The therapeutic potential of targeting ABC transporters to combat multi-drug resistance

Expert Opinion on Therapeutic Targets

Volumn 21, Issue 5, 2017, Pages 511-530

  Bugde, Piyush ^a   Biswas, Riya ^a   Merien, Fabrice ^a   Lu, Jun ^a   Liu, Dong Xu ^a   Chen, Mingwei ^b   Zhou, Shufeng ^c   Li, Yan ^a  

^a AUCKLAND UNIVERSITY OF TECHNOLOGY   (New Zealand)

^b THE FIRST AFFILIATED HOSPITAL OF XI AN JIAOTONG UNIVERSITY   (China)

^c HUAQIAO UNIVERSITY   (China)

Author keywords

ABC transporter; cancer; multidrug resistance; nanotechnology; pharmacokinetics

Indexed keywords

ABC TRANSPORTER; BREAST CANCER RESISTANCE PROTEIN; MICRORNA; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 1; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 2; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 3; MULTIDRUG RESISTANCE ASSOCIATED PROTEIN 4; MULTIDRUG RESISTANCE PROTEIN 1; MULTIDRUG RESISTANCE PROTEIN 5; ANTINEOPLASTIC AGENT;

CRISPR CAS SYSTEM; DRUG DELIVERY SYSTEM; GENE MUTATION; GENETIC POLYMORPHISM; HUMAN; MULTIDRUG RESISTANCE; NANOTECHNOLOGY; PROTEIN FUNCTION; PROTEIN METABOLISM; PROTEIN TARGETING; REGULATORY MECHANISM; REVIEW; ANIMAL; DRUG EFFECTS; DRUG RESISTANCE; GENE EXPRESSION REGULATION; GENETICS; NEOPLASMS; PATHOLOGY;

ANIMALS; ANTINEOPLASTIC AGENTS; ATP-BINDING CASSETTE TRANSPORTERS; DRUG DELIVERY SYSTEMS; DRUG RESISTANCE, MULTIPLE; DRUG RESISTANCE, NEOPLASM; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; NANOTECHNOLOGY; NEOPLASMS;

EID: 85017544185     PISSN: 14728222     EISSN: 17447631     Source Type: Journal    
DOI: 10.1080/14728222.2017.1310841     Document Type: Review

References (256)

1. Tiwari KA, Sodani K, Dai C-L, et al. Revisiting the ABCs of multidrug resistance in cancer chemotherapy. Curr Pharm Biotechnol. 2011;12(4):570–594.
2. Binkhathlan Z, Lavasanifar A., P-glycoprotein inhibition as a therapeutic approach for overcoming multidrug resistance in cancer:current status and future perspectives. Curr Cancer Drug Targets. 2013;13(3):326–346.
3. Chen Z, Shi T, Zhang L, et al. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance:a review of the past decade. Cancer Lett. 2016;370(1):153–164.
4. Baguley BC., Multiple drug resistance mechanisms in cancer. Mol Biotechnol. 2010;46(3):308–316.
5. Volm MAM. Oncogenesis. J Crit Rev. 1996;7:227–244.
6. Dietel M. What’s new in cytostatic drug resistance and pathology. Pathology-Research Pract. 1991;187(7):892–905.
7. Beck WT. Mechanisms of multidrug resistance in human tumor cells. The roles of P-glycoprotein, DNA topoisomerase II, and other factors. Cancer Treat Rev. 1990;17:11–20.
8. Morrow C, Cowan K. Glutathione S-transferases and drug resistance. Cancer Cells (Cold Spring Harbor, NY:1989). 1990;2(1):15–22.
9. Hammond JR, Johnstone RM, Gros P. Enhanced efflux of [3H] vinblastine from Chinese hamster ovary cells transfected with a full-length complementary DNA clone for the mdr1 gene. Cancer Res. 1989;49(14):3867–3871.
10. Liu Y, Han TY, Giuliano AE, et al. Ceramide glycosylation potentiates cellular multidrug resistance. Faseb J. 2001;15(3):719–730.
11. Fukuda Y, Schuetz JD. ABC transporters and their role in nucleoside and nucleotide drug resistance. Biochem Pharmacol. 2012;83(8):1073–1083.• An overview on effect of ABC transporters and their interaction with other process affecting the efficacy of nucleoside drugs.
12. Bosch I, Croop J. P-glycoprotein multidrug resistance and cancer. Biochimica Et Biophysica Acta (Bba)-Reviews on Cancer. 1996;1288(2):F37–F54.
13. Danø K. Active outward transport of daunomycin in resistant Ehrlich ascites tumor cells. Biochimica Et Biophysica Acta (Bba)-Biomembranes. 1973;323(3):466–483.
14. Fletcher JI, Haber M, Henderson MJ, et al. ABC transporters in cancer:more than just drug efflux pumps. Nat Rev Cancer. 2010;10(2):147–156.•• A recent review on significance of ABC transporters in cancer and their roles beyond drug transport
15. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.• An insightful review on the characteristic of cancer cells.
16. Jonker JW, Smit JW, Brinkhuis RF, et al. Role of breast cancer resistance protein in the bioavailability and fetal penetration of topotecan. J Natl Cancer Inst. 2000;92(20):1651–1656.
17. Leggas M, Adachi M, Scheffer GL, et al. Mrp4 confers resistance to topotecan and protects the brain from chemotherapy. Mol Cell Biol. 2004;24(17):7612–7621.
18. Paulusma CC, Bosma PJ, Zaman GJR, et al. Congenital jaundice in rats with mutation in a multidrug resistance–associated protein gene. Science. 1996;271(5252):1126.
19. Rao, V.V., Dahlheimer, J.L., Bardgett, M.E., et al. Choroid plexus epithelial expression of MDR1 P glycoprotein and multidrug resistance-associated protein contribute to the blood–cerebrospinal-fluid drug-permeability barrier. Proc Natl Acad Sci. 1999;96(7):3900–3905.
20. Schinkel A, Smit JJ, Van Tellingen O, et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell. 1994;77(4):491–502.
21. Linton K, Holland I. The ABC transporters of human physiology and disease. Singapore:World Scientific; 2011.
22. Dean M. The genetics of ATP-binding cassette transporters. Methods Enzymol. 2005;400:409–429.
23. Kim S, Saito Y, Maekawa K, et al. Thirty novel genetic variations in the SLC29A1 gene encoding human equilibrative nucleoside transporter 1 (hENT1). Drug Metab Pharmacokinet. 2006;21(3):248–256.
24. Juliano RL, Ling V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochimica Et Biophysica Acta (Bba)-Biomembranes. 1976;455(1):152–162.
25. Roninson, I.B., H.T. Abelson, D.E. Housman, N. Howell, and A. Varshavsky, Amplification of specific DNA sequences correlates with multi-drug resistance in Chinese hamster cells. Nature, 1984. 309:626–628.
26. Riordan, J.R., K. Deuchars, N. Kartner, N. Alon, J. Trent, and V. Ling, Amplification of P-glycoprotein genes in multidrug-resistant mammalian cell lines. Nature, 1985. 316(6031):817–819.
27. Loo TW, Bartlett MC, Clarke DM. Human P-glycoprotein contains a greasy ball-and-socket joint at the second transmission interface. J Biol Chem. 2013;288(28):20326–20333.
28. Schinkel AH, Jonker JW. Mammalian drug efflux transporters of the ATP binding cassette (ABC) family:an overview. Adv Drug Deliv Rev. 2003;55(1):3–29.•• Comprehensive review on pharmacological properties of ABC transporters and their inhibitors.
29. Slot AJ, Molinski SV, Cole SP. Mammalian multidrug-resistance proteins (MRPs). Essays Biochem. 2011;50:179–207.
30. Zhang YK, Wang Y-J, Gupta P, et al. Multidrug resistance proteins (MRPs) and cancer therapy. Aaps J. 2015;17(4):802–812.
31. Kim RB. Drugs as P-glycoprotein substrates, inhibitors, and inducers. Drug Metab Rev. 2002;34(1–2):47–54.
32. 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. 2006;25(4):231–259.
33. Borst P, Evers R, Kool M, et al. A family of drug transporters:the multidrug resistance-associated proteins. J Natl Cancer Inst. 2000;92(16):1295–1302.
34. 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. 2006;2(3):351–366.
35. Nies AT, Keppler D. The apical conjugate efflux pump ABCC2 (MRP2). Pflugers Arch. 2007;453(5):643–659.
36. Nies AT, Schwab M, Keppler D. Interplay of conjugating enzymes with OATP uptake transporters and ABCC/MRP efflux pumps in the elimination of drugs. Expert Opin Drug Metab Toxicol. 2008;4(5):545–568.
37. Zhou SF, Wang -L-L, Di YM, et al. Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development. Curr Med Chem. 2008;15(20):1981–2039.
38. 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. 2005;69(4):699–708.
39. Sharom FJ. The P-glycoprotein multidrug transporter. Essays Biochem. 2011;50:161–178.•• A recent review on molecular mechanism of P-glycoprotein
40. Zolnerciks JK, Andress EJ, Nicolaou M, et al. Structure of ABC transporters. Essays Biochem. 2011;50:43–61.
41. Holland IB, Blight MA. ABC-ATPases, adaptable energy generators fuelling transmembrane movement of a variety of molecules in organisms from bacteria to humans. J Mol Biol. 1999;293(2):381–399.
42. Jones PM, George AM. Mechanism of the ABC transporter ATPase domains:catalytic models and the biochemical and biophysical record. Crit Rev Biochem Mol Biol. 2013;48(1):39–50.
43. George AM, Jones PM. Perspectives on the structure–function of ABC transporters:the Switch and Constant Contact Models. Prog Biophys Mol Biol. 2012;109(3):95–107.
44. Qu Q, Sharom FJ. Proximity of bound Hoechst 33342 to the ATPase catalytic sites places the drug binding site of P-glycoprotein within the cytoplasmic membrane leaflet. Biochemistry. 2002;41(14):4744–4752.
45. Lugo MR, Sharom FJ. Interaction of LDS-751 with P-glycoprotein and mapping of the location of the R drug binding site. Biochemistry. 2005;44(2):643–655.
46. Lugo MR, Sharom FJ. Interaction of LDS-751 and rhodamine 123 with P-glycoprotein:evidence for simultaneous binding of both drugs. Biochemistry. 2005;44(42):14020–14029.
47. Lugo MR, Sharom FJ. Interaction of LDS-751 with the drug-binding site of P-glycoprotein:a Trp fluorescence steady-state and lifetime study. Arch Biochem Biophys. 2009;492(1):17–28.
48. Loo TW, Clarke DM. Mutational analysis of ABC proteins. Arch Biochem Biophys. 2008;476(1):51–64.
49. Jin MS, Oldham ML, Zhang Q, et al. Crystal structure of the multidrug transporter P-glycoprotein from Caenorhabditis elegans. Nature. 2012;490(7421):566–569.
50. Loo TW, Clarke DM. Drug rescue distinguishes between different structural models of human P-glycoprotein. Biochemistry. 2013;52(41):7167–7169.
51. Matheny CJ, Lamb MW, Brouwer KLR, et al. Pharmacokinetic and pharmacodynamic implications of P-glycoprotein modulation. Pharmacotherapy:J Hum Pharmacol Drug Ther. 2001;21(7):778–796.
52. Sharom FJ. ABC multidrug transporters:structure, function and role in chemoresistance. Pharmacogenomics. 2008;9:105–127.
53. Zhou S-F. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica. 2008;38(7–8):802–832.
54. Morrissey K, Wen CC, Johns SJ, et al. The UCSF‐FDA TransPortal:a public drug transporter database. Clin Pharmacol Ther. 2012;92(5):545–546.
55. Kathawala RJ, Gupta P, Ashby CR, et al. The modulation of ABC transporter-mediated multidrug resistance in cancer:A review of the past decade. Drug Resist Updat. 2015;18:1–17.
56. Gottesman MM, Fojo T, Bates SE. Multidrug resistance in cancer:role of ATP–dependent transporters. Nat Rev Cancer. 2002;2(1):48–58.•• Review with detailed analysis of role of ABC transporters in MDR.
57. Findling-Kagan S, Sivan H, Ostrovsky O, et al. Establishment and characterization of new cellular lymphoma model expressing transgenic human MDR1. Leuk Res. 2005;29(4):407–414.
58. Liu J, Chen H, Miller DS, et al. Overexpression of glutathione S-transferase II and multidrug resistance transport proteins is associated with acquired tolerance to inorganic arsenic. Mol Pharmacol. 2001;60(2):302–309.
59. Sauna ZE, Smith MM, Müller M, et al. The mechanism of action of multidrug-resistance-linked P-glycoprotein. J Bioenerg Biomembr. 2001;33(6):481–491.
60. Peng -X-X, Tiwari AK, Wu H-C, et al. Overexpression of P-glycoprotein induces acquired resistance to imatinib in chronic myelogenous leukemia cells. Chin J Cancer. 2012;31(2):110–118.
61. Marchetti S, De Vries NA, Buckle T, et al. Effect of the ATP-binding cassette drug transporters ABCB1, ABCG2, and ABCC2 on erlotinib hydrochloride (Tarceva) disposition in in vitro and in vivo pharmacokinetic studies employing Bcrp1−/−/Mdr1a/1b−/−(triple-knockout) and wild-type mice. Mol Cancer Ther. 2008;7(8):2280–2287.
62. Schinkel AH, Mayer U, Wagenaar E, et al. Normal viability and altered pharmacokinetics in mice lacking mdr1-type (drug-transporting) P-glycoproteins. Proc Natl Acad Sci. 1997;94(8):4028–4033.
63. Alvarez M, Paull K, Monks A, et al. Generation of a drug resistance profile by quantitation of mdr-1/P-glycoprotein in the cell lines of the National Cancer Institute Anticancer Drug Screen. J Clin Investig. 1995;95(5):2205–2214.
64. Schöndorf T., Kurbacher CM, Göhring UJ, et al. Induction of MDR1-gene expression by antineoplastic agents in ovarian cancer cell lines. Anticancer Res. 2001;22(4):2199–2203.
65. Schöndorf T, Scharl A, Kurbacher CM, et al. Amplification of the mdr1-gene is uncommon in recurrent ovarian carcinomas. Cancer Lett. 1999;146(2):195–199.
66. Parekh H, Wiesen K, Simpkins H. Acquisition of taxol resistance via P-glycoprotein-and non-P-glycoprotein-mediated mechanisms in human ovarian carcinoma cells. Biochem Pharmacol. 1997;53(4):461–470.
67. Xu X, Leo C, Jang Y, et al. Dominant effector genetics in mammalian cells. Nat Genet. 2001;27(1):23–29.
68. Choi K, Chen CJ, Kriegler M, et al. An altered pattern of cross-resistance in multidrug-resistant human cells results from spontaneous mutations in the mdr1 (P-glycoprotein) gene. Cell. 1988;53(4):519–529.
69. Devine SE, Ling V, Melera PW. Amino acid substitutions in the sixth transmembrane domain of P-glycoprotein alter multidrug resistance. Proc Natl Acad Sci. 1992;89(10):4564–4568.
70. Gros P, Dhir R, Croop J, et al. A single amino acid substitution strongly modulates the activity and substrate specificity of the mouse mdr1 and mdr3 drug efflux pumps. Proc Natl Acad Sci. 1991;88(16):7289–7293.
71. Mickley LA, Spengler BA, Knutsen TA, et al. Gene rearrangement:a novel mechanism for MDR-1 gene activation. J Clin Investig. 1997;99(8):1947–1957.
72. Coley HM. Overcoming multidrug resistance in cancer:clinical studies of p-glycoprotein inhibitors. Multi-Drug Resis Cancer. 2010;596:341–358.
73. Tan B, Piwnica-Worms D, Ratner L. Multidrug resistance transporters and modulation. Curr Opin Oncol. 2000;12(5):450–458.
74. Leonard GD, Fojo T, Bates SE. The role of ABC transporters in clinical practice. The Oncologist. 2003;8(5):411–424.
75. Szakács G, Paterson JK, Ludwig JA, et al. Targeting multidrug resistance in cancer. Nat Rev Drug Discov. 2006;5(3):219–234.
76. Tsuruo T, Hamada H, Sato S, et al. Inhibition of multidrug resistant human tumor growth in athymic mice by anti p-glycoprotein monoclonal antibodies. Jpn J Cancer Res. 1989;80(7):627–631.
77. Köhler S, Stein WD. Optimizing chemotherapy by measuring reversal of P-glycoprotein activity in plasma membrane vesicles. Biotechnol Bioeng. 2003;81(5):507–517.
78. Ozols RF, Cunnion RE, Klecker RW, et al. Verapamil and adriamycin in the treatment of drug-resistant ovarian cancer patients. J Clin Oncol. 1987;5(4):641–647.
79. Chan HS, DeBoer G, Thiessen JJ, et al. Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation. Clin Cancer Res. 1996;2(9):1499–1508.
80. List AF, Kopecky KJ, Willman CL, et al. Benefit of cyclosporine modulation of drug resistance in patients with poor-risk acute myeloid leukemia:a Southwest Oncology Group study. Blood. 2001;98(12):3212–3220.
81. Li G-Y, Liu J-Z, Zhang B, et al. Cyclosporine diminishes multidrug resistance in K562/ADM cells and improves complete remission in patients with acute myeloid leukemia. Biomed Pharmacother. 2009;63(8):566–570.
82. Sonneveld P, Suciu S, Weijermans P, et al. Cyclosporin A combined with vincristine, doxorubicin and dexamethasone (VAD) compared with VAD alone in patients with advanced refractory multiple myeloma:an EORTC–HOVON randomized phase III study (06914). Br J Haematol. 2001;115(4):895–902.
83. Warner E, Tobe SW, Andrulis IL, et al. Phase I-II study of vinblastine and oral cyclosporin A in metastatic renal cell carcinoma. Am J Clin Oncol. 1995;18(3):251–256.
84. Weber D, Dimopoulos M, Sinicrope F, et al. VAD-cyclosporine therapy for VAD-resistant multiple myeloma. Leuk Lymphoma. 1995;19(1–2):159–163.
85. Darby AJ, Callaghan R,R, McMahon RM. P-glycoprotein inhibition:the past, the present and the future. Curr Drug Metab. 2011;12(8):722–731.
86. Ries F, Dicato M. Treatment of advanced and refractory breast cancer with doxorubicin, vincristine and continuous infusion of verapamil. A phase I-II clinical trial. Med Oncol Tumor Pharmacother. 1991;8(1):39–43.
87. Yahanda AM, Alder KM, Fisher GA, et al. Phase I trial of etoposide with cyclosporine as a modulator of multidrug resistance. J Clin Oncol. 1992;10(10):1624–1634.
88. Sonneveld P, Schoester M, De Leeuw K. Clinical modulation of multidrug resistance in multiple myeloma:effect of cyclosporine on resistant tumor cells. J Clin Oncol. 1994;12(8):1584–1591.
89. Nobili S, Landini I, Giglioni B, et al. Pharmacological strategies for overcoming multidrug resistance. Curr Drug Targets. 2006;7(7):861–879.
90. Nobili S, Landini I, Mazzei T, et al. Overcoming tumor multidrug resistance using drugs able to evade P‐glycoprotein or to exploit its expression. Med Res Rev. 2012;32(6):1220–1262.
91. Palmeira A, Sousa E, Vasconcelos MH, et al. Three decades of P-gp inhibitors:skimming through several generations and scaffolds. Curr Med Chem. 2012;19(13):1946–2025.
92. Shaffer BC, Gillet J-P, Patel C, et al. Drug resistance:still a daunting challenge to the successful treatment of AML. Drug Resist Updat. 2012;15(1):62–69.
93. Chico I, Kang MH, Bergan R, et al. Phase I study of infusional paclitaxel in combination with the P-glycoprotein antagonist PSC 833. J Clin Oncol. 2001;19(3):832–842.
94. Lum BL, Gosland MP. MDR expression in normal tissues. Pharmacologic implications for the clinical use of P-glycoprotein inhibitors. Hematol Oncol Clin North Am. 1995;9(2):319–336.
95. Minderman H, O’Loughlin KL, Pendyala L, et al. VX-710 (biricodar) increases drug retention and enhances chemosensitivity in resistant cells overexpressing P-glycoprotein, multidrug resistance protein, and breast cancer resistance protein. Clin Cancer Res. 2004;10(5):1826–1834.
96. Gandhi L, Harding MW, Neubauer M, et al. A phase II study of the safety and efficacy of the multidrug resistance inhibitor VX-710 combined with doxorubicin and vincristine in patients with recurrent small cell lung cancer. Cancer. 2007;109(5):924–932.
97. Saeki T, Nomizu T, Toi M, et al. Dofequidar fumarate (MS-209) in combination with cyclophosphamide, doxorubicin, and fluorouracil for patients with advanced or recurrent breast cancer. J Clin Oncol. 2007;25(4):411–417.
98. Hyafil F, Vergely C, Du Vignaud P, et al. In vitro and in vivo reversal of multidrug resistance by GF120918, an acridonecarboxamide derivative. Cancer Res. 1993;53(19):4595–4602.
99. Thomas H, Coley HM. Overcoming multidrug resistance in cancer:an update on the clinical strategy of inhibiting p-glycoprotein. Cancer Cont. 2003;10(2):159–159.
100. Dantzig A, Shepard RL, Law KL, et al. Selectivity of the multidrug resistance modulator, LY335979, for P-glycoprotein and effect on cytochrome P-450 activities. J Pharmacol Exp Ther. 1999;290(2):854–862.
101. Fracasso PM, Goldstein LJ, De Alwis DP, et al. Phase I study of docetaxel in combination with the P-glycoprotein inhibitor, zosuquidar, in resistant malignancies. Clin Cancer Res. 2004;10(21):7220–7228.
102. Martin C, Berridge G, Mistry P, et al. The molecular interaction of the high affinity reversal agent XR9576 with P-glycoprotein. Br J Pharmacol. 1999;128(2):403–411.
103. Mistry P, Stewart AJ, Dangerfield W, et al. In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576. Cancer Res. 2001;61(2):749–758.
104. Kruijtzer CM, Beijnen JH, Rosing H, et al. Increased oral bioavailability of topotecan in combination with the breast cancer resistance protein and P-glycoprotein inhibitor GF120918. J Clin Oncol. 2002;20(13):2943–2950.
105. Kuppens IE, Witteveen EO, Jewell RC, et al. A phase I, randomized, open-label, parallel-cohort, dose-finding study of elacridar (GF120918) and oral topotecan in cancer patients. Clin Cancer Res. 2007;13(11):3276–3285.
106. Dantzig AH, Shepard RL, Cao J, et al. Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979. Cancer Res. 1996;56(18):4171–4179.
107. Gerrard G, Payne E, Baker RJ, et al. Clinical effects and P-glycoprotein inhibition in patients with acute myeloid leukemia treated with zosuquidar trihydrochloride, daunorubicin and cytarabine. Haematologica. 2004;89(7):782–790.
108. Morschhauser F, Zinzani PL, Burgess M, et al. Phase I/II trial of a P-glycoprotein inhibitor, Zosuquidar.3HCl trihydrochloride (LY335979), given orally in combination with the CHOP regimen in patients with non-Hodgkin’s lymphoma. Leuk Lymphoma. 2007;48(4):708–715.
109. Cripe LD, Uno H, Paietta EM, et al. Zosuquidar, a novel modulator of P-glycoprotein, does not improve the outcome of older patients with newly diagnosed acute myeloid leukemia:a randomized, placebo-controlled trial of the Eastern Cooperative Oncology Group 3999. Blood. 2010;116(20):4077–4085.
110. Mistry P, Stewart AJ, Dangerfield W, et al. In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576. Cancer Res. 2001;61(2):749–758.
111. Pusztai L, Wagner P, Ibrahim N, et al. Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carcinoma. Cancer. 2005;104(4):682–691.
112. Kadioglu O, Saeed MEM, Valoti M, et al. Interactions of human P-glycoprotein transport substrates and inhibitors at the drug binding domain:functional and molecular docking analyses. Biochem Pharmacol. 2016;104:42–51.
113. Cole S, Bhardwaj G, Gerlach J, et al. Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line. Science-New York Then Washington-. 1992;258:1650–1650.
114. Zhao Y, Butler EB, Tan M. Targeting cellular metabolism to improve cancer therapeutics. Cell Death Dis. 2013;4:e532.
115. Sodani K, Patel A, Kathawala RJ, et al. Multidrug resistance associated proteins in multidrug resistance. Chin J Cancer. 2012;31(2):58.
116. Cole SP, Sparks KE, Fraser K, et al. Pharmacological characterization of multidrug resistant MRP-transfected human tumor cells. Cancer Res. 1994;54(22):5902–5910.
117. Ishikawa T. The ATP-dependent glutathione S-conjugate export pump. Trends Biochem Sci. 1992;17(11):463–468.
118. Brevig T, Krühne U, Kahn RA, et al. Hydrodynamic guiding for addressing subsets of immobilized cells and molecules in microfluidic systems. BMC Biotechnol. 2003;3(1):1.
119. Sun Y-L, Patel A, Kumar P, et al. Role of ABC transporters in cancer chemotherapy. Chin J Cancer. 2012;31(2):51.
120. Zhou S-F, Wang -L-L, Di YM, et al. Substrates and inhibitors of human multidrug resistance associated proteins and the implications in drug development. Curr Med Chem. 2008;15(20):1981–2039.
121. Jemnitz K, Heredi-Szabo K, Janossy J, et al. ABCC2/Abcc2:a multispecific transporter with dominant excretory functions. Drug Metab Rev. 2010;42(3):402–436.
122. Mayer R, Kartenbeck J, Büchler M, et al. Expression of the MRP gene-encoded conjugate export pump in liver and its selective absence from the canalicular membrane in transport-deficient mutant hepatocytes. J Cell Biol. 1995;131(1):137–150.
123. Schaub TP, Kartenbeck J, König J, et al. Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma. J Am Soc Nephrol. 1999;10(6):1159–1169.
124. Schaub TP, Kartenbeck J, König J, et al. Expression of the MRP2 gene-encoded conjugate export pump in human kidney proximal tubules and in renal cell carcinoma. J Am Soc Nephrol. 1999;10(6):1159–1169.
125. Zamek-Gliszczynski MJ, Hoffmaster KA, Nezasa K-I, et al. Integration of hepatic drug transporters and phase II metabolizing enzymes:mechanisms of hepatic excretion of sulfate, glucuronide, and glutathione metabolites. European J Pharmaceut Sci. 2006;27(5):447–486.
126. Cui Y, König J, Buchholz JK, et al. Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol Pharmacol. 1999;55(5):929–937.
127. Taniguchi K, Wada M, Kohno K, et al. A human canalicular multispecific organic anion transporter (cMOAT) gene is overexpressed in cisplatin-resistant human cancer cell lines with decreased drug accumulation. Cancer Res. 1996;56(18):4124–4129.
128. Haufroid V. Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCC2 and their impact on drug disposition. Curr Drug Targets. 2011;12(5):631–646.
129. Borst P, Elferink RO. Mammalian ABC transporters in health and disease. Annu Rev Biochem. 2002;71:537–592.
130. Chu XY, Kato Y, Niinuma K, et al. Multispecific organic anion transporter is responsible for the biliary excretion of the camptothecin derivative irinotecan and its metabolites in rats. J Pharmacol Exp Ther. 1997;281(1):304–314.
131. Keitel V, Kartenbeck J, Nies AT, et al. Impaired protein maturation of the conjugate export pump multidrug resistance protein 2 as a consequence of a deletion mutation in Dubin-Johnson syndrome. Hepatology. 2000;32(6):1317–1328.
132. Konig J, Nies AT, Cui Y, et al. Conjugate export pumps of the multidrug resistance protein (MRP) family:localization, substrate specificity, and MRP2-mediated drug resistance. Biochim Biophys Acta. 1999;1461(2):377–394.
133. Myint K, Li Y, Paxton J, et al. Multidrug resistance-associated protein 2 (MRP2) mediated transport of oxaliplatin-derived platinum in membrane vesicles. Plos One. 2015;10(7):e0130727.
134. Koike K, Kawabe T, Tanaka T, et al. A canalicular multispecific organic anion transporter (cMOAT) antisense cDNA enhances drug sensitivity in human hepatic cancer cells. Cancer Res. 1997;57(24):5475–5479.
135. Leslie EM, Deeley RG, Cole SP. Multidrug resistance proteins:role of P-glycoprotein, MRP1, MRP2, and BCRP (ABCG2) in tissue defense. Toxicol Appl Pharmacol. 2005;204(3):216–237.
136. 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. 2002;302(2):407–415.
137. Matsson P, Pedersen JM, Norinder U, et al. 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. 2009;26(8):1816–1831.
138. 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. 2003;16(12):1642–1651.
139. Kiuchi Y, Suzuki H, Hirohashi T, et al. cDNA cloning and inducible expression of human multidrug resistance associated protein 3 (MRP3). FEBS Lett. 1998;433(1):149–152.
140. 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. 1997;57(16):3537–3547.
141. Scheffer GL, Kool M, De Haas M, et al. Tissue distribution and induction of human multidrug resistant protein 3. Lab Investigation. 2002;82(2):193–201.
142. König J, Rost D, Cui Y, et al. Characterization of the human multidrug resistance protein isoform MRP3 localized to the basolateral hepatocyte membrane. Hepatology. 1999;29(4):1156–1163.
143. Rost D, König J, Weiss G, et al. Expression and localization of the multidrug resistance proteins MRP2 and MRP3 in human gallbladder epithelia. Gastroenterology. 2001;121(5):1203–1208.
144. Kool M, van der Linden M, De Haas M, et al. MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc Natl Acad Sci. 1999;96(12):6914–6919.
145. Zeng H, Bain LJ, Belinsky MG, et al. Expression of multidrug resistance protein-3 (multispecific organic anion transporter-D) in human embryonic kidney 293 cells confers resistance to anticancer agents. Cancer Res. 1999;59(23):5964–5967.
146. Zelcer N, Saeki T, Reid G, et al. Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). J Biol Chem. 2001;276(49):46400–46407.
147. Borst P, Balzarini J, Ono N, et al. The potential impact of drug transporters on nucleoside-analog-based antiviral chemotherapy. Antiviral Res. 2004;62(1):1–7.
148. Schuetz JD, Connelly MC, Sun D, et al. MRP4:a previously unidentified factor in resistance to nucleoside-based antiviral drugs. Nat Med. 1999;5(9):1048–1051.
149. Robbins BL, Connelly MC, Marshall DR, et al. A human T lymphoid cell variant resistant to the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl) adenine shows a unique combination of a phosphorylation defect and increased efflux of the agent. Mol Pharmacol. 1995;47(2):391–397.
150. Alt FW, Kellems RE, Bertino JR, et al. Selective multiplication of dihydrofolate reductase genes in methotrexate-resistant variants of cultured murine cells. J Biol Chem. 1978;253(5):1357–1370.
151. Schimke RT, Kaufman RJ, Alt FW, et al. Gene amplification and drug resistance in cultured murine cells. Science. 1978;202(4372):1051–1055.
152. Schimke RT. Gene amplification, drug resistance, and cancer. Cancer Res. 1984;44(5):1735–1742.
153. Zalatnai A. and Molnar J. Molecular background of chemoresistance in pancreatic cancer. in vivo, 2007;21(2):339–347.
154. Van Aubel RA, Smeets PHE, Peters JGP, et al. The MRP4/ABCC4 gene encodes a novel apical organic anion transporter in human kidney proximal tubules:putative efflux pump for urinary cAMP and cGMP. J Am Soc Nephrol. 2002;13(3):595–603.
155. Sassi Y, Lipskaia L, Vandecasteele G, et al. Multidrug resistance-associated protein 4 regulates cAMP-dependent signaling pathways and controls human and rat SMC proliferation. J Clin Invest. 2008;118(8):2747–2757.
156. Borst P, De Wolf C, van de Wetering K. Multidrug resistance-associated proteins 3, 4, and 5. Pflügers Archiv-European J Physiol. 2007;453(5):661–673.
157. Reid G, Wielinga P, Zelcer N, et al. The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci. 2003;100(16):9244–9249.
158. Lin ZP, Zhu YL, Johnson DR, et al., Disruption of cAMP and PGE2 transport by Mrp4 deficiency alters cAMP-mediated signaling and nociceptive response. Molecular Pharmacology, 2007;91(5).
159. Hanaka H, Pawelzik S-C, Johnsen JI, et al. Microsomal prostaglandin E synthase 1 determines tumor growth in vivo of prostate and lung cancer cells. Proc Natl Acad Sci. 2009;106(44):18757–18762.
160. Wielinga P, Reid G, Challa EE, et al. Thiopurine metabolism and identification of the thiopurine metabolites transported by MRP4 and MRP5 overexpressed in human embryonic kidney cells. Mol Pharmacol. 2002;62(6):1321–1331.
161. Zhu Q, Feng C, Liao W, et al. Target delivery of MYCN siRNA by folate-nanoliposomes delivery system in a metastatic neuroblastoma model. Cancer cell int. 2013;13(1):65.
162. Reid G, Wielinga P, Zelcer N, et al. Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Mol Pharmacol. 2003;63(5):1094–1103.
163. Wijnholds J, Mol CAAM, Van Deemter L, et al. Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc Natl Acad Sci. 2000;97(13):7476–7481.
164. Dean M. The human auditory brain-stem response to high click rates:aging effects. Am J Audiol. 2002;11:12–12.
165. Pratt S, Shepard RL, Kandasamy RA, et al. The multidrug resistance protein 5 (ABCC5) confers resistance to 5-fluorouracil and transports its monophosphorylated metabolites. Mol Cancer Ther. 2005;4(5):855–863.
166. Oguri T, Achiwa H, Sato S, et al. The determinants of sensitivity and acquired resistance to gemcitabine differ in non–small cell lung cancer:a role of ABCC5 in gemcitabine sensitivity. Mol Cancer Ther. 2006;5(7):1800–1806.
167. Sho M., Adachi M, Taki T, et al. Transmembrane 4 superfamily as a prognostic factor in pancreatic cancer. International journal of cancer, 1998. 79(5):509-516.
168. Deeley RG, Westlake C, Cole SP. Transmembrane transport of endo-and xenobiotics by mammalian ATP-binding cassette multidrug resistance proteins. Physiol Rev. 2006;86(3):849–899.
169. Berge KE, Tian H, Graf GA, et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science. 2000;290(5497):1771–1775.
170. Lee M-H, Lu K, Hazard S, et al. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet. 2001;27(1):79–83.
171. Jani M, Ambrus C, Magnan R, et al. Structure and function of BCRP, a broad specificity transporter of xenobiotics and endobiotics. Arch Toxicol. 2014;88(6):1205–1248.
172. Mao Q, Unadkat JD. Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport—an update. Aaps J. 2015;17(1):65–82.
173. König J, Müller F, Fromm MF. Transporters and drug-drug interactions:important determinants of drug disposition and effects. Pharmacol Rev. 2013;65(3):944–966.
174. Mo W., Liu JY, Zhang J, et al. Biochemistry and pharmacology of human ABCC1/MRP1 and its role in detoxification and in multidrug resistance of cancer chemotherapy. In:Recent advances in cancer research and therapy. Amsterdam, The Netherlands:Elsevier; 2012. p. 371–404.
175. Doyle LA, Yang W, Abruzzo LV, et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci. 1998;95(26):15665–15670.•• Mitoxantrone resistance explained by cloning ABCG2.
176. Lee JS, Scala S, Matsumoto Y, et al. Reduced drug accumulation and multidrug resistance in human breast cancer cells without associated P-glycoprotein or MRP overexpression. J Cell Biochem. 1997;65(4):513–526.
177. Chen YN, Mickley LA, Schwartz AM, et al. Characterization of adriamycin-resistant human breast cancer cells which display overexpression of a novel resistance-related membrane protein. J Biol Chem. 1990;265(17):10073–10080.
178. Özvegy C, Litman T, Szakács G, et al. Functional characterization of the human multidrug transporter, ABCG2, expressed in insect cells. Biochem Biophys Res Commun. 2001;285(1):111–117.
179. Sarkadi B, Homolya L, Szakács G, et al. Human multidrug resistance ABCB and ABCG transporters:participation in a chemoimmunity defense system. Physiol Rev. 2006;86(4):1179–1236.•• A detailed and insightful review on ABC transporters and their role in drug resistance.
180. Krishnamurthy P, Ross DD, Nakanishi T, et al. The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. J Biol Chem. 2004;279(23):24218–24225.
181. Woodward OM, Kottgen A, Coresh J, et al. Identification of a urate transporter, ABCG2, with a common functional polymorphism causing gout. Proc Natl Acad Sci. 2009;106(25):10338–10342.
182. Ding X-W, Wu J-H, Jiang C-P. ABCG2:a potential marker of stem cells and novel target in stem cell and cancer therapy. Life Sciences. 2010;86(17):631–637.
183. Brózik A, Hegedüs C, Erdei Z, et al. Tyrosine kinase inhibitors as modulators of ATP binding cassette multidrug transporters:substrates, chemosensitizers or inducers of acquired multidrug resistance? Expert Opin Drug Metab Toxicol. 2011;7(5):623–642.
184. Cusatis G, Gregorc V, Li J, et al. Pharmacogenetics of ABCG2 and adverse reactions to gefitinib. J Natl Cancer Inst. 2006;98(23):1739–1742.
185. Hegedus C, Ozvegy-Laczka C, Szakács G, et al. Interaction of ABC multidrug transporters with anticancer protein kinase inhibitors:substrates and/or inhibitors? Curr Cancer Drug Targets. 2009;9(3):252–272.
186. Maliepaard M, Scheffer GL, Faneyte IF, et al. Subcellular localization and distribution of the breast cancer resistance protein transporter in normal human tissues. Cancer Res. 2001;61(8):3458–3464.
187. Scheffer GL, Maliepaard M, Pijnenborg AC, et al. Breast cancer resistance protein is localized at the plasma membrane in mitoxantrone-and topotecan-resistant cell lines. Cancer Res. 2000;60(10):2589–2593.
188. Rocchi E, Khodjakov A, Volk EL, et al. The product of the ABC half-transporter gene ABCG2 (BCRP/MXR/ABCP) is expressed in the plasma membrane. Biochem Biophys Res Commun. 2000;271(1):42–46.
189. Allen JD, Brinkhuis RF, Wijnholds J, et al. The mouse Bcrp1/Mxr/Abcp gene amplification and overexpression in cell lines selected for resistance to topotecan, mitoxantrone, or doxorubicin. Cancer Res. 1999;59(17):4237–4241.
190. Voutsadakis IA. Molecular predictors of gemcitabine response in pancreatic cancer. World J Gastrointest Oncol. 2011;3(11):153–164.
191. Li D, Xie K, Wolff R, et al. Pancreatic cancer. The Lancet. 2004;363(9414):1049–1057.
192. Reid G, Wielinga P, Zelcer N, et al., Characterization of the transport of nucleoside analog drugs by the human multidrug resistance proteins MRP4 and MRP5. Molecular Pharmacology, 2003;63(5):1094–1103.
193. Jordheim LP, Durantel D, Zoulim F, et al. Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat Rev Drug Discov. 2013;12(6):447–464.
194. Robey RW, Honjo Y, van de Laar A, et al. A functional assay for detection of the mitoxantrone resistance protein, MXR (ABCG2). Biochimica Et Biophysica Acta (Bba)-Biomembranes. 2001;1512(2):171–182.
195. Honjo Y, Hrycyna CA, Yan QW, et al. Acquired mutations in the MXR/BCRP/ABCP gene alter substrate specificity in MXR/BCRP/ABCP-overexpressing cells. Cancer Res. 2001;61(18):6635–6639.
196. Samalin E, Bouché O, Thézenas S, et al. Sorafenib and irinotecan (NEXIRI) as second- or later-line treatment for patients with metastatic colorectal cancer and KRAS-mutated tumours:a multicentre phase I/II trial. Br J Cancer. 2014;110(5):1148–1154.
197. Stacy AE, Jansson PJ, Richardson DR. Molecular pharmacology of ABCG2 and its role in chemoresistance. Mol Pharmacol. 2013;84(5):655–669.
198. Morisaki K, Robey RW, Ozvegy-Laczka C, et al. Single nucleotide polymorphisms modify the transporter activity of ABCG2. Cancer Chemother Pharmacol. 2005;56(2):161–172.• Insightful review on polymorphism of BCRP
199. Özvegy C, Váradi A, Sarkadi B. Characterization of drug transport, ATP hydrolysis, and nucleotide trapping by the human ABCG2 multidrug transporter modulation of substrate specificity by a point mutation. J Biol Chem. 2002;277(50):47980–47990.
200. Yu M, Ocana A, Tannock IF. 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.
201. Yu M, Ocana A, Tannock IF. Reversal of ATP-binding cassette drug transporter activity to modulate chemoresistance:why has it failed to provide clinical benefit? Cancer Meta Rev. 2013;32(1–2):211–227.
202. Ueda K. ABC proteins protect the human body and maintain optimal health. Biosci Biotechnol Biochem. 2011;75(3):401–409.
203. Fromm MF. Importance of P-glycoprotein at blood–tissue barriers. Trends Pharmacol Sci. 2004;25(8):423–429.
204. Patel J, Mitra AK. Strategies to overcome simultaneous P-glycoprotein mediated efflux and CYP3A4 mediated metabolism of drugs. Pharmacogenomics. 2001;2(4):401–415.
205. Eckford PD, Sharom FJ. ABC efflux pump-based resistance to chemotherapy drugs. Chem Rev. 2009;109(7):2989–3011.
206. Eckford PD, Sharom FJ. ABC efflux pump-based resistance to chemotherapy drugs. Chem Rev. 2009;109(7):2989–3011.
207. Roy S, Kenny E, Kennedy S, et al. MDR1/P-glycoprotein and MRP-1 mRNA and protein expression in non-small cell lung cancer. Anticancer Res. 2007;27(3A):1325–1330.
208. Li J, Li Z-N, Du Y-J, et al. Expression of MRP1, BCRP, LRP, and ERCC1 in advanced non-small-cell lung cancer:correlation with response to chemotherapy and survival. Clin Lung Cancer. 2009;10(6):414–421.
209. Robey RW, Steadman K, Polgar O, et al. Pheophorbide a is a specific probe for ABCG2 function and inhibition. Cancer Res. 2004;64(4):1242–1246.
210. Gottesman MM, Lavi O, Hall MD, et al. Toward a better understanding of the complexity of cancer drug resistance. Annu Rev Pharmacol Toxicol. 2016;56:85–102.•• Review has in-depth analysis of cardinal features of drug resistance in clinical cancer.
211. Yang K, Fu L-W. Mechanisms of resistance to BCR–ABL TKIs and the therapeutic strategies:a review. Crit Rev Oncol Hematol. 2015;93(3):277–292.
212. Druker BJ, Talpaz M, Resta DJ, et al. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med. 2001;2001(344):1031–1037.
213. Galaverna F, Ghiggi C, Guolo F, et al. Management of early stage chronic myeloid leukemia:state-of-the-art approach and future perspectives. Curr Cancer Drug Targets. 2013;13(7):749–754.
214. Weisberg E, Manley PW, Breitenstein W, et al. Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl. Cancer Cell. 2005;7(2):129–141.
215. Davies H, Bignell GR, Cox C, et al. Mutations of the BRAF gene in human cancer. Nature. 2002;417(6892):949–954.
216. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448(7153):561–566.
217. Van Beijnum JR, Nowak-Sliwinska P, Huijbers EJM, et al. The great escape; the hallmarks of resistance to antiangiogenic therapy. Pharmacol Rev. 2015;67(2):441–461.
218. Wu C-P, Calcagno AM, Ambudkar SV. Reversal of ABC drug transporter-mediated multidrug resistance in cancer cells:evaluation of current strategies. Curr Mol Pharmacol. 2008;1(2):93–105.
219. Cong L, Ran FA, Cox D, et al. Multiplex genome engineering using CRISPR/Cas systems. Science. 2013;339(6121):819–823.
220. Liu T, Li Z, Zhang Q, et al. Targeting ABCB1 (MDR1) in multi-drug resistant osteosarcoma cells using the CRISPR-Cas9 system to reverse drug resistance. Oncotarget, 2016;7(50):83502–83513.
221. Fisher M, Abramov M, Van Aerschot A, et al. Inhibition of MDR1 expression with altritol-modified siRNAs. Nucleic Acids Res. 2007;35(4):1064–1074.
222. Li H, Zhou S, Li T, et al. Suppression of BCRP expression and restoration of sensitivity to chemotherapy in multidrug-resistant HCC cell line HEPG2/ADM by RNA interference. Hepato-Gastroenterology. 2012;59(119):2238–2242.
223. Perez J, Bardin C, Rigal C, et al. Anti-MDR1 siRNA restores chemosensitivity in chemoresistant breast carcinoma and osteosarcoma cell lines. Anticancer Res. 2011;31(9):2813–2820.
224. Wu H, Hait WN, Yang J-M. Small interfering RNA-induced suppression of MDR1 (P-glycoprotein) restores sensitivity to multidrug-resistant cancer cells. Cancer Res. 2003;63(7):1515–1519.
225. Eckstein F. The versatility of oligonucleotides as potential therapeutics. Expert Opin Biol Ther. 2007;7(7):1021–1034.
226. Zhang G, Wang Z, Qian F, et al. Silencing of the ABCC4 gene by RNA interference reverses multidrug resