vegetables, such as onion, tea, apples and berries. It exhibits antioxidative, anti-inflammatory and vasodilating effects, and has been proposed to be a potential anti-cancer agent (Erlund 2004). Epidemiological studies in the U.S., Europe, and Asia have estimated that the daily dietary intake of quercetin by an individual ranges from 4 to 68 mg (Hertog et al. 1993, 1995; Knekt et al. 1997; Rimm et al. 1996). Recently, quercetin has been marketed in the United States primarily as a dietary supplement (Theoharides and Bielory 2004). In this review, we firstly discuss the chemical reactivity of quercetin and its anti-carcinogenic mechanisms. Then, we focus on the interactions of quercetin with some ABC transporters and explore its MDR reversal effects. Chemistry of quercetin Quercetin is a typical flavonol-type flavonoid. Flavonoids are characterized by 2 benzene rings (A and B) which are connected by an oxygen-containing pyrene ring (C). The three rings are planar and the molecule is relatively polarized. Three intermolecular hydrogen bonds are observed: two with the carbonyl group and the other between the hydroxyl groups in ring B (Mendoza-Wilson and Glossman-Mitnik 2004). Dietary quercetin is mostly present as its glycoside form in which one or more sugar groups is bound to phenolic groups by glycosidic linkage. The water-solubility of quercetin increases with increasing number of sugar groups. Quercetin was stable in human urine, human plasma, acetonitrile and water at 4 °C, −20 °C and −80 °C. Instability of quercetin under basic conditions is likely due to the instability of the center ring structure in quercetin, resulting in fragmentation of the ring structure. The center ring structure in quercetin seems essential to its stability (Moon et al. 2008). Analysis of the structure–activity relationships showed that the physical properties of quercetin are determined by its chemical structure. Quercetin can participate in the complex reactions with metals, affecting the transportation, reactivity, bioavailability and toxicity of metal ions. It possesses three possible chelating sites in competition which could be classified in the following way: catechol N α-hydroxycarbonyl N β-hydroxycarbonyl (Cornard et al. 2005).

Quercetin possesses all the structural elements characteristic of an anti-oxidant: (1) an ortho-dihydroxy or catechol group in ring B, (2) a 2, 3-double bond, and (3) the 3- and 5-OH groups with the 4-oxo group (Silva et al. 2002; Bors et al. 1990). The anti-proliferation potency of quercetin may be attributed to hydroxyl substitutions, particularly, the hydroxyl-substitutions at carbon 3 of ring B and carbon 5 of ring A. In contrast, some other substitutions were found to lower its potency: e.g. substitutions by sugar moieties in flavones (Loa et al. 2009). Pharmacokinetics of quercetin At present, the pharmacokinetics of quercetin has not been fully characterized, although a number of studies have been carried out both in animals and humans. Flavonoid glycosides from diet are believed to pass through the small intestine, be hydrolyzed to aglycone by enterobacteria in the cecum and colon and absorbed into epithelial cells via lipophilicity-dependent simple diffusion (Bokkenheuser et al. 1987). Quercetin glucosides can also be directly absorbed via the sodium-dependent glucose transporter-1 (SGLT-1) or excreted into the lumen via multidrug resistance protein 2 (MRP-2) (Murota and Terao 2003). After their facilitated uptake by means of carrier-mediated transport, quercetin glycosides are often hydrolyzed by intracellular β-glucosidases (Németh et al. 2003). The intestinal lactase phlorizin hydrolase (LPH) displays a specific activity towards flavonoid glycosides (Day et al. 2000). Hydrolysis to aglycone by enterocytes or enterobacteria is crucial for the efficient absorption of quercetin glucosides in the intestinal tract. Quercetin absorbed from the intestinal lumen is mostly converted to conjugated metabolites before entering circulation, and the major metabolites present in human plasma are quercetin 3′-O-β-Dglucuronide (Q3′GA) and quercetin 4′-O-β-D-glucuronide (Q4′GA). Some metabolites still possess considerable activity, including Q3GA, Q3′GA and Q4′GA (Williamson et al. 2005). Regarding the tissue distribution, a recent study observed that quercetin concentrated in lungs, testes, kidneys, thymus, heart and liver, with the highest concentrations of quercetin and its methylated derivatives detected in the pulmonary tissue (de Boer et al. 2005). Urinary elimination of quercetin is not the main excretion routes in human subjects or in rats. A substantial portion of the metabolites may be excreted in the bile (Murota and Terao). Quercetin can undergo microbial degradation in the colon to phenolic acids and CO2, which is exhaled in the breath (Abrahamse et al. 2005). The low bioavailability of quercetin and high metabolite concentrations indicate an extensive first-pass metabolism in the gut and/or the liver (Ader et al. 2000; Oliveira et al. 2002). Additionally, the high concentration of conjugated quercetin observed in the bile indicates potential enterohepatic recirculation (Liu et al. 2003). However, Chen et al. (Chen et al. 2005) did not find any significant enterohepatic recirculation of quercetin and its conjugates. Following ingestion of quercetin (100 mg), a half-life range of 31–50 h was observed in humans, with peak plasma levels observed at 30 min and again at 8 h post-treatment (Walle et al. 2001). The half lives of the quercetin metabolites are 11 to 28 h, indicating that the metabolites could attain a considerable plasma level upon repeated quercetin supplementation (Hollman and Katan 1997; Manach et al. 2005). Anti-cancer properties of quercetin

Fig. 1. Molecular structure of quercetin.

Quercetin has attracted much attention as a potential anti-cancer agent. Numerous reports on the chemopreventive and anti-genotoxic effects of quercetin have been published. The cancer-preventive effects have been attributed to various mechanisms including the antioxidative activity, the inhibition of enzymes that activate carcinogens, the modification of signal transduction pathways, and interactions with receptors and other proteins (Moon et al. 2006; Shih et al. 2000).

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Various cellular receptors have been reported to be involved in the cancer-preventive activities of quercetin, including an aryl hydrocarbon receptor (AhR) (Fukuda and Ashida 2008), the androgen receptor (Xing et al. 2001), the ErbB protein family which is also known as the epidermal growth factor receptor (EGFR) family (Kim et al. 2005), death receptor (DR) (Chen et al. 2007), and so on. Quercetin is multitargeted. For example, quercetin can trigger DNA fragmentation, up-regulation of Bax and posttranslational modification of anti-apoptotic Bcl-2 (Duraj et al. 2005). Quercetin can enhance TRAIL-induced apoptosis (Psahoulia et al. 2007). Quercetin can also induce apoptosis through the activation of mitochondrial pathway and the blockade of pro-survival signaling (Granado-Serrano et al. 2006). In addition, a recent study showed that quercetin reduced the formation of aberrant crypt focus in a rat colon cancer induction model, suggesting the importance of this compound in the prevention of colon cancer by decreasing cancer initiating events (Volate et al. 2005).

Quercetin as a chemosensitizer of the multi-pump category In vitro studies Quercetin itself showed growth inhibitory activity on both drugsensitive and MDR cells, e.g. HL60 (promyelocyte leukemia cells), K562(erythroleukemic cells), CCRF-CEM(T-lymphocytic leukemia cells) and their respective drug resistant counterparts HL60/VCR, K562/adr, CEM/ADR5000, CEM/VLB100 and CEM/E1000 (Duraj et al. 2005; Kothan et al. 2004; Efferth et al. 2002). In addition, quercetin at a non-cytotoxic concentration has enhanced the effect of chemotherapeutic drug on MDR cells. Quercetin's candidacy as a chemosensitizer for the ABC pump-proteins has been tested in a number of MDR tumor cell lines. Data have shown that quercetin interacts directly with transporter proteins to inhibit drug efflux mediated by either MDR1 or MRP1 or BCRP (Limtrakul et al. 2005; Shapiro and Ling 1997; Leslie et al. 2001; Zhang and Wong 1996). The tested drugs include [3H]daunomycin (DNM), the fluorescent substrate Rhodamine-123, vinblastine, 2, 4-dinitrophenyl-S-glutathione (DNP-SG) and mitoxan-

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trone (Table 1). In one study, the addition of quercetin resulted in an increased DNM accumulation (201.8 + 16.4%) in the resistant cell line MCF-7/ADR, which was comparable to verapamil (229.4 + 17.6%), a well-known P-gp inhibitor (Chung et al. 2005). In another study, the exposure of MDR cells expressing MRP1 to 50 μM quercetin resulted in a 40% decrease of the basolateral efflux of DNP-SG with a concomitant increase of the intracellular DNP-SG concentration, which was comparable to the effects of 50 μM of MK571(an MRP1 specific inhibitor) (van Zanden et al. 2005).

In vivo studies Quercetin has been studied in several animal models. In Sang-Chul Shin's study (Shin et al. 2006), quercetin was given at the doses of 2.5, 7.5 and 15 mg/kg to female Sprague–Dawley rats, with tamoxifen as the test drug. Oral tamoxifen underwent extensive hepatic metabolism and subsequent biliary excretion. Tamoxifen and its metabolites such as 4-hydroxytamoxifen are substrates for the efflux of P-gp, BCRP and MRP2. It was found that quercetin was capable of increasing absorption rate, peak concentration, the absolute bioavailability and the relative bioavailability of tamoxifen while quercetin significantly decreased the metabolite ratios (MR, AUC of 4-hydroxytamoxifen to tamoxifen) of tamoxifen. These results indicate that quercetin inhibits both MDR transporter-mediated efflux of tamoxifen and its first-pass metabolism. Quercetin has been reported to modulate the bioavailability of drugs by competitively inhibiting P-gp, MRP1, BCRP and the metabolizing enzyme CYP3A4. Wang et al. (2004a,b) reported that the oral coadministration of 40 mg/kg quercetin increased the Cmax and the AUC of digoxin (substrate for P-gp) in pigs by 413% and 170%. Another study showed that short-term use of quercetin elevated the plasma concentrations of fexofenadine, probably by the inhibition of P-gp mediated efflux in healthy humans(treated daily for 7 days with 500 mg quercetin and a single dose of 60 mg fexofenadine was administered orally on day 7) (Kim et al. 2009). However, all of the test subjects were healthy. The experimental data about the effect of quercetin in subjects with MDR tumors are still lacking.

Table 1 Overview of literature on the effect of quercetin on cellular accumulation, transport or bioavailability of drugs in different model systems. Model systems In vitro HCT-15 colon cells MCF-7 ADR-resistant cells KB-C2 cells MCF-7/ADR cells KB-V1 cells MCF-7 cells ,MDA-MB 231 cells HeLa cells HK-2 cells, Caco-2/VCR cells Caco-2 cells MCF-7 MX100 cells, NCI-H460 MX20 cells MCF/MR ,K562/BCRP Panc-1 cells Glutathione S-transferase P1-1 (GSTP1-1) transfected MCF7 pMTG5 human breast cancer cells Caco-2 cells In vivo Female Sprague–Dawley rats Rats Rabbits Male Sprague–Dawley rats Male Yorkshire pigs Healthy volunteers

Compounds of which cellular accumulation, sensitivity or bioavailability is increased

Involved transporters

References

Adriamycin Rhodamine 123 Daunomycin Daunomycin, Rodamine123

P-gp P-gp P-gp P-gp

Vinblastine, Paclitaxel Topotecan Cisplatin Rhodamine 123 Cimetidine

P-gp P-gp P-gp P-gp P-gp

Mitoxantrone Mitoxantrone, Bodipy-fl-prazosin Daunomycin, Vinblastine 2,4-dinitrophenyl-S-glutathione (DNP-SG)

BCRP BCRP MRP1 MRP1

Critchfield et al. (1994) Scambia et al. (1994) Kitagawa et al. (2005) Chung et al. (2005), De Vincenzo et al. (2000) Limtrakul et al. (2005) Akbas et al. (2005) Jakubowicz-Gil et al. (2005) Chieli et al. (2009) Taur and RodriguezProteau (2008) Zhang et al. (2004) Cooray et al. (2004) Nguyen et al. (2003) van Zanden et al. (2005)

N-acetyl 5-aminosalicylic acid (5-AcASA)

MRP

Yoshimura et al. (2009)

Tamoxifen Etoposide Diltiazem Paclitaxel Digoxin Fexofenadine

P-gp P-gp P-gp P-gp P-gp P-gp

Shin et al. (2006) Li and Choi (2009) Bansal et al. (2008) Choi et al. (2004) Wang et al. (2004a,b) Kim et al. 2009

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Mechanisms for reversion of MDR Interaction between quercetin and P-gp Quercetin can inhibit its activity or decrease its expression P-gp, a glycoprotein encoded by human MDR1 gene, is one of the best characterized multidrug efflux pump. Earlier studies demonstrated that quercetin interacts with purified P-gp and efficiently inhibits its activity (Shapiro and Ling 1997). In addition, quercetin is capable of decreasing P-gp expression in a dose-dependent manner (Limtrakul et al. 2005). A study by Jing et al. showed that quercetin inhibited the up-regulation of P-gp protein and mRNA in response to hyperthermia (Jing et al. 2008). The effect may be via inhibition of HSF (heat shock factor) DNA-binding activity (Kim et al. 1998) or downregulation of the beta-catenin signalling pathway (Lim et al. 2008). Quercetin can interact with the ATP-binding site or the substrate-binding site It is known that a biologically active ABC transporter protein contains two transmembrane domains (TMDs) and two ABCs or nucleotide binding domains (NBDs) (Lage 2008). TMDs form the substrate-binding sites and/or substrate translocation pathways through the membrane to the efflux substrates, whereas NBDs are located in the interior of the cytoplasm, participating in ATP binding and hydrolysis and acting as the “engines” (Loo and Clarke 2008). Pgp has multiple binding sites and can bind or release substrates in multiple pathways. Inhibition of either TMDs or NBDs may cause the impairment of P-gp function. Quercetin can modulate P-gp by directly interacting with the vicinal ATP-binding site or the substrate-binding site (Conseil et al. 1998). A direct interaction of quercetin with NBDs of the transporter leads to inhibition of ATP-binding and ATPase activity, and consequently efflux of drugs such as daunomycin. It is reported that structurally diverse P-gp substrates (phenazine, doxorubicin, cephalexin, ampicillin, quinidine, chloramphenicol, nicardipine, and penicillin G) exhibit a similar interaction pattern within membrane lipids, and are found predominantly within the membrane interface region (Siarheyeva et al. 2006). Therefore, the substrate-binding sites in P-gp are most likely accessible from within the interface region. Quercetin itself is a P-gp substrate (Wang et al. 2004a,b). It is postulated that quercetin may competitively or noncompetitively interact with other substrates for substrate-binding sites. In some studies, flavonoids, such as flavonols (quercetin), flavanones (naringenin), isoflavones (genistein), and glycosylated flavonol derivatives (rutin), are shown to directly interact with the ATP-binding site and the vicinal steroidbinding site, leading to inhibition of P-gp function (Conseil et al. 1998). Interaction between quercetin and MRP1 Unlike many other ABC transporters, multidrug resistance protein 1 (MRP1) (ABCC1) contains an additional TMD0 structure. This unique membrane spanning domain may give these proteins a specialized function, as demonstrated by the requirement of TMD0 for leukotriene C4 transport on MRP1 (Hipfner et al. 1997). MRP1 acts as a glutathione S-conjugate efflux pump (GS-X pump) (Zaman et al. 1995). Glutathione (GSH) participates in an MRP1mediated efflux. It is thought that GSH induces a conformational change in MRP1 that favours the binding of the substrates (Cole and Deeley 2006). Depletion of GSH impairs the function of MRP1 and leads to MDR reversion. It is found that quercetin could decrease intracellular concentrations of glutathione (Nguyen et al. 2003). Further studies demonstrated that quercetin had the capacity to reduce GSH synthesis, to stimulate MRP1-mediated GSH transport by increasing the affinity of MRP1 for GSH (Leslie et al. 2003), and to down-regulate Akt phosphorylation (Ramos and Aller 2008). Leslie

