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Modulators of the human ABCC2: hope from natural sources?

    Elisabeta Baiceanu

    *Author for correspondence:

    E-mail Address: ebaiceanu@ibcp.fr

    Drug Resistance Modulation & Membrane Proteins Laboratory, Molecular & Structural Basis of Infectious Systems, Mixed Research Unit between the National Centre for Scientific Research & Lyon I University n 5086, Institute of Biology & Chemistry of Proteins, 7 passage du Vercors 69367, Lyon, Cedex, France

    Pharmaceutical Botany Department, Faculty of Pharmacy, University of Medicine & Pharmacy ‘Iuliu Haţieganu’ Cluj-Napoca, 23 Marinescu Street, Cluj-Napoca, Romania

    ,
    Gianina Crisan

    Pharmaceutical Botany Department, Faculty of Pharmacy, University of Medicine & Pharmacy ‘Iuliu Haţieganu’ Cluj-Napoca, 23 Marinescu Street, Cluj-Napoca, Romania

    ,
    Felicia Loghin

    Toxicology Department, Faculty of Pharmacy, University of Medicine & Pharmacy ‘Iuliu Haţieganu’ Cluj-Napoca, 5–9 Louis Pasteur Street, Cluj-Napoca, Romania

    &
    Pierre Falson

    **Author for correspondence:

    E-mail Address: pierre.falson@ibcp.fr

    Drug Resistance Modulation & Membrane Proteins Laboratory, Molecular & Structural Basis of Infectious Systems, Mixed Research Unit between the National Centre for Scientific Research & Lyon I University n 5086, Institute of Biology & Chemistry of Proteins, 7 passage du Vercors 69367, Lyon, Cedex, France

    Published Online:https://doi.org/10.4155/fmc.15.131

    Human ABCC2 is an ATP-binding cassette transporter involved in the export of endobiotics and xenobiotics. It is involved in cisplatin resistance in cancer cells, particularly in ovarian cancer. The few known ABCC2 modulators are poorly efficient, so it is necessary to explore new ways to select and optimize efficient compounds ABCC2. Natural products offer an original scaffold for such a strategy and brings hope for this aim. This review covers basic knowledge about ABCC2, from distribution and topology aspects to physiological and pathological functions. It summarizes the effect of natural products as ABCC2 modulators. Certain plant metabolites act on different ABCC2 regulation levels and therefore are promising candidates to block the multidrug resistance mediated by ABCC2 in cancer cells.

    References

    • 1 Efferth T. The human ATP-binding cassette transporter genes: from the bench to the bedside. Curr. Mol. Med. 1, 45–65 (2001).
    • 2 Szakacs G, Hall MD, Gottesman MM et al. Targeting the Achilles heel of multidrug-resistant cancer by exploiting the fitness cost of resistance. Chem. Rev. 114(11), 5753–5774 (2014).
    • 3 Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Annu. Rev. Biochem. 71, 537–592 (2002).
    • 4 Glavinas H, Krajcsi P, Cserepes J, Sarkadi B. The role of ABC transporters in drug resistance, metabolism and toxicity. Curr. Drug Deliv. 1(1), 27–42 (2004).
    • 5 Dean M, Rzhetsky A, Allikmets R. The human ATP-binding cassette (ABC) transporter superfamily. Genome Res. 11(7), 1156–1166 (2001).
    • 6 Cole SP, Bhardwaj G, Gerlach JH et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science 258, 1650–1654 (1992).
    • 7 Szakács G, Paterson JK, Ludwig JA, Booth-Genthe C. Targeting multidrug resistance in cancer. Nat. Rev. Drug Discov. 5(3), 219–234 (2006).
    • 8 Gerk PM, Vore M. Regulation of expression of the multidrug resistance-associated protein 2 (MRP2) and its role in drug disposition. J. Pharmacol. Exp. Ther. 302(2), 407–415 (2002).
    • 9 Jemnitz K, Heredi-Szabo K, Janossy J, Ioja E, Vereczkey L, Krajcsi P. ABCC2/Abcc2: a multispecific transporter with dominant excretory functions. Drug Metab. Rev. 42(3), 402–436 (2010).
    • 10 Chen Z-S, Tiwari AK. Multidrug resistance proteins (MRPs/ABCCs) in cancer chemotherapy and genetic diseases. FEBS J. 278(18), 3226–3245 (2011).
    • 11 Hoffmann U, Kroemer HK. The ABC transporters MDR1 and MRP2: multiple functions in disposition of xenobiotics and drug resistance. Drug Metab. Rev. 36(3–4), 669–701 (2004).
    • 12 Fardel O, Jigorel E, Le Vee M, Payen L. Physiological, pharmacological and clinical features of the multidrug resistance protein 2. Biomed. Pharmacother. 59(3), 104–114 (2005).
    • 13 Deeley RG, Westlake C, Cole SP. Transmembrane transport of endo- and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. Physiol. Rev. 86(3), 849–899 (2006).
    • 14 Nagashige M, Ushigome F, Koyabu N et al. Basal membrane localization of MRP1 in human placental trophoblast. Placenta 24(10), 951–958 (2003).
    • 15 Scheffer GL, Pijnenborg AC, Smit EF et al. Multidrug resistance related molecules in human and murine lung. J. Clin. Pathol. 55(5), 332–339 (2002).
    • 16 Nishimura M, Naito S. Tissue-specific mRNA expression profiles of human ATP-binding cassette and solute carrier transporter superfamilies. Drug Metab. Pharmacokinet. 20(6), 452–477 (2005).
    • 17 Drozdzik M, Groer C, Penski J et al. Protein abundance of clinically relevant multidrug transporters along the entire length of the human intestine. Mol. Pharm. 11(10), 3547–3555 (2014).
    • 18 Wang L, Prasad B, Salphati L et al. Interspecies variability in expression of hepatobiliary transporters across human, dog, monkey, and rat as determined by quantitative proteomics. Drug. Metab. Dispos. 43(3), 367–374 (2015).
    • 19 Uchida Y, Ohtsuki S, Katsukura Y et al. Quantitative targeted absolute proteomics of human blood–brain barrier transporters and receptors. J. Neurochem. 117(2), 333–345 (2011).
    • 20 Nies AT, Keppler D. The apical conjugate efflux pump ABCC2 (MRP2). Pflugers Arch. 453(5), 643–659 (2007).
    • 21 Tarling EJ, Vallim TQDA, Edwards PA. Role of ABC transporters in lipid transport and human disease. Trends Endocrinol. Metab. 24(7), 342–350 (2013).
    • 22 Li J, Jaimes KF, Aller SG. Refined structures of mouse P-glycoprotein. Protein Sci. 23(1), 34–46 (2014).
    • 23 Aller SG, Yu J, Ward A et al. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 323(5922), 1718–1722 (2009).
    • 24 Ward AB, Szewczyk P, Grimard V et al. Structures of P-glycoprotein reveal its conformational flexibility and an epitope on the nucleotide-binding domain. Proc. Natl Acad. Sci. USA 110(33), 13386–13391 (2013).
    • 25 Szewczyk P, Tao H, Mcgrath AP et al. Snapshots of ligand entry, malleable binding and induced helical movement in P-glycoprotein. Acta Crystallogr. D Biol. Crystallogr. 71(Pt 3), 732–741 (2015).
