Flavonoids as P-gp Inhibitors: A Systematic Review of SARs

Author(s): Jiahua Cui*, Xiaoyang Liu, Larry M.C. Chow.

Journal Name: Current Medicinal Chemistry

Volume 26 , Issue 25 , 2019

Abstract:

P-glycoprotein, also known as ABCB1 in the ABC transporter family, confers the simultaneous resistance of metastatic cancer cells towards various anticancer drugs with different targets and diverse chemical structures. The exploration of safe and specific inhibitors of this pump has always been the pursuit of scientists for the past four decades. Naturally occurring flavonoids as benzopyrone derivatives were recognized as a class of nontoxic inhibitors of P-gp. The recent advent of synthetic flavonoid dimer FD18, as a potent P-gp modulator in reversing multidrug resistance both in vitro and in vivo, specifically targeted the pseudodimeric structure of the drug transporter and represented a new generation of inhibitors with high transporter binding affinity and low toxicity. This review concerned the recent updates on the structure-activity relationships of flavonoids as P-gp inhibitors, the molecular mechanisms of their action and their ability to overcome P-gp-mediated MDR in preclinical studies. It had crucial implications on the discovery of new drug candidates that modulated the efflux of ABC transporters and also provided some clues for the future development in this promising area.

Keywords: P-glycoprotein, multidrug resistance, flavonoids, inhibitors, SARs, anticancer.

[1]
Xin, L.; Cao, J.; Cheng, H.; Zeng, F.; Hu, X.; Shao, J. Human monoclonal antibodies in cancer therapy: a review of recent developments. Front. Biosci., 2013, 18, 765-772.
[http://dx.doi.org/10.2741/4139] [PMID: 23276961]
[2]
Scott, A.M.; Allison, J.P.; Wolchok, J.D. Monoclonal antibodies in cancer therapy. Cancer Immun., 2012, 12, 14.
[PMID: 22896759]
[3]
Garber, K. China approves world’s first oncolytic virus therapy for cancer treatment. J. Natl. Cancer Inst., 2006, 98(5), 298-300.
[http://dx.doi.org/10.1093/jnci/djj111] [PMID: 16507823]
[4]
Felt, S.A.; Grdzelishvili, V.Z. Recent advances in vesicular stomatitis virus-based oncolytic virotherapy: a 5-year update. J. Gen. Virol., 2017. 10.1099/jgv.0.000980
[http://dx.doi.org/10.1099/jgv.0.000980] [PMID: 29143726]
[5]
Rowan, K. Oncolytic viruses move forward in clinical trials. J. Natl. Cancer Inst., 2010, 102(9), 590-595.
[http://dx.doi.org/10.1093/jnci/djq165] [PMID: 20421567]
[6]
Davila, M.L.; Riviere, I.; Wang, X.; Bartido, S.; Park, J.; Curran, K.; Chung, S.S.; Stefanski, J.; Borquez-Ojeda, O.; Olszewska, M.; Qu, J.; Wasielewska, T.; He, Q.; Fink, M.; Shinglot, H.; Youssif, M.; Satter, M.; Wang, Y.; Hosey, J.; Quintanilla, H.; Halton, E.; Bernal, Y.; Bouhassira, D.C.; Arcila, M.E.; Gonen, M.; Roboz, G.J.; Maslak, P.; Douer, D.; Frattini, M.G.; Giralt, S.; Sadelain, M.; Brentjens, R. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl. Med., 2014, 6(224)224ra25
[http://dx.doi.org/10.1126/scitranslmed.3008226] [PMID: 24553386]
[7]
Fournier, C.; Martin, F.; Zitvogel, L.; Kroemer, G.; Galluzzi, L.; Apetoh, L. Trial Watch: adoptively transferred cells for anticancer immunotherapy. OncoImmunology, 2017, 6(11)e1363139
[http://dx.doi.org/10.1080/2162402X.2017.1363139] [PMID: 29147628]
[8]
Pluchino, K.M.; Hall, M.D.; Goldsborough, A.S.; Callaghan, R.; Gottesman, M.M. Collateral sensitivity as a strategy against cancer multidrug resistance. Drug Resist. Updat., 2012, 15(1-2), 98-105.
[http://dx.doi.org/10.1016/j.drup.2012.03.002] [PMID: 22483810]
[9]
Goldstein, D.A.; Zeichner, S.B.; Bartnik, C.M.; Neustadter, E.; Flowers, C.R. Metastatic colorectal cancer: a systematic review of the value of current therapies. Clin. Colorectal Cancer, 2016, 15(1), 1-6.
[http://dx.doi.org/10.1016/j.clcc.2015.10.002] [PMID: 26541320]
[10]
Gottesman, M.M.; Fojo, T.; Bates, S.E. Multidrug resistance in cancer: role of ATP-dependent transporters. Nat. Rev. Cancer, 2002, 2(1), 48-58.
[http://dx.doi.org/10.1038/nrc706] [PMID: 11902585]
[11]
Begicevic, R.R.; Falasca, M. ABC Transporters in cancer stem cells: beyond chemoresistance. Int. J. Mol. Sci., 2017, 18(11), 2362.
[http://dx.doi.org/10.3390/ijms18112362] [PMID: 29117122]
[12]
Li, W.; Zhang, H.; Assaraf, Y.G.; Zhao, K.; Xu, X.; Xie, J.; Yang, D.H.; Chen, Z.S. Overcoming ABC transporter-mediated multidrug resistance: molecular mechanisms and novel therapeutic drug strategies. Drug Resist. Updat., 2016, 27, 14-29.
[http://dx.doi.org/10.1016/j.drup.2016.05.001] [PMID: 27449595]
[13]
Szakács, G.; Paterson, J.K.; Ludwig, J.A.; Booth-Genthe, C.; Gottesman, M.M. Targeting multidrug resistance in cancer. Nat. Rev. Drug Discov., 2006, 5(3), 219-234.
[http://dx.doi.org/10.1038/nrd1984] [PMID: 16518375]
[14]
Giacomini, K.M.; Huang, S-M.; Tweedie, D.J.; Benet, L.Z.; Brouwer, K.L.; Chu, X.; Dahlin, A.; Evers, R.; Fischer, V.; Hillgren, K.M.; Hoffmaster, K.A.; Ishikawa, T.; Keppler, D.; Kim, R.B.; Lee, C.A.; Niemi, M.; Polli, J.W.; Sugiyama, Y.; Swaan, P.W.; Ware, J.A.; Wright, S.H.; Yee, S.W.; Zamek-Gliszczynski, M.J.; Zhang, L. Membrane transporters in drug development. Nat. Rev. Drug Discov., 2010, 9(3), 215-236.
[http://dx.doi.org/10.1038/nrd3028] [PMID: 20190787]
[15]
Pérez-Tomás, R. Multidrug resistance: retrospect and prospects in anti-cancer drug treatment. Curr. Med. Chem., 2006, 13(16), 1859-1876.
[http://dx.doi.org/10.2174/092986706777585077] [PMID: 16842198]
[16]
Leonard, G.D.; Fojo, T.; Bates, S.E. The role of ABC trans-porters in clinical practice. Oncologist, 2003, 8(5), 411-424.
[http://dx.doi.org/10.1634/theoncologist.8-5-411] [PMID: 14530494]
[17]
Juliano, R.L.; Ling, V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta, 1976, 455(1), 152-162.
[http://dx.doi.org/10.1016/0005-2736(76)90160-7] [PMID: 990323]
[18]
Dawson, R.J.; Locher, K.P. Structure of a bacterial multidrug ABC transporter. Nature, 2006, 443(7108), 180-185.
[http://dx.doi.org/10.1038/nature05155] [PMID: 16943773]
[19]
Dawson, R.J.; Locher, K.P. Structure of the multidrug ABC transporter Sav1866 from Staphylococcus aureus in complex with AMP-PNP. FEBS Lett., 2007, 581(5), 935-938.
[http://dx.doi.org/10.1016/j.febslet.2007.01.073] [PMID: 17303126]
[20]
Aller, S.G.; Yu, J.; Ward, A.; Weng, Y.; Chittaboina, S.; Zhuo, R.; Harrell, P.M.; Trinh, Y.T.; Zhang, Q.; Urbatsch, I.L.; Chang, G. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science, 2009, 323(5922), 1718-1722.
[http://dx.doi.org/10.1126/science.1168750] [PMID: 19325113]
[21]
Hohl, M.; Briand, C.; Grütter, M.G.; Seeger, M.A. Crystal structure of a heterodimeric ABC transporter in its inward-facing conformation. Nat. Struct. Mol. Biol., 2012, 19(4), 395-402.
[http://dx.doi.org/10.1038/nsmb.2267] [PMID: 22447242]
[22]
Choudhury, H.G.; Tong, Z.; Mathavan, I.; Li, Y.; Iwata, S.; Zirah, S.; Rebuffat, S.; van Veen, H.W.; Beis, K. Structure of an antibacterial peptide ATP-binding cassette transporter in a novel outward occluded state. Proc. Natl. Acad. Sci. USA, 2014, 111(25), 9145-9150.
[http://dx.doi.org/10.1073/pnas.1320506111] [PMID: 24920594]
[23]
Cascorbi, I. P-glycoprotein: Tissue Distribution, Substrates, and Functional Consequences of Genetic Variations. In: Drug Transporters; Fromm, M.F.; Kim, R.B., Eds.; Springer Berlin Heidelberg: Berlin, Heidelberg, 2011; pp. 261-283.
[http://dx.doi.org/10.1007/978-3-642-14541-4_6]
[24]
Yu, M.; Ocana, A.; Tannock, I.F. Reversal of ATP-binding cassette drug transporter activity to modulate chemoresistance: why has it failed to provide clinical benefit? Cancer Metastasis Rev., 2013, 32(1-2), 211-227.
[http://dx.doi.org/10.1007/s10555-012-9402-8] [PMID: 23093326]
[25]
Thomas, H.; Coley, H.M. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Contr., 2003, 10(2), 159-165.
[http://dx.doi.org/10.1177/107327480301000207] [PMID: 12712010]
[26]
Hrycyna, C.A.; Airan, L.E.; Germann, U.A.; Ambudkar, S.V.; Pastan, I.; Gottesman, M.M. Structural flexibility of the linker region of human P-glycoprotein permits ATP hydrolysis and drug transport. Biochemistry, 1998, 37(39), 13660-13673.
[http://dx.doi.org/10.1021/bi9808823] [PMID: 9753453]
[27]
Esser, L.; Zhou, F.; Pluchino, K.M.; Shiloach, J.; Ma, J.; Tang, W.K.; Gutierrez, C.; Zhang, A.; Shukla, S.; Madigan, J.P.; Zhou, T.; Kwong, P.D.; Ambudkar, S.V.; Gottesman, M.M.; Xia, D. Structures of the multidrug transporter P-glycoprotein reveal asymmetric ATP binding and the mechanism of polyspecificity. J. Biol. Chem., 2017, 292(2), 446-461.
[http://dx.doi.org/10.1074/jbc.M116.755884] [PMID: 27864369]
[28]
Hafkemeyer, P.; Dey, S.; Ambudkar, S.V.; Hrycyna, C.A.; Pastan, I.; Gottesman, M.M. Contribution to substrate specificity and transport of nonconserved residues in transmembrane domain 12 of human P-glycoprotein. Biochemistry, 1998, 37(46), 16400-16409.
[http://dx.doi.org/10.1021/bi980871+] [PMID: 9819232]
[29]
Kajiji, S.; Talbot, F.; Grizzuti, K.; Van Dyke-Phillips, V.; Agresti, M.; Safa, A.R.; Gros, P. Functional analysis of P-glycoprotein mutants identifies predicted transmembrane domain 11 as a putative drug binding site. Biochemistry, 1993, 32(16), 4185-4194.
[http://dx.doi.org/10.1021/bi00067a005] [PMID: 7682843]
[30]
Loo, T.W.; Clarke, D.M. Mutations to amino acids located in predicted transmembrane segment 6 (TM6) modulate the activity and substrate specificity of human P-glycoprotein. Biochemistry, 1994, 33(47), 14049-14057.
[http://dx.doi.org/10.1021/bi00251a013] [PMID: 7947814]
[31]
Loo, T.W.; Clarke, D.M. Recent progress in understanding the mechanism of P-glycoprotein-mediated drug efflux. J. Membr. Biol., 2005, 206(3), 173-185.
[http://dx.doi.org/10.1007/s00232-005-0792-1] [PMID: 16456713]
[32]
Hennessy, M.; Spiers, J.P. A primer on the mechanics of P-glycoprotein the multidrug transporter. Pharmacol. Res., 2007, 55(1), 1-15.
[http://dx.doi.org/10.1016/j.phrs.2006.10.007] [PMID: 17095241]
[33]
Hrycyna, C.A.; Ramachandra, M.; Ambudkar, S.V.; Ko, Y.H.; Pedersen, P.L.; Pastan, I.; Gottesman, M.M. Mechanism of action of human P-glycoprotein ATPase activity. Photochemical cleavage during a catalytic transition state using orthovanadate reveals cross-talk between the two ATP sites. J. Biol. Chem., 1998, 273(27), 16631-16634.
[http://dx.doi.org/10.1074/jbc.273.27.16631] [PMID: 9642211]
[34]
Urbatsch, I.L.; Sankaran, B.; Weber, J.; Senior, A.E. P-glycoprotein is stably inhibited by vanadate-induced trapping of nucleotide at a single catalytic site. J. Biol. Chem., 1995, 270(33), 19383-19390.
[http://dx.doi.org/10.1074/jbc.270.33.19383] [PMID: 7642618]
[35]
Stenham, D.R.; Campbell, J.D.; Sansom, M.S.; Higgins, C.F.; Kerr, I.D.; Linton, K.J. An atomic detail model for the human ATP binding cassette transporter P-glycoprotein derived from disulfide cross-linking and homology modeling. FASEB J., 2003, 17(15), 2287-2289.
[http://dx.doi.org/10.1096/fj.03-0107fje] [PMID: 14563687]
[36]
O’Mara, M.L.; Tieleman, D.P. P-glycoprotein models of the apo and ATP-bound states based on homology with Sav1866 and MalK. FEBS Lett., 2007, 581(22), 4217-4222.
[http://dx.doi.org/10.1016/j.febslet.2007.07.069] [PMID: 17706648]
[37]
Domicevica, L.; Biggin, P.C. Homology modelling of human P-glycoprotein. Biochem. Soc. Trans., 2015, 43(5), 952-958.
[http://dx.doi.org/10.1042/BST20150125] [PMID: 26517909]
[38]
Jin, M.S.; Oldham, M.L.; Zhang, Q.; Chen, J. Crystal structure of the multidrug transporter P-glycoprotein from Caenorhabditis elegans. Nature, 2012, 490(7421), 566-569.
[http://dx.doi.org/10.1038/nature11448] [PMID: 23000902]
[39]
Kodan, A.; Yamaguchi, T.; Nakatsu, T.; Sakiyama, K.; Hipolito, C.J.; Fujioka, A.; Hirokane, R.; Ikeguchi, K.; Watanabe, B.; Hiratake, J.; Kimura, Y.; Suga, H.; Ueda, K.; Kato, H. Structural basis for gating mechanisms of a eukaryotic P-glycoprotein homolog. Proc. Natl. Acad. Sci. USA, 2014, 111(11), 4049-4054.
[http://dx.doi.org/10.1073/pnas.1321562111] [PMID: 24591620]
[40]
Leonard, G.D.; Polgar, O.; Bates, S.E. ABC transporters and inhibitors: new targets, new agents. Curr. Opin. Investig. Drugs, 2002, 3(11), 1652-1659.
[PMID: 12476969]
[41]
Fu, L.; Liang, Y.; Deng, L.; Ding, Y.; Chen, L.; Ye, Y.; Yang, X.; Pan, Q. Characterization of tetrandrine, a potent inhibitor of P-glycoprotein-mediated multidrug resistance. Cancer Chemother. Pharmacol., 2004, 53(4), 349-356.
[http://dx.doi.org/10.1007/s00280-003-0742-5] [PMID: 14666379]
[42]
Safa, A.R. Photoaffinity labeling of the multidrug-resistance-related P-glycoprotein with photoactive analogs of verapamil. Proc. Natl. Acad. Sci. USA, 1988, 85(19), 7187-7191.
[http://dx.doi.org/10.1073/pnas.85.19.7187] [PMID: 2902625]
[43]
Tsuruo, T.; Iida, H.; Tsukagoshi, S.; Sakurai, Y. Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer Res., 1981, 41(5), 1967-1972.
[PMID: 7214365]
[44]
Yan, C.S.W.; Wong, I.L.K.; Chan, K-F.; Kan, J.W.Y.; Chong, T.C.; Law, M.C.; Zhao, Y.; Chan, S.W.; Chan, T.H.; Chow, L.M.C. A New Class of Safe, Potent, and Specific P-gp Modulator: flavonoid Dimer FD18 Reverses P-gp-mediated multidrug resistance in human breast xenograft in vivo. Mol. Pharm., 2015, 12(10), 3507-3517.
[http://dx.doi.org/10.1021/mp500770e] [PMID: 26291333]
[45]
Bin, J.W.; Wong, I.L.; Hu, X.; Yu, Z.X.; Xing, L.F.; Jiang, T.; Chow, L.M.; Biao, W.S. Structure-activity relationship study of permethyl ningalin B analogues as P-glycoprotein chemosensitizers. J. Med. Chem., 2013, 56(22), 9057-9070.
[http://dx.doi.org/10.1021/jm400930e] [PMID: 24171478]
[46]
Perloff, M.D.; von Moltke, L.L.; Störmer, E.; Shader, R.I.; Greenblatt, D.J. Saint John’s wort: an in vitro analysis of P-glycoprotein induction due to extended exposure. Br. J. Pharmacol., 2001, 134(8), 1601-1608.
[http://dx.doi.org/10.1038/sj.bjp.0704399] [PMID: 11739235]
[47]
Ferreira, A.; Santos, A.O.; Falcão, A.; Alves, G. In vitro screening of dual flavonoid combinations for reversing P-glycoprotein-mediated multidrug resistance: focus on antiepileptic drugs. Food Chem. Toxicol., 2018, 111, 84-93.
[http://dx.doi.org/10.1016/j.fct.2017.11.004] [PMID: 29122665]
[48]
Homolya, L.; Holló, Z.; Germann, U.A.; Pastan, I.; Gottesman, M.M.; Sarkadi, B. Fluorescent cellular indicators are extruded by the multidrug resistance protein. J. Biol. Chem., 1993, 268(29), 21493-21496.
[PMID: 8104940]
[49]
Tiberghien, F.; Loor, F. Ranking of P-glycoprotein substrates and inhibitors by a calcein-AM fluorometry screening assay. Anticancer Drugs, 1996, 7(5), 568-578.
[http://dx.doi.org/10.1097/00001813-199607000-00012] [PMID: 8862725]
[50]
Polli, J.W.; Wring, S.A.; Humphreys, J.E.; Huang, L.; Morgan, J.B.; Webster, L.O.; Serabjit-Singh, C.S. Rational use of in vitro P-glycoprotein assays in drug discovery. J. Pharmacol. Exp. Ther., 2001, 299(2), 620-628.
[PMID: 11602674]
[51]
Glavinas, H.; Krajcsi, P.; Cserepes, J.; Sarkadi, B. The role of ABC transporters in drug resistance, metabolism and toxicity. Curr. Drug Deliv., 2004, 1(1), 27-42.
[http://dx.doi.org/10.2174/1567201043480036] [PMID: 16305368]
[52]
Chan, K.F.; Zhao, Y.; Burkett, B.A.; Wong, I.L.; Chow, L.M.; Chan, T.H. Flavonoid dimers as bivalent modulators for P-glycoprotein-based multidrug resistance: synthetic apigenin homodimers linked with defined-length poly(ethylene glycol) spacers increase drug retention and enhance chemosensitivity in resistant cancer cells. J. Med. Chem., 2006, 49(23), 6742-6759.
[http://dx.doi.org/10.1021/jm060593+] [PMID: 17154505]
[53]
Zhang, Y.; Li, H.; Wang, H.; Su, F.; Qu, R.; Yin, D.; Dai, J.; Li, Y.; Chen, X. Syl611, a novel semisynthetic taxane derivative, reverses multidrug resistance by p-glycoprotein inhibition and facilitating inward transmembrane action. Cancer Chemother. Pharmacol., 2010, 66(5), 851-859.
[http://dx.doi.org/10.1007/s00280-009-1229-9] [PMID: 20052473]
[54]
Palmeira, A.; Rodrigues, F.; Sousa, E.; Pinto, M.; Vasconcelos, M.H.; Fernandes, M.X. New uses for old drugs: pharmacophore-based screening for the discovery of P-glycoprotein inhibitors. Chem. Biol. Drug Des., 2011, 78(1), 57-72.
[http://dx.doi.org/10.1111/j.1747-0285.2011.01089.x] [PMID: 21235729]
[55]
Chan, K.F.; Wong, I.L.; Kan, J.W.; Yan, C.S.; Chow, L.M.; Chan, T.H. Amine linked flavonoid dimers as modulators for P-glycoprotein-based multidrug resistance: structure-activity relationship and mechanism of modulation. J. Med. Chem., 2012, 55(5), 1999-2014.
[http://dx.doi.org/10.1021/jm201121b] [PMID: 22320402]
[56]
Ambudkar, S.V.; Lelong, I.H.; Zhang, J.; Cardarelli, C.O.; Gottesman, M.M.; Pastan, I. Partial purification and reconstitution of the human multidrug-resistance pump: characterization of the drug-stimulatable ATP hydrolysis. Proc. Natl. Acad. Sci. USA, 1992, 89(18), 8472-8476.
[http://dx.doi.org/10.1073/pnas.89.18.8472] [PMID: 1356264]
[57]
Sarkadi, B.; Price, E.M.; Boucher, R.C.; Germann, U.A.; Scarborough, G.A. Expression of the human multidrug resistance cDNA in insect cells generates a high activity drug-stimulated membrane ATPase. J. Biol. Chem., 1992, 267(7), 4854-4858.