et al. found that quercetin inhibited the ATPase activity of purified reconstituted MRP1 (Leslie et al. 2001). It is reported that quercetin interacted with MRP1 at the substrate-binding sites and mediated inhibition of MRP1 function (Wu et al. 2005). This assumption is corroborated by results from Leslie et al. who showed that quercetin and other flavonoids were capable of inhibiting the transport of Leukotrine C4 in MRP1-enriched HeLa membrane vesicles in a competitive manner (Leslie et al. 2001). Moreover, the flavonoid decreased MRP expression in neuroblastoma cells and in neurons (Jakubowicz-Gil et al. 2008). So, the potential mechanisms of quercetin to inhibit MRP1mediated efflux include: (1) decreasing intracellular concentrations of glutathione which is necessary for MRP1 effux, (2) acting as substrates thereby causing competitive inhibition towards other substrates, (3) direct or indirect binding with MRP1 at ATP-binding sites, (4) modulating MRP expression, and (5) other mechanisms, e.g. to alter the activity of glutathione S-transferase, to bind with MRP1 at other binding sites, and so on. Additionally, a study reported that the major phase II metabolites of quercetin were equally potent or even better inhibitors of human MRP1 and MRP2 than quercetin itself (van Zanden et al. 2007). The finding indicates that phase II metabolism of quercetin could enhance the potential use of quercetin as an inhibitor to overcome MRP-mediated multidrug resistance. Interaction between quercetin and BCRP BCRP was first cloned in 1998 based on its overexpression in a highly doxorubicin-resistant MCF7 breast cancer cell line (MCF-7) (Doyle et al. 1998). Quercetin can interact directly with BCRP to modulate its transport function, resulting in an increase in intracellular concentration of anti-cancer drugs. It was observed that quercetin was capable of down-regulating the beta-catenin signalling pathway, leading to a decreased expression of BCRP at the blood– brain barrier (Lim et al. 2008). However, Ebert et al. reported that quercetin showed a strong induction of BCRP expression on mRNA level in Caco-2 cells (Ebert et al. 2007). Whether quercetin is a substrate of BCRP remains unclear. The mechanisms by which quercetin interacts with BCRP to modulate MDR need further investigation. Conclusions Transporter-mediated active efflux of cytotoxic agents is one of the best characterized mechanisms by which cancer cells develop MDR. Pgp, MRP1 and BCRP have been shown to confer resistance to a number of anti-cancer agents. However, potent and nontoxic inhibitors remain to be identified for clinical use in MDR reversal. Quercetin being a class of integral flavonoids in our common diet should have the advantage of low toxicity. In fact, in the pharmacokinetic phase I study in cancer patients, quercetin was well tolerated (Ferry et al. 1996). As to its mechanism of action, the data generated so far indicate that quercetin is a multitargeted agent. It can act as a pump inhibitor and has been associated with a variety of anti-cancer mechanisms. Quercetin co-administered with cytotoxic agent may exert anticancer effect through mechanisms other than reversion of MDR. It should be noted that quercetin exhibits a concentrationdependent biphasic action on P-gp, as observed by Mitsunaga et al. (2000) that low concentrations of quercetin indirectly activate P-gp while high concentrations of quercetin inhibit P-gp. It remains undetermined whether quercetin has the capacity to reverse MDR in vivo. Since quercetin presents in a variety of fruits and vegetables, it is plausible to observe the effect in volunteers with a diet rich in quercetin. Further studies are needed to define the appropriate and safe doses at which quercetin can not only inhibit tumor cells but also reverse MDR. The quercetin derivatives such as quercetin pentaethyl

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ether, quercetin pentaallyl ether and quercetin pentamethyl ether are worthy of further evaluation based on the encouraging preliminary results (Ikegawa et al. 2002; Ohtani et al. 2007). Conflict of interest statement The authors declare that there are no conflicts of interest.

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