    • 26 Chai S, To KKW, Lin G. Circumvention of multi-drug resistance of cancer cells by Chinese herbal medicines. Chin. Med. 5, 26 (2010).
    • 27 Linton KJ, Higgins CF. Structure and function of ABC transporters: the ATP switch provides flexible control. Pflugers Arch. 453(5), 555–567 (2007).
    • 28 Jin MS, Oldham ML, Zhang Q, Chen J. Crystal structure of the multidrug transporter P-glycoprotein from Caenorhabditis elegans. Nature 490(7421), 566–569 (2012).
    • 29 Kodan A, Yamaguchi T, Nakatsu T et al. Structural basis for gating mechanisms of a eukaryotic P-glycoprotein homolog. Proc. Natl Acad. Sci. USA 111(11), 4049–4054 (2014).
    • 30 Martinez L, Arnaud O, Henin E et al. Understanding polyspecificity within the substrate-binding cavity of the human multidrug resistance P-glycoprotein. FEBS J. 281(3), 673–682 (2014).
    • 31 Zelcer N, Huisman MT, Reid G et al. Evidence for two interacting ligand binding sites in human multidrug resistance protein 2 (ATP binding cassette C2). J. Biol. Chem. 278(26), 23538–23544 (2003).
    • 32 Xing L, Hu Y, Lai Y. Advancement of structure-activity relationship of multidrug resistance-associated protein 2 interactions. AAPS J. 11(3), 406–413 (2009).
    • 33 Borst P, Zelcer N, Van De Wetering K. MRP2 and 3 in health and disease. Cancer Lett. 234(1), 51–61 (2006).
    • 34 Pedersen JM, Matsson P, Bergström CA, Norinder U, Hoogstraate J, Artursson P. Prediction and identification of drug interactions with the human ATP-binding cassette transporter multidrug-resistance associated protein 2 (MRP2; ABCC2). J. Med. Chem. 51(11), 3275–3287 (2008).
    • 35 Myette RL, Conseil G, Ebert SP, Wetzel B, Detty MR, Cole SP. Chalcogenopyrylium dyes as differential modulators of organic anion transport by multidrug resistance protein 1 (MRP1), MRP2, and MRP4. Drug Metab. Dispos. 41(6), 1231–1239 (2013).
    • 36 Leslie EM, Deeley RG, Cole SP. Multidrug resistance proteins: role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol. Appl. Pharmacol. 204(3), 216–237 (2005).
    • 37 Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: an overview. Adv. Drug Deliv. Rev. 55(1), 3–29 (2003).
    • 38 Itoh Y, Tamai M, Yokogawa K et al. Involvement of multidrug resistance-associated protein 2 in in vivo cisplatin resistance of rat hepatoma AH66 cells. Anticancer Res. 22(3), 1649–1653 (2002).
    • 39 Zhou SF, Wang LL, Di YM et al. Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development. Curr. Med. Chem. 15(20), 1981–2039 (2008).
    • 40 Lagas JS, Van Der Kruijssen CM, Van De Wetering K, Beijnen JH, Schinkel AH. Transport of diclofenac by breast cancer resistance protein (ABCG2) and stimulation of multidrug resistance protein 2 (ABCC2)-mediated drug transport by diclofenac and benzbromarone. Drug Metab. Dispos. 37(1), 129–136 (2009).
    • 41 Nozaki Y, Kusuhara H, Kondo T et al. Species difference in the inhibitory effect of nonsteroidal anti-inflammatory drugs on the uptake of methotrexate by human kidney slices. J. Pharmacol. Exp. Ther. 322(3), 1162–1170 (2007).
    • 42 Nozaki Y, Kusuhara H, Kondo T et al. Species difference in the inhibitory effect of nonsteroidal anti-inflammatory drugs on the uptake of methotrexate by human kidney slices. J. Pharmacol. Exp. Ther. 322(3), 1162–1170 (2007).
    • 43 Kusuhara H, Sugiyama Y. Role of transporters in the tissue-selective distribution and elimination of drugs: transporters in the liver, small intestine, brain and kidney. J. Control. Release 78(1–3), 43–54 (2002).
    • 44 Holohan C, Van Schaeybroeck S, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer 13(10), 714–726 (2013).
    • 45 Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat. Rev. Cancer 2(1), 48–58 (2002).
    • 46 Kapoor K, Sim H, Ambudkar S. Multidrug resistance in cancer: a tale of ABC drug transporters. In: Molecular Mechanisms of Tumor Cell Resistance to Chemotherapy. Bonavida B (Eds). Springer, NY, USA, 1–34 (2013).