[PMID: 1347044]
[58]
Scarborough, G.A. Drug-stimulated ATPase activity of the human P-glycoprotein. J. Bioenerg. Biomembr., 1995, 27(1), 37-41.
[http://dx.doi.org/10.1007/BF02110329] [PMID: 7629050]
[59]
Chifflet, S.; Torriglia, A.; Chiesa, R.; Tolosa, S. A method for the determination of inorganic phosphate in the presence of labile organic phosphate and high concentrations of protein: application to lens ATPases. Anal. Biochem., 1988, 168(1), 1-4.
[http://dx.doi.org/10.1016/0003-2697(88)90002-4] [PMID: 2834977]
[60]
Martin, C.; Berridge, G.; Mistry, P.; Higgins, C.; Charlton, P.; Callaghan, R. The molecular interaction of the high affinity reversal agent XR9576 with P-glycoprotein. Br. J. Pharmacol., 1999, 128(2), 403-411.
[http://dx.doi.org/10.1038/sj.bjp.0702807] [PMID: 10510451]
[61]
Rothnie, A.; Theron, D.; Soceneantu, L.; Martin, C.; Traikia, M.; Berridge, G.; Higgins, C.F.; Devaux, P.F.; Callaghan, R. The importance of cholesterol in maintenance of P-glycoprotein activity and its membrane perturbing influence. Eur. Biophys. J., 2001, 30(6), 430-442.
[http://dx.doi.org/10.1007/s002490100156] [PMID: 11718296]
[62]
Matsunaga, T.; Kose, E.; Yasuda, S.; Ise, H.; Ikeda, U.; Ohmori, S. Determination of p-glycoprotein ATPase activity using luciferase. Biol. Pharm. Bull., 2006, 29(3), 560-564.
[http://dx.doi.org/10.1248/bpb.29.560] [PMID: 16508168]
[63]
Hassan, H.E.; Myers, A.L.; Lee, I.J.; Coop, A.; Eddington, N.D. Oxycodone induces overexpression of P-glycoprotein (ABCB1) and affects paclitaxel’s tissue distribution in Sprague Dawley rats. J. Pharm. Sci., 2007, 96(9), 2494-2506.
[http://dx.doi.org/10.1002/jps.20893] [PMID: 17593551]
[64]
Palmeira, A.; Sousa, E.; Vasconcelos, M.H.; Pinto, M.M. Three decades of P-gp inhibitors: skimming through several generations and scaffolds. Curr. Med. Chem., 2012, 19(13), 1946-2025.
[http://dx.doi.org/10.2174/092986712800167392] [PMID: 22257057]
[65]
Yang, K.; Wu, J.; Li, X. Recent advances in the research of P-glycoprotein inhibitors. Biosci. Trends, 2008, 2(4), 137-146.
[PMID: 20103919]
[66]
Fox, E.; Bates, S.E. Tariquidar (XR9576): a P-glycoprotein drug efflux pump inhibitor. Expert Rev. Anticancer Ther., 2007, 7(4), 447-459.
[http://dx.doi.org/10.1586/14737140.7.4.447] [PMID: 17428165]
[67]
Bansal, T.; Mishra, G.; Jaggi, M.; Khar, R.K.; Talegaonkar, S. Effect of P-glycoprotein inhibitor, verapamil, on oral bioavailability and pharmacokinetics of irinotecan in rats. Eur. J. Pharm. Sci., 2009, 36(4-5), 580-590.
[http://dx.doi.org/10.1016/j.ejps.2008.12.005] [PMID: 19135530]
[68]
Potschka, H. Role of CNS efflux drug transporters in antiepileptic drug delivery: overcoming CNS efflux drug transport. Adv. Drug Deliv. Rev., 2012, 64(10), 943-952.
[http://dx.doi.org/10.1016/j.addr.2011.12.007] [PMID: 22210135]
[69]
Coley, H.M. Overcoming multidrug resistance in cancer: clinical studies of p-glycoprotein inhibitors. Methods Mol. Biol., 2010, 596, 341-358.
[http://dx.doi.org/10.1007/978-1-60761-416-6_15] [PMID: 19949931]
[70]
Boesch, D.; Gavériaux, C.; Jachez, B.; Pourtier-Manzanedo, A.; Bollinger, P.; Loor, F. In vivo circumvention of P-glycoprotein-mediated multidrug resistance of tumor cells with SDZ PSC 833. Cancer Res., 1991, 51(16), 4226-4233.
[PMID: 1678313]
[71]
Friedenberg, W.R.; Rue, M.; Blood, E.A.; Dalton, W.S.; Shustik, C.; Larson, R.A.; Sonneveld, P.; Greipp, P.R. Phase III study of PSC‐833 (valspodar) in combination with vincristine, doxorubicin, and dexamethasone (valspo-dar/VAD) versus VAD alone in patients with recurring or refractory multiple myeloma (E1A95). Cancer, 2006, 106(4), 830-838.
[http://dx.doi.org/10.1002/cncr.21666] [PMID: 16419071]
[72]
Critchfield, J.W.; Welsh, C.J.; Phang, J.M.; Yeh, G.C. Modulation of adriamycin accumulation and efflux by flavonoids in HCT-15 colon cells. Activation of P-glycoprotein as a putative mechanism. Biochem. Pharmacol., 1994, 48(7), 1437-1445.
[http://dx.doi.org/10.1016/0006-2952(94)90568-1] [PMID: 7945444]
[73]
Conseil, G.; Baubichon-Cortay, H.; Dayan, G.; Jault, J.M.; Barron, D.; Di Pietro, A. Flavonoids: a class of modulators with bifunctional interactions at vicinal ATP- and steroid-binding sites on mouse P-glycoprotein. Proc. Natl. Acad. Sci. USA, 1998, 95(17), 9831-9836.
[http://dx.doi.org/10.1073/pnas.95.17.9831] [PMID: 9707561]
[74]
Sadzuka, Y.; Sugiyama, T.; Sonobe, T. Efficacies of tea components on doxorubicin induced antitumor activity and reversal of multidrug resistance. Toxicol. Lett., 2000, 114(1-3), 155-162.
[http://dx.doi.org/10.1016/S0378-4274(99)00290-8] [PMID: 10713480]
[75]
Scambia, G.; Ranelletti, F.O.; Panici, P.B.; De Vincenzo, R.; Bonanno, G.; Ferrandina, G.; Piantelli, M.; Bussa, S.; Rumi, C.; Cianfriglia, M. Quercetin potentiates the effect of adriamycin in a multidrug-resistant MCF-7 human breast-cancer cell line: P-glycoprotein as a possible target. Cancer Chemother. Pharmacol., 1994, 34(6), 459-464.
[http://dx.doi.org/10.1007/BF00685655] [PMID: 7923555]
[76]
Ikegawa, T.; Ushigome, F.; Koyabu, N.; Morimoto, S.; Shoyama, Y.; Naito, M.; Tsuruo, T.; Ohtani, H.; Sawada, Y. Inhibition of P-glycoprotein by orange juice components, polymethoxyflavones in adriamycin-resistant human myelogenous leukemia (K562/ADM) cells. Cancer Lett., 2000, 160(1), 21-28.
[http://dx.doi.org/10.1016/S0304-3835(00)00549-8] [PMID: 11098080]
[77]
Dumaitre, B. A.; Dodic, N. ACRIDINE DERIVATIVES.US 5,604,237, 1997.
[78]
Wu, C-P.; Ohnuma, S.; Ambudkar, S.V. Discovering natural product modulators to overcome multidrug resistance in cancer chemotherapy. Curr. Pharm. Biotechnol., 2011, 12(4), 609-620.
[http://dx.doi.org/10.2174/138920111795163887] [PMID: 21118092]
[79]
Bois, F.; Beney, C.; Boumendjel, A.; Mariotte, A.M.; Conseil, G.; Di Pietro, A. Halogenated chalcones with high-affinity binding to P-glycoprotein: potential modulators of multidrug resistance. J. Med. Chem., 1998, 41(21), 4161-4164.
[http://dx.doi.org/10.1021/jm9810194] [PMID: 9767651]
[80]
Ferté, J.; Kühnel, J.M.; Chapuis, G.; Rolland, Y.; Lewin, G.; Schwaller, M.A. Flavonoid-related modulators of multidrug resistance: synthesis, pharmacological activity, and structure-activity relationships. J. Med. Chem., 1999, 42(3), 478-489.
[http://dx.doi.org/10.1021/jm981064b] [PMID: 9986718]
[81]
Tchamo, D.N.; Dijoux-Franca, M.G.; Mariotte, A.M.; Tsamo, E.; Daskiewicz, J.B.; Bayet, C.; Barron, D.; Conseil, G.; Di Pietro, A. Prenylated xanthones as potential P-glycoprotein modulators. Bioorg. Med. Chem. Lett., 2000, 10(12), 1343-1345.
[http://dx.doi.org/10.1016/S0960-894X(00)00234-1] [PMID: 10890160]
[82]
Dzubák, P.; Hajdúch, M.; Gazák, R.; Svobodová, A.; Psotová, J.; Walterová, D.; Sedmera, P.; Kren, V. New derivatives of silybin and 2,3-dehydrosilybin and their cytotoxic and P-glycoprotein modulatory activity. Bioorg. Med. Chem., 2006, 14(11), 3793-3810.
[http://dx.doi.org/10.1016/j.bmc.2006.01.035] [PMID: 16466920]
[83]
Mohana, S.; Ganesan, M.; Agilan, B.; Karthikeyan, R.; Srithar, G.; Beaulah Mary, R.; Ananthakrishnan, D.; Velmurugan, D.; Rajendra Prasad, N.; Ambudkar, S.V. Screening dietary flavonoids for the reversal of P-glycoprotein-mediated multidrug resistance in cancer. Mol. Biosyst., 2016, 12(8), 2458-2470.
[http://dx.doi.org/10.1039/C6MB00187D] [PMID: 27216424]
[84]
Ofer, M.; Wolffram, S.; Koggel, A.; Spahn-Langguth, H.; Langguth, P. Modulation of drug transport by selected flavonoids: Involvement of P-gp and OCT? Eur. J. Pharm. Sci., 2005, 25(2-3), 263-271.
[http://dx.doi.org/10.1016/j.ejps.2005.03.001] [PMID: 15911222]
[85]
Brand, W.; Schutte, M.E.; Williamson, G.; van Zanden, J.J.; Cnubben, N.H.; Groten, J.P.; van Bladeren, P.J.; Rietjens, I.M. Flavonoid-mediated inhibition of intestinal ABC transporters may affect the oral bioavailability of drugs, food-borne toxic compounds and bioactive ingredients. Biomed. Pharmacother., 2006, 60(9), 508-519.
[http://dx.doi.org/10.1016/j.biopha.2006.07.081] [PMID: 16978825]
[86]
Lai, M.Y.; Hsiu, S.L.; Hou, Y.C.; Tsai, S.Y.; Chao, P.D. Significant decrease of cyclosporine bioavailability in rats caused by a decoction of the roots of Scutellaria baicalensis. Planta Med., 2004, 70(2), 132-137.
[http://dx.doi.org/10.1055/s-2004-815489] [PMID: 14994190]
[87]
Choi, J.S.; Jo, B.W.; Kim, Y.C. Enhanced paclitaxel bioavailability after oral administration of paclitaxel or prodrug to rats pretreated with quercetin. Eur. J. Pharm. Biopharm., 2004, 57(2), 313-318.
[http://dx.doi.org/10.1016/j.ejpb.2003.11.002] [PMID: 15018990]
[88]
Deferme, S.; Augustijns, P. The effect of food components on the absorption of P-gp substrates: a review. J. Pharm. Pharmacol., 2003, 55(2), 153-162.
[http://dx.doi.org/10.1211/002235702603] [PMID: 12631407]
[89]
Lohner, K.; Schnäbele, K.; Daniel, H.; Oesterle, D.; Rechkemmer, G.; Göttlicher, M.; Wenzel, U. Flavonoids alter P-gp expression in intestinal epithelial cells in vitro and in vivo. Mol. Nutr. Food Res., 2007, 51(3), 293-300.
[http://dx.doi.org/10.1002/mnfr.200600225] [PMID: 17295420]
[90]
Kitagawa, S.; Nabekura, T.; Takahashi, T.; Nakamura, Y.; Sakamoto, H.; Tano, H.; Hirai, M.; Tsukahara, G. Structure-activity relationships of the inhibitory effects of flavonoids on P-glycoprotein-mediated transport in KB-C2 cells. Biol. Pharm. Bull., 2005, 28(12), 2274-2278.
[http://dx.doi.org/10.1248/bpb.28.2274] [PMID: 16327165]
[91]
Shin, S.C.; Li, C.; Choi, J.S. Effects of baicalein, an antioxidant, on the bioavailability of doxorubicin in rats: possible role of P-glycoprotein inhibition by baicalein. Pharmazie, 2009, 64(9), 579-583.
[PMID: 19827298]
[92]
Go, W.J.; Ryu, J.H.; Qiang, F.; Han, H.K. Evaluation of the flavonoid oroxylin A as an inhibitor of P-glycoprotein-mediated cellular efflux. J. Nat. Prod., 2009, 72(9), 1616-1619.
[http://dx.doi.org/10.1021/np9003036] [PMID: 19739602]
[93]
Sheu, M.T.; Liou, Y.B.; Kao, Y.H.; Lin, Y.K.; Ho, H.O. A quantitative structure-activity relationship for the modulation effects of flavonoids on p-glycoprotein-mediated transport. Chem. Pharm. Bull. (Tokyo), 2010, 58(9), 1187-1194.
[http://dx.doi.org/10.1248/cpb.58.1187] [PMID: 20823598]
[94]
Di Pietro, A.; Conseil, G.; Pérez-Victoria, J.M.; Dayan, G.; Baubichon-Cortay, H.; Trompier, D.; Steinfels, E.; Jault, J.M.; de Wet, H.; Maitrejean, M.; Comte, G.; Boumendjel, A.; Mariotte, A.M.; Dumontet, C.; McIntosh, D.B.; Goffeau, A.; Castanys, S.; Gamarro, F.; Barron, D. Modulation by flavonoids of cell multidrug resistance mediated by P-glycoprotein and related ABC transporters. Cell. Mol. Life Sci., 2002, 59(2), 307-322.
[http://dx.doi.org/10.1007/s00018-002-8424-8] [PMID: 11915946]
[95]
Choi, C.H.; Kim, J.H.; Kim, S.H. Reversal of P-glycoprotein-mediated MDR by 5,7,3′,4′,5′-pentamethoxyflavone and SAR. Biochem. Biophys. Res. Commun., 2004, 320(3), 672-679.
[http://dx.doi.org/10.1016/j.bbrc.2004.06.020] [PMID: 15240100]
[96]
Kothandan, G.; Gadhe, C.G.; Madhavan, T.; Choi, C.H.; Cho, S.J. Docking and 3D-QSAR (quantitative structure activity relationship) studies of flavones, the potent inhibitors of p-glycoprotein targeting the nucleotide binding domain. Eur. J. Med. Chem., 2011, 46(9), 4078-4088.
[http://dx.doi.org/10.1016/j.ejmech.2011.06.008] [PMID: 21723648]
[97]
Li, Y.; Wang, Y.; Yang, L.; Zhang, S.; Jiang, D.; Liu, C.; Yang, S. Research on structural-activity relationship of inhibitory effects of flavonoid derivatives on P-glycoprotein. Journal of Dalian University of technology, 2007, 47(1), 15-20.
[98]
Mitsunaga, Y.; Takanaga, H.; Matsuo, H.; Naito, M.; Tsuruo, T.; Ohtani, H.; Sawada, Y. Effect of bioflavonoids on vincristine transport across blood-brain barrier. Eur. J. Pharmacol., 2000, 395(3), 193-201.
[http://dx.doi.org/10.1016/S0014-2999(00)00180-1] [PMID: 10812049]
[99]
Ferreira, A.; Pousinho, S.; Fortuna, A.; Falcão, A.; Alves, G. Flavonoid compounds as reversal agents of the P-glycoprotein-mediated multidrug resistance: biology, chemis-try and pharmacology. Phytochem. Rev., 2015, 14(2), 233-272.
[http://dx.doi.org/10.1007/s11101-014-9358-0]
[100]
Hadjeri, M.; Barbier, M.; Ronot, X.; Mariotte, A.M.; Boumendjel, A.; Boutonnat, J. Modulation of P-glycoprotein-mediated multidrug resistance by flavonoid derivatives and analogues. J. Med. Chem., 2003, 46(11), 2125-2131.
[http://dx.doi.org/10.1021/jm021099i] [PMID: 12747785]
[101]
Choi, C.H.; Sun, K.H.; An, C.S.; Yoo, J.C.; Hahm, K.S.; Lee, I.H.; Sohng, J.K.; Kim, Y.C. Reversal of P-glycoprotein-mediated multidrug resistance by 5,6,7,3′,4′-pentamethoxyflavone (Sinensetin). Biochem. Biophys. Res. Commun., 2002, 295(4), 832-840.
[http://dx.doi.org/10.1016/S0006-291X(02)00755-6] [PMID: 12127970]
[102]
Takanaga, H.; Ohnishi, A.; Yamada, S.; Matsuo, H.; Morimoto, S.; Shoyama, Y.; Ohtani, H.; Sawada, Y. Polymethoxylated flavones in orange juice are inhibitors of P-glycoprotein but not cytochrome P450 3A4. J. Pharmacol. Exp. Ther., 2000, 293(1), 230-236.
[PMID: 10734174]
[103]
Ohtani, H.; Ikegawa, T.; Honda, Y.; Kohyama, N.; Morimoto, S.; Shoyama, Y.; Juichi, M.; Naito, M.; Tsuruo, T.; Sawada, Y. Effects of various methoxyflavones on vincristine uptake and multidrug resistance to vincristine in P-gp-overexpressing K562/ADM cells. Pharm. Res., 2007, 24(10), 1936-1943.
[http://dx.doi.org/10.1007/s11095-007-9320-6] [PMID: 17492365]
[104]
Boumendjel, A.; Di Pietro, A.; Dumontet, C.; Barron, D. Recent advances in the discovery of flavonoids and analogs with high-affinity binding to P-glycoprotein responsible for cancer cell multidrug resistance. Med. Res. Rev., 2002, 22(5), 512-529.
[http://dx.doi.org/10.1002/med.10015] [PMID: 12210557]
[105]
Ecker, G.; Huber, M.; Schmid, D.; Chiba, P. The importance of a nitrogen atom in modulators of multidrug resistance. Mol. Pharmacol., 1999, 56(4), 791-796.
[PMID: 10496963]
[106]
Bois, F.; Boumendjel, A.; Mariotte, A.M.; Conseil, G.; Di Petro, A. Synthesis and biological activity of 4-alkoxy chalcones: potential hydrophobic modulators of P-glycoprotein-mediated multidrug resistance. Bioorg. Med. Chem., 1999, 7(12), 2691-2695.
[http://dx.doi.org/10.1016/S0968-0896(99)00218-7] [PMID: 10658573]
[107]
Liu, X.L.; Tee, H.W.; Go, M.L. Functionalized chalcones as selective inhibitors of P-glycoprotein and breast cancer resistance protein. Bioorg. Med. Chem., 2008, 16(1), 171-180.
[http://dx.doi.org/10.1016/j.bmc.2007.10.006] [PMID: 17964170]
[108]
Manna, F.; Chimenti, F.; Fioravanti, R.; Bolasco, A.; Secci, D.; Chimenti, P.; Ferlini, C.; Scambia, G. Synthesis of some pyrazole derivatives and preliminary investigation of their affinity binding to P-glycoprotein. Bioorg. Med. Chem. Lett., 2005, 15(20), 4632-4635.
[http://dx.doi.org/10.1016/j.bmcl.2005.05.067] [PMID: 16099651]
[109]
Boumendjel, A.; McLeer-Florin, A.; Champelovier, P.; Allegro, D.; Muhammad, D.; Souard, F.; Derouazi, M.; Peyrot, V.; Toussaint, B.; Boutonnat, J. A novel chalcone derivative which acts as a microtubule depolymerising agent and an inhibitor of P-gp and BCRP in in-vitro and in-vivo glioblastoma models. BMC Cancer, 2009, 9(1), 242.
[http://dx.doi.org/10.1186/1471-2407-9-242] [PMID: 19619277]
[110]
Shapiro, A.B.; Ling, V. Effect of quercetin on Hoechst 33342 transport by purified and reconstituted P-glycoprotein. Biochem. Pharmacol., 1997, 53(4), 587-596.
[http://dx.doi.org/10.1016/S0006-2952(96)00826-X] [PMID: 9105411]
[111]
Chung, S.Y.; Jang, D.S.; Han, A.R.; Jang, J.O.; Kwon, Y.; Seo, E.K.; Lee, H.J. Modulation of P-glycoprotein-mediated resistance by kaempferol derivatives isolated from Zingiber zerumbet. Phytother. Res., 2007, 21(6), 565-569.
[http://dx.doi.org/10.1002/ptr.2113] [PMID: 17335117]
[112]
Maitrejean, M.; Comte, G.; Barron, D.; El Kirat, K.; Conseil, G.; Di Pietro, A. The flavanolignan silybin and its hemisynthetic derivatives, a novel series of potential modulators of P-glycoprotein. Bioorg. Med. Chem. Lett., 2000, 10(2), 157-160.
[http://dx.doi.org/10.1016/S0960-894X(99)00636-8] [PMID: 10673101]
[113]
Boumendjel, A.; Bois, F.; Beney, C.; Mariotte, A.M.; Conseil, G.; Di Pietro, A. B-ring substituted 5,7-dihydroxyflavonols with high-affinity binding to P-glycoprotein responsible for cell multidrug resistance. Bioorg. Med. Chem. Lett., 2001, 11(1), 75-77.
[http://dx.doi.org/10.1016/S0960-894X(00)00595-3] [PMID: 11140738]
[114]
Kitagawa, S.; Nabekura, T.; Kamiyama, S. Inhibition of P-glycoprotein function by tea catechins in KB-C2 cells. J. Pharm. Pharmacol., 2004, 56(8), 1001-1005.
[http://dx.doi.org/10.1211/0022357044003] [PMID: 15285844]
[115]
Mei, Y.; Qian, F.; Wei, D.; Liu, J. Reversal of cancer multidrug resistance by green tea polyphenols. J. Pharm. Pharmacol., 2004, 56(10), 1307-1314.
[http://dx.doi.org/10.1211/0022357044364] [PMID: 15482646]
[116]
Satonaka, H.; Ishida, K.; Takai, M.; Koide, R.; Shigemasa, R.; Ueyama, J.; Ishikawa, T.; Hayashi, K.; Goto, H.; Wakusawa, S. (-)-Epigallocatechin-3-gallate down-regulates doxorubicin-induced overexpression of P-glycoprotein through the co-ordinate inhibition of PI3K/Akt and MEK/ERK signaling pathways. Anticancer Res., 2017, 37(11), 6071-6077.
[PMID: 29061787]
[117]
Wong, I.L.; Wang, B.C.; Yuan, J.; Duan, L.X.; Liu, Z.; Liu, T.; Li, X.M.; Hu, X.; Zhang, X.Y.; Jiang, T.; Wan, S.B.; Chow, L.M. Potent and Nontoxic Chemosensitizer of P-Glycoprotein-Mediated Multidrug Resistance in Cancer: Synthesis and Evaluation of Methylated Epigallocatechin, Gallocatechin, and Dihydromyricetin Derivatives. J. Med. Chem., 2015, 58(11), 4529-4549.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00085] [PMID: 25985195]
[118]
Pinto, M.M.; Sousa, M.E.; Nascimento, M.S. Xanthone derivatives: new insights in biological activities. Curr. Med. Chem., 2005, 12(21), 2517-2538.
[http://dx.doi.org/10.2174/092986705774370691] [PMID: 16250875]
[119]
Chieli, E.; Romiti, N.; Rodeiro, I.; Garrido, G. In vitro effects of Mangifera indica and polyphenols derived on ABCB1/P-glycoprotein activity. Food Chem. Toxicol., 2009, 47(11), 2703-2710.
[http://dx.doi.org/10.1016/j.fct.2009.07.017] [PMID: 19632288]
[120]
Wilkinson, A.S.; Monteith, G.R.; Shaw, P.N.; Lin, C.N.; Gidley, M.J.; Roberts-Thomson, S.J. Effects of the mango components mangiferin and quercetin and the putative mangiferin metabolite norathyriol on the transactivation of peroxisome proliferator-activated receptor isoforms. J. Agric. Food Chem., 2008, 56(9), 3037-3042.
[http://dx.doi.org/10.1021/jf800046n] [PMID: 18393431]
[121]
Sousa, E.; Palmeira, A.; Cordeiro, A.S.; Sarmento, B.; Fer-reira, D.; Lima, R.T.; Helena Vasconcelos, M.; Pinto, M. Bioactive xanthones with effect on P-glycoprotein and pre-diction of intestinal absorption. Med. Chem. Res., 2013, 22(5), 2115-2123.
[http://dx.doi.org/10.1007/s00044-012-0203-y]
[122]
Rancon, S.; Chaboud, A.; Darbour, N.; Comte, G.; Bayet, C.; Simon, P.N.; Raynaud, J.; Di Pietro, A.; Cabalion, P.; Barron, D. Natural and synthetic benzophenones: interaction with the cytosolic binding domain of P-glycoprotein. Phytochemistry, 2001, 57(4), 553-557.
[http://dx.doi.org/10.1016/S0031-9422(01)00120-0] [PMID: 11394856]
[123]
Palmeira, A.; Vasconcelos, M.H.; Paiva, A.; Fernandes, M.X.; Pinto, M.; Sousa, E. Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones. Biochem. Pharmacol., 2012, 83(1), 57-68.
[http://dx.doi.org/10.1016/j.bcp.2011.10.004] [PMID: 22044878]
[124]
Hyafil, F.; Vergely, C.; Du Vignaud, P.; Grand-Perret, T. In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative. Cancer Res., 1993, 53(19), 4595-4602.
[PMID: 8402633]
[125]
Wallstab, A.; Koester, M.; Böhme, M.; Keppler, D. Selective inhibition of MDR1 P-glycoprotein-mediated transport by the acridone carboxamide derivative GG918. Br. J. Cancer, 1999, 79(7-8), 1053-1060.
[http://dx.doi.org/10.1038/sj.bjc.6690169] [PMID: 10098736]
[126]
Traunecker, H.C.; Stevens, M.C.; Kerr, D.J.; Ferry, D.R. The acridonecarboxamide GF120918 potently reverses P-glycoprotein-mediated resistance in human sarcoma MES-Dx5 cells. Br. J. Cancer, 1999, 81(6), 942-951.
[http://dx.doi.org/10.1038/sj.bjc.6690791] [PMID: 10576649]
[127]
Krishnegowda, G.; Thimmaiah, P.; Hegde, R.; Dass, C.; Houghton, P.J.; Thimmaiah, K.N. Synthesis and chemical characterization of 2-methoxy-N(10)-substituted acridones needed to reverse vinblastine resistance in multidrug resistant (MDR) cancer cells. Bioorg. Med. Chem., 2002, 10(7), 2367-2380.
[http://dx.doi.org/10.1016/S0968-0896(02)00068-8] [PMID: 11983534]
[128]
Boumendjel, A.; Beney, C.; Deka, N.; Mariotte, A.M.; Lawson, M.A.; Trompier, D.; Baubichon-Cortay, H.; Di Pietro, A. 4-Hydroxy-6-methoxyaurones with high-affinity binding to cytosolic domain of P-glycoprotein. Chem. Pharm. Bull. (Tokyo), 2002, 50(6), 854-856.
[http://dx.doi.org/10.1248/cpb.50.854] [PMID: 12045348]
[129]
Václavíková, R.; Boumendjel, A.; Ehrlichová, M.; Kovár, J.; Gut, I. Modulation of paclitaxel transport by flavonoid derivatives in human breast cancer cells. Is there a correlation between binding affinity to NBD of P-gp and modulation of transport? Bioorg. Med. Chem., 2006, 14(13), 4519-4525.
[http://dx.doi.org/10.1016/j.bmc.2006.02.025] [PMID: 16516478]
[130]
Chow, L.M.; Chan, T.H. Novel classes of dimer antitumour drug candidates. Curr. Pharm. Des., 2009, 15(6), 659-674.
[http://dx.doi.org/10.2174/138161209787315576] [PMID: 19199989]
[131]
Litman, T.; Druley, T.E.; Stein, W.D.; Bates, S.E. From MDR to MXR: new understanding of multidrug resistance systems, their properties and clinical significance. Cell. Mol. Life Sci., 2001, 58(7), 931-959.
[http://dx.doi.org/10.1007/PL00000912] [PMID: 11497241]
[132]
Chan, K-F.; Zhao, Y.; Chow, T.W.S.; Yan, C.S.W.; Ma, D.L.; Burkett, B.A.; Wong, I.L.K.; Chow, L.M.C.; Chan, T.H. Flavonoid dimers as bivalent modulators for p-glycoprotein-based multidrug resistance: structure-activity relationships. ChemMedChem, 2009, 4(4), 594-614.
[http://dx.doi.org/10.1002/cmdc.200800413] [PMID: 19288491]
[133]
Burns, J.M.; Dairaghi, D.J.; Deitz, M.; Tsang, M.; Schall, T.J. Comprehensive mapping of poxvirus vCCI chemokine-binding protein. Expanded range of ligand interactions and unusual dissociation kinetics. J. Biol. Chem., 2002, 277(4), 2785-2789.
[http://dx.doi.org/10.1074/jbc.M109884200] [PMID: 11696549]
[134]
Di Pietro, A.; Dayan, G.; Conseil, G.; Steinfels, E.; Krell, T.; Trompier, D.; Baubichon-Cortay, H.; Jault, J. P-glycoprotein-mediated resistance to chemotherapy in cancer cells: using recombinant cytosolic domains to establish structure-function relationships. Braz. J. Med. Biol. Res., 1999, 32(8), 925-939.
[http://dx.doi.org/10.1590/S0100-879X1999000800001] [PMID: 10454753]
[135]
Yuan, Z.P.; Chen, L.J.; Fan, L.Y.; Tang, M.H.; Yang, G.L.; Yang, H.S.; Du, X.B.; Wang, G.Q.; Yao, W.X.; Zhao, Q.M.; Ye, B.; Wang, R.; Diao, P.; Zhang, W.; Wu, H.B.; Zhao, X.; Wei, Y.Q. Liposomal quercetin efficiently suppresses growth of solid tumors in murine models. Clin. Cancer Res., 2006, 12(10), 3193-3199.
[http://dx.doi.org/10.1158/1078-0432.CCR-05-2365] [PMID: 16707620]
[136]
Kan, J.; Yan, C.; Wong, I.; Chan, K.; Chan, T.; Chow, L. 205-Pharmacokinetics and metabolite identification study of flavonoid dimer FD18: A potent P-glycoprotein modulator in reversing cancer drug resistance. Eur. J. Cancer, 2016, 69(1)(Suppl.), S71.
[http://dx.doi.org/10.1016/S0959-8049(16)32803-9]
[137]
Kan, W.Y. Characterization of in vivo activity of flavonoid dimer in modulating p-glycoprotein.. Thesis, The Hong Kong Polytechnic University:, 2015.hdl.handle.net/10397/69893]
[138]
Meng, L.; Xia, X.; Yang, Y.; Ye, J.; Dong, W.; Ma, P.; Jin, Y.; Liu, Y. Co-encapsulation of paclitaxel and baicalein in nanoemulsions to overcome multidrug resistance via oxidative stress augmentation and P-glycoprotein inhibition. Int. J. Pharm., 2016, 513(1-2), 8-16.
[http://dx.doi.org/10.1016/j.ijpharm.2016.09.001] [PMID: 27596118]
[139]
Angelini, A.; Di Ilio, C.; Castellani, M.L.; Conti, P.; Cuccurullo, F. Modulation of multidrug resistance p-glycoprotein activity by flavonoids and honokiol in human doxorubicin- resistant sarcoma cells (MES-SA/DX-5): implications for natural sedatives as chemosensitizing agents in cancer therapy. J. Biol. Regul. Homeost. Agents, 2010, 24(2), 197-205.
[PMID: 20487633]
[140]
Kim, M.K.; Park, K.S.; Choo, H.; Chong, Y. Quercetin-POM (pivaloxymethyl) conjugates: modulatory activity for P-glycoprotein-based multidrug resistance. Phytomedicine, 2015, 22(7-8), 778-785.
[http://dx.doi.org/10.1016/j.phymed.2015.05.055] [PMID: 26141765]
[141]
Boulton, D.W.; Walle, U.K.; Walle, T. Fate of the flavonoid quercetin in human cell lines: chemical instability and metabolism. J. Pharm. Pharmacol., 1999, 51(3), 353-359.
[http://dx.doi.org/10.1211/0022357991772367] [PMID: 10344638]
[142]
Kim, M.K.; Park, K.S.; Lee, C.; Park, H.R.; Choo, H.; Chong, Y. Enhanced stability and intracellular accumulation of quercetin by protection of the chemically or metabolically susceptible hydroxyl groups with a pivaloxymethyl (POM) promoiety. J. Med. Chem., 2010, 53(24), 8597-8607.
[http://dx.doi.org/10.1021/jm101252m] [PMID: 21090565]
[143]
Spencer, J.P.; Kuhnle, G.G.; Williams, R.J.; Rice-Evans, C. Intracellular metabolism and bioactivity of quercetin and its in vivo metabolites. Biochem. J., 2003, 372(Pt 1), 173-181.
[http://dx.doi.org/10.1042/bj20021972] [PMID: 12578560]
[144]
Lv, L.; Liu, C.; Chen, C.; Yu, X.; Chen, G.; Shi, Y.; Qin, F.; Ou, J.; Qiu, K.; Li, G. Quercetin and doxorubicin co-encapsulated biotin receptor-targeting nanoparticles for minimizing drug resistance in breast cancer. Oncotarget, 2016, 7(22), 32184-32199.
[http://dx.doi.org/10.18632/oncotarget.8607] [PMID: 27058756]
[145]
Kim, M.K.; Choo, H.; Chong, Y. Water-soluble and cleavable quercetin-amino acid conjugates as safe modulators for P-glycoprotein-based multidrug resistance. J. Med. Chem., 2014, 57(17), 7216-7233.
[http://dx.doi.org/10.1021/jm500290c] [PMID: 25122155]
[146]
Kim, M.K.; Kim, Y.; Choo, H.; Chong, Y. Quercetin-glutamic acid conjugate with a non-hydrolysable linker; a novel scaffold for multidrug resistance reversal agents through inhibition of P-glycoprotein. Bioorg. Med. Chem., 2017, 25(3), 1219-1226.
[http://dx.doi.org/10.1016/j.bmc.2016.12.034] [PMID: 28043777]
[147]
Harvey, A.L. Natural products in drug discovery. Drug Discov. Today, 2008, 13(19-20), 894-901.
[http://dx.doi.org/10.1016/j.drudis.2008.07.004] [PMID: 18691670]
[148]
Li, J.W-H.; Vederas, J.C. Drug discovery and natural products: end of an era or an endless frontier? Science, 2009, 325(5937), 161-165.
[http://dx.doi.org/10.1126/science.1168243] [PMID: 19589993]
[149]
Dorr, R.T. Pharmacology and toxicology of Cremophor EL diluent. Ann. Pharmacother., 1994, 28(5)(Suppl.), S11-S14.
[http://dx.doi.org/10.1177/10600280940280S503] [PMID: 7915152]
[150]
Gelderblom, H.; Verweij, J.; Nooter, K.; Sparreboom, A. Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. Eur. J. Cancer, 2001, 37(13), 1590-1598.
[http://dx.doi.org/10.1016/S0959-8049(01)00171-X] [PMID: 11527683]
[151]
Benet, L.Z.; Izumi, T.; Zhang, Y.; Silverman, J.A.; Wacher, V.J. Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery. J. Control. Release, 1999, 62(1-2), 25-31.
[http://dx.doi.org/10.1016/S0168-3659(99)00034-6] [PMID: 10518631]
[152]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[153]
Tron, G.C.; Pirali, T.; Billington, R.A.; Canonico, P.L.; Sorba, G.; Genazzani, A.A. Click chemistry reactions in medicinal chemistry: applications of the 1,3-dipolar cycloaddition between azides and alkynes. Med. Res. Rev., 2008, 28(2), 278-308.
[http://dx.doi.org/10.1002/med.20107] [PMID: 17763363]
[154]
Kolb, H.C.; Sharpless, K.B. The growing impact of click chemistry on drug discovery. Drug Discov. Today, 2003, 8(24), 1128-1137.
[http://dx.doi.org/10.1016/S1359-6446(03)02933-7] [PMID: 14678739]


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VOLUME: 26
ISSUE: 25
Year: 2019
Page: [4799 - 4831]
Pages: 33
DOI: 10.2174/0929867325666181001115225
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