    • 47 Eckstein N. Platinum resistance in breast and ovarian cancer cell lines. J. Exp. Clin. Cancer Res. 30, 91 (2011).
    • 48 Gillet JP, Gottesman MM. Mechanisms of multidrug resistance in cancer. Methods Mol. Biol. 596 47–76 (2010).
    • 49 Shukla S, Ohnuma S, Ambudkar SV. Improving cancer chemotherapy with modulators of ABC drug transporters. Curr. Drug Targets 12(5), 621–630 (2011).
    • 50 Tiwari AK, Sodani K, Dai CL, Ashby CR Jr, Chen ZS. Revisiting the ABCs of multidrug resistance in cancer chemotherapy. Curr. Pharm. Biotechnol. 12(4), 570–594 (2011).
    • 51 Huisman MT, Chhatta AA, Van Tellingen O, Beijnen JH, Schinkel AH. MRP2 (ABCC2) transports taxanes and confers paclitaxel resistance and both processes are stimulated by probenecid. Int. J. Cancer 116(5), 824–829 (2005).
    • 52 Van Waterschoot RA, Lagas JS, Wagenaar E, Rosing H, Beijnen JH, Schinkel AH. Individual and combined roles of CYP3A, P-glycoprotein (MDR1/ABCB1) and MRP2 (ABCC2) in the pharmacokinetics of docetaxel. Int. J. Cancer 127(12), 2959–2964 (2010).
    • 53 Vlaming ML, Van Esch A, Van De Steeg E et al. Impact of abcc2 [multidrug resistance-associated protein (MRP) 2], abcc3 (MRP3), and abcg2 (breast cancer resistance protein) on the oral pharmacokinetics of methotrexate and its main metabolite 7-hydroxymethotrexate. Drug Metab. Dispos. 39(8), 1338–1344 (2011).
    • 54 Guminski AD, Balleine RL, Chiew YE et al. MRP2 (ABCC2) and cisplatin sensitivity in hepatocytes and human ovarian carcinoma. Gynecol. Oncol. 100(2), 239–246 (2006).
    • 55 Korita PV, Wakai T, Shirai Y et al. Multidrug resistance-associated protein 2 determines the efficacy of cisplatin in patients with hepatocellular carcinoma. Oncol. Rep. 23(4), 965–972 (2010).
    • 56 Yamasaki M, Makino T, Masuzawa T et al. Role of multidrug resistance protein 2 (MRP2) in chemoresistance and clinical outcome in oesophageal squamous cell carcinoma. Br. J. Cancer 104(4), 707–713 (2011).
    • 57 Ma JJ, Chen BL, Xin XY. Inhibition of multi-drug resistance of ovarian carcinoma by small interfering RNA targeting to MRP2 gene. Arch. Gynecol. Obstet. 279(2), 149–157 (2009).
    • 58 Rigalli JP, Ciriaci N, Arias A et al. Regulation of multidrug resistance proteins by genistein in a hepatocarcinoma cell line: impact on sorafenib cytotoxicity. PLoS ONE 10(3), e0119502 (2015).
    • 59 Vlaming ML, Mohrmann K, Wagenaar E et al. Carcinogen and anticancer drug transport by Mrp2 in vivo: studies using Mrp2 (Abcc2) knockout mice. J. Pharmacol. Exp. Ther. 318(1), 319–327 (2006).
    • 60 Van Der Schoor LW, Verkade HJ, Kuipers F, Jonker JW. New insights in the biology of ABC transporters ABCC2 and ABCC3: impact on drug disposition. Expert Opin. Drug Metab. Toxicol. 11(2), 273–293 (2014).
    • 61 Wu CP, Hsieh CH, Wu YS. The emergence of drug transporter-mediated multidrug resistance to cancer chemotherapy. Mol. Pharm. 8(6), 1996–2011 (2011).
    • 62 Sharom FJ. ABC multidrug transporters: structure, function and role in chemoresistance. Pharmacogenomics 9(1), 105–127 (2008).
    • 63 Tang F, Horie K, Borchardt RT. Are MDCK cells transfected with the human MRP2 gene a good model of the human intestinal mucosa? Pharm. Res. 19(6), 773–779 (2002).
    • 64 Matsson P, Pedersen JM, Norinder U, Bergström CA, Artursson P. Identification of novel specific and general inhibitors of the three major human ATP-binding cassette transporters P-gp, BCRP and MRP2 among registered drugs. Pharm. Res. 26(8), 1816–1831 (2009).
    • 65 Mease K, Sane R, Podila L, Taub ME. Differential selectivity of efflux transporter inhibitors in Caco-2 and MDCK-MDR1 monolayers: a strategy to assess the interaction of a new chemical entity with P-gp, BCRP, and MRP2. J. Pharm. Sci. 101(5), 1888–1897 (2012).
    • 66 Shu-Feng Z, Lin-Lin W, Yuan Ming D et al. Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development. Curr. Med. Chem. 15(20), 1981–2039 (2008).
    • 67 Gibbs JP, Adeyeye MC, Yang Z, Shen DD. Valproic acid uptake by bovine brain microvessel endothelial cells: role of active efflux transport. Epilepsy Res. 58(1), 53–66 (2004).
    • 68 Wortelboer HM, Usta M, Van Der Velde AE et al. Interplay between MRP inhibition and metabolism of MRP inhibitors: the case of curcumin. Chem. Res. Toxicol. 16(12), 1642–1651 (2003).
    • 69 Weiss J, Theile D, Ketabi-Kiyanvash N, Lindenmaier H, Haefeli WE. Inhibition of MRP1/ABCC1, MRP2/ABCC2, and MRP3/ABCC3 by nucleoside, nucleotide, and non-nucleoside reverse transcriptase inhibitors. Drug Metab. Dispos. 35(3), 340–344 (2007).
    • 70 Vadlapatla RK, Vadlapudi AD, Kwatra D, Pal D, Mitra AK. Differential effect of P-gp and MRP2 on cellular translocation of gemifloxacin. Int. J. Pharm. 420(1), 26–33 (2011).
    • 71 SuperNatural II. http://bioinf-applied.charite.de/supernatural_new/index.php
    • 72 Universal Natural Product Database. http://bioinf-applied.charite.de/supernatural_new/index.php
    • 73 Universal Natural Product Database. www.chemtcm.com
    • 74 Drug Discovery Portal. www.ddp.strath.ac.uk
    • 75 iSmart. http://ismart.cmu.edu.tw
    • 76 NuBBE Database. http://nubbe.iq.unesp.br/portal/nubbedb.html
    • 77 Drug Bank. www.drugbank.ca
    • 78 Natural Compound Library. www.timtec.net/natural-compound-library.html
    • 79 Screen-Well Natural Product library, Enzo. www.enzolifesciences.com/BML-2865/screen-well-natural-product-library
    • 80 Drug Compound Libraries, Albany Molecular Research. www.amriglobal.com/products_and_services/Small_Molecule_Drug_Compound_Libraries_1_4_service2.htm
    • 81 MEGx: Natural Product Screening Products,AnalytiCon discovery. www.ac-discovery.com/content/Products& Technologies/MEGAbolite.php
    • 82 Natural product-like library. www.otavachemicals.com/products/compound-libraries-for-hts/natural-product-like-library
    • 83 Greenpharma Natural Compound Library. www.greenpharma.com/products/greenpharma-natural-compound-library
    • 84 The Natural Products Library Initiative (NRPLI) atThe Scripps Research Institute (TSRI). www.scripps.edu/shen/NPLI/npliattsri.html
    • 85 ChemBridge. www.chembridge.com/index.php
    • 86 ChemDiv Libraries. www.chemdiv.com/products/screening-libraries
    • 87 Enamine Collections. www.enamine.net
    • 88 Life Chemicals Library. www.lifechemicals.com
    • 89 The Specs Library. www.specs.net/snpage.php?snpageid=home
    • 90 Wu CP, Ohnuma S, Ambudkar SV. Discovering natural product modulators to overcome multidrug resistance in cancer chemotherapy. Curr. Pharm. Biotechnol. 12(4), 609–620 (2011).
    • 91 Shukla S, Wu CP, Ambudkar SV. Development of inhibitors of ATP-binding cassette drug transporters: present status and challenges. Expert. Opin. Drug Metab. Toxicol. 4(2), 205–223 (2008).
    • 92 Lai Y, Xing L, Poda GI, Hu Y. Structure–activity relationships for interaction with multidrug resistance protein 2 (ABCC2/MRP2): the role of torsion angle for a series of biphenyl-substituted heterocycles. Drug Metab. Dispos. 35(6), 937–945 (2007).
    • 93 Lo YL, Wang W, Ho CT. 7,3′,4′-trihydroxyisoflavone modulates multidrug resistance transporters and induces apoptosis via production of reactive oxygen species. Toxicology 302(2–3), 221–232 (2012).
    • 94 Watanabe M, Matsumoto N, Takeba Y et al. Orange juice and its component, hesperidin, decrease the expression of multidrug resistance-associated protein 2 in rat small intestine and liver. J. Biomed. Biotechnol. 2011, 502057 (2011).
    • 95 Wang H, Zhai Z, Li N et al. Steroidal saponin of Trillium tschonoskii. Reverses multidrug resistance of hepatocellular carcinoma. Phytomedicine 20(11), 985–991 (2013).
    • 96 Udomsuk L, Juengwatanatrakul T, Putalun W, Jarukamjorn K. Suppression of BSEP and MRP2 in mouse liver by miroestrol and deoxymiroestrol isolated from Pueraria candollei. Phytomedicine 19(14), 1332–1335 (2012).
    • 97 Sergent T, Garsou S, Schaut A et al. Differential modulation of ochratoxin A absorption across Caco-2 cells by dietary polyphenols, used at realistic intestinal concentrations. Toxicol. Lett. 159(1), 60–70 (2005).
    • 98 Siewert E, Dietrich CG, Lammert F et al. Interleukin-6 regulates hepatic transporters during acute-phase response. Biochem. Biophys. Res. Commun. 322(1), 232–238 (2004).
    • 99 Ducheix S, Montagner A, Polizzi A et al. Essential fatty acids deficiency promotes lipogenic gene expression and hepatic steatosis through the liver X receptor. J. Hepatol. 58(5), 984–992 (2013).
    • 100 Kong B, Csanaky IL, Aleksunes LM et al. Gender-specific reduction of hepatic Mrp2 expression by high-fat diet protects female mice from ANIT toxicity. Toxicol. Appl. Pharmacol. 261(2), 189–195 (2012).
    • 101 Nishimura M, Yamaguchi M, Yamauchi A, Ueda N, Naito S. Role of soybean oil fat emulsion in the prevention of hepatic xenobiotic transporter mRNA up- and down-regulation induced by overdose of fat-free total parenteral nutrition in infant rats. Drug Metab. Pharmacokinet. 20(1), 46–54 (2005).
    • 102 Maher JM, Cheng X, Slitt AL, Dieter MZ, Klaassen CD. Induction of the multidrug resistance-associated protein family of transporters by chemical activators of receptor-mediated pathways in mouse liver. Drug Metab. Dispos. 33(7), 956–962 (2005).
    • 103 Arias A, Rigalli JP, Villanueva SS et al. Regulation of expression and activity of multidrug resistance proteins MRP2 and MDR1 by estrogenic compounds in Caco-2 cells. Role in prevention of xenobiotic-induced cytotoxicity. Toxicology 320 46–55 (2014).
    • 104 Prouillac C, Videmann B, Mazallon M, Lecoeur S. Induction of cells differentiation and ABC transporters expression by a myco-estrogen, zearalenone, in human choriocarcinoma cell line (BeWo). Toxicology 263(2–3), 100–107 (2009).
    • 105 Kamisako T, Ogawa H. Alteration of the expression of adenosine triphosphate-binding cassette transporters associated with bile acid and cholesterol transport in the rat liver and intestine during cholestasis. J. Gastroenterol. Hepatol. 20(9), 1429–1434 (2005).
    • 106 Hoffmann K, Gastens AM, Volk HA, Loscher W. Expression of the multidrug transporter MRP2 in the blood–brain barrier after pilocarpine-induced seizures in rats. Epilepsy Res. 69(1), 1–14 (2006).
    • 107 Zhu QN, Zhang D, Jin T, Wu Q, Liu J, Lu YF. Rutaecarpine effects on expression of hepatic phase-1, phase-2 metabolism and transporter genes as a basis of herb–drug interactions. J. Ethnopharmacol. 147(1), 215–219 (2013).
    • 108 Zhou X, Bi H, Jin J et al. Effects of praeruptorin A and praeruptorin C, a racemate isolated from Peucedanum praeruptorum, on MRP2 through the CAR pathway. Planta Med. 79(17), 1641–1647 (2013).
    • 109 Kim J-H, Chen C, Tony Kong A-N. Resveratrol inhibits genistein-induced multi-drug resistance protein 2 (MRP2) expression in HepG2 cells. Arch. Biochem. Biophys. 512(2), 160–166 (2011).
    • 110 Juan ME, Gonzalez-Pons E, Planas JM. Multidrug resistance proteins restrain the intestinal absorption of trans-resveratrol in rats. J. Nutr. 140(3), 489–495 (2010).
    • 111 Jakubikova J. Role of PI3K/Akt and MEK/ERK signaling pathways in sulforaphane- and erucin-induced Phase II enzymes and MRP2 transcription, G2/M arrest and cell death in Caco-2 cells. 69(11), 1543–1552 (2005).
    • 112 Takabatake M, Shibutani M, Dewa Y et al. Concurrent administration of ascorbic acid enhances liver tumor-promoting activity of kojic acid in rats. J. Toxicol. Sci. 33(2), 127–140 (2008).
    • 113 Veeriah S, Miene C, Habermann N et al. Apple polyphenols modulate expression of selected genes related to toxicological defence and stress response in human colon adenoma cells. Int. J. Cancer 122(12), 2647–2655 (2008).
    • 114 Mu Y, Zhang J, Zhang S et al. Traditional Chinese medicines Wu Wei Zi (Schisandra chinensis Bail) and Gan Cao (Glycyrrhiza uralensis Fisch) activate pregnane X receptor and increase warfarin clearance in rats. J. Pharmacol. Exp. Ther. 316(3), 1369–1377 (2006).
    • 115 Li L, Stanton JD, Tolson AH, Luo Y, Wang H. Bioactive terpenoids and flavonoids from Ginkgo biloba extract induce the expression of hepatic drug-metabolizing enzymes through pregnane X receptor, constitutive androstane receptor, and aryl hydrocarbon receptor-mediated pathways. Pharm. Res. 26(4), 872–882 (2009).
    • 116 Van Zanden JJ, Van Der Woude H, Vaessen J et al. The effect of quercetin Phase II metabolism on its MRP1 and MRP2 inhibiting potential. Biochem. Pharmacol. 74(2), 345–351 (2007).
    • 117 Yokooji T, Kawabe Y, Mori N, Murakami T. Effect of genistein, a natural soy isoflavone, on the pharmacokinetics and intestinal toxicity of irinotecan hydrochloride in rats. J. Pharm. Pharmacol. 65(2), 280–291 (2013).
    • 118 Van Zanden JJ, De Mul A, Wortelboer HM et al. Reversal of in vitro cellular MRP1 and MRP2 mediated vincristine resistance by the flavonoid myricetin. Biochem. Pharmacol. 69(11), 1657–1665 (2005).
    • 119 Wortelboer HM, Usta M, Van Zanden JJ, Van Bladeren PJ, Rietjens IM, Cnubben NH. Inhibition of multidrug resistance proteins MRP1 and MRP2 by a series of alpha,beta-unsaturated carbonyl compounds. Biochem. Pharmacol. 69(12), 1879–1890 (2005).
    • 120 Domitrovic R, Cvijanovic O, Pugel EP, Zagorac GB, Mahmutefendic H, Skoda M. Luteolin ameliorates cisplatin-induced nephrotoxicity in mice through inhibition of platinum accumulation, inflammation and apoptosis in the kidney. Toxicology 310 115–123 (2013).
    • 121 Akao T, Sakashita Y, Hanada M, Goto H, Shimada Y, Terasawa K. Enteric excretion of baicalein, a flavone of Scutellariae Radix, via glucuronidation in rat: involvement of multidrug resistance-associated protein 2. Pharm. Res. 21(11), 2120–2126 (2004).
    • 122 Liu L, Guo L, Zhao C, Wu X, Wang R, Liu C. Characterization of the intestinal absorption of seven flavonoids from the flowers of Trollius chinensis using the Caco-2 cell monolayer model. PLoS ONE 10(3), e0119263 (2015).
    • 123 Netsch MI, Gutmann H, Luescher S et al. Inhibitory activity of a green tea extract and some of its constituents on multidrug resistance-associated protein 2 functionality. Planta Med. 71(2), 135–141 (2005).
    • 124 Ye L, Yang X, Yang Z et al. The role of efflux transporters on the transport of highly toxic aconitine, mesaconitine, hypaconitine, and their hydrolysates, as determined in cultured Caco-2 and transfected MDCKII cells. Toxicol. Lett. 216(2–3), 86–99 (2013).
    • 125 Dai P, Zhua L, Yang X et al. Multidrug resistance-associated protein 2 is involved in the efflux of aconitum alkaloids determined by MRP2-MDCKII cells. Life Sci 127, 66–72 (2015).
    • 126 Henry C, Vitrac X, Decendit A, Ennamany R, Krisa S, Merillon JM. Cellular uptake and efflux of trans-piceid and its aglycone trans-resveratrol on the apical membrane of human intestinal Caco-2 cells. J. Agric. Food Chem. 53(3), 798–803 (2005).
    • 127 Ohashi M, Sano N, Takikawa H. Effects of phalloidin on the biliary excretion of cholephilic compounds in rats. Pharmacology 66(1), 31–35 (2002).
    • 128 Yoshida N, Takada T, Yamamura Y, Adachi I, Suzuki H, Kawakami J. Inhibitory effects of terpenoids on multidrug resistance-associated protein 2- and breast cancer resistance protein-mediated transport. Drug Metab. Dispos. 36(7), 1206–1211 (2008).
    • 129 Makino T, Ohtake N, Watanabe A et al. Down-regulation of a hepatic transporter multidrug resistance-associated protein 2 is involved in alteration of pharmacokinetics of glycyrrhizin and its metabolites in a rat model of chronic liver injury. Drug Metab. Dispos. 36(7), 1438–1443 (2008).
    • 130 Wissel G, Kudryavtsev P, Ghemtio L et al. Exploring the structure–activity relationships of ABCC2 modulators using a screening approach. Biorg. Med. Chem. 23(13), 3513–3525 (2015).
    • 131 Sheng J, Tian X, Xu G et al. The hepatobiliary disposition of timosaponin b2 is highly dependent on influx/efflux transporters but not metabolism. Drug Metab. Dispos. 43(1), 63–72 (2015).
    • 132 Patanasethanont D, Nagai J, Matsuura C et al. Modulation of function of multidrug resistance associated-proteins by Kaempferia parviflora extracts and their components. Eur. J. Pharmacol. 566(1–3), 67–74 (2007).
    • 133 Yokooji T, Kida M, Mori M et al. Interaction of Rhei Rhizoma extract with cytochrome P450 3A and efflux transporters in rats. Pharmazie 65(5), 367–374 (2010).
    • 134 Bonavida B. Molecular Mechanisms of Tumor Cell Resistance to Chemotherapy : Targeted Therapies to Reverse Resistance. Springer, New York, USA (2013).
    • 135 Rangel LP, Winter E, Gauthier C et al. New structure-activity relationships of chalcone inhibitors of breast cancer resistance protein: polyspecificity toward inhibition and critical substitutions against cytotoxicity. Drug Des. Devel. Ther. 7 1043–1052 (2013).
    • 136 Valdameri G, Pereira Rangel L, Spatafora C et al. Methoxy stilbenes as potent, specific, untransported, and noncytotoxic inhibitors of breast cancer resistance protein. ACS Chem. Biol. 7(2), 322–330 (2012).
    • 137 Boumendjel A, Macalou S, Valdameri G et al. Targeting the multidrug ABCG2 transporter with flavonoidic inhibitors: in vitro optimization and in vivo validation. Curr. Med. Chem. 18(22), 3387–3401 (2011).
    • 138 Honorat M, Guitton J, Gauthier C et al. MBL-II-141, a chromone derivative, enhances irinotecan (CPT-11) anticancer efficiency in ABCG2-positive xenografts. Oncotarget 5(23), 11957–11970 (2014).
    • 139 Harvey AL, Edrada-Ebel R, Quinn RJ. The re-emergence of natural products for drug discovery in the genomics era. Nat. Rev. Drug Discov. 14 111–129 (2015).
    • 140 Shoichet BK. Virtual screening of chemical libraries. Nature 432(7019), 862–865 (2004).
    • 141 Lagarde N, Zagury JF, Montes M. Benchmarking data sets for the evaluation of virtual ligand screening methods: review and perspectives. J. Chem. Inf. Model. 55(7), 1297–307 (2015).
    • 142 Jedlitschky G, Hoffmann U, Kroemer HK. Structure and function of the MRP2 (ABCC2) protein and its role in drug disposition. Expert Opin. Drug Metab. Toxicol. 2(3), 351–366 (2006).
    • 143 Marquez B, Van Bambeke F. ABC multidrug transporters: target for modulation of drug pharmacokinetics and drug-drug interactions. Curr. Drug Targets 12(5), 600–620 (2011).
    • 144 Brouwer KL, Keppler D, Hoffmaster KA et al. In vitro methods to support transporter evaluation in drug discovery and development. Clin. Pharmacol. Ther. 94(1), 95–112 (2013).
    • 145 Wink M, Ashour ML, El-Readi MZ. Secondary metabolites from plants inhibiting ABC transporters and reversing resistance of cancer cells and microbes to cytotoxic and antimicrobial agents. Front. Microbiol. 3, 130 (2012).
    • 146 Van Zanden JJ, Wortelboer HM, Bijlsma S et al. Quantitative structure activity relationship studies on the flavonoid mediated inhibition of multidrug resistance proteins 1 and 2. Biochem. Pharmacol. 69(4), 699–708 (2005).
    • 147 Walgren RA, Karnaky KJ, Lindenmayer GE, Walle T. Efflux of dietary flavonoid quercetin 4′-beta-glucoside across human intestinal Caco-2 cell monolayers by apical multidrug resistance-associated protein-2. J. Pharmacol. Exp. Ther. 294(3), 830–836 (2000).
    • 148 Choudhuri S, Klaassen CD. Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters. Int. J. Toxicol. 25(4), 231–259 (2006).
    • 149 Walle T, Walle UK. The beta-D-glucoside and sodium-dependent glucose transporter 1 (SGLT1)-inhibitor phloridzin is transported by both SGLT1 and multidrug resistance-associated proteins 1/2. Drug Metab. Dispos. 31(11), 1288–1291 (2003).
    • 150 Kool M, De Haas M, Scheffer GL et al. Analysis of expression of cMOAT (MRP2), MRP3, MRP4, and MRP5, homologues of the multidrug resistance-associated protein gene (MRP1), in human cancer cell lines. Cancer Res. 57(16), 3537–3547 (1997).
    • 151 Sprowl JA, Gregorc V, Lazzari C, Mathijssen RH, Loos WJ, Sparreboom A. Associations between ABCC2 polymorphisms and cisplatin disposition and efficacy. Clin. Pharmacol. Ther. 91(6), 1022–1026 (2012).
    • 152 Chang Q, Ornatsky OI, Koch CJ et al. Single-cell measurement of the uptake, intratumoral distribution and cell cycle effects of cisplatin using mass cytometry. Int. J. Cancer 136(5), 1202–1209 (2015).
    • 153 Newman DJ, Cragg GM. Natural products as sources of new drugs over the 30 years from 1981 to 2010. J. Nat. Prod. 75(3), 311–335 (2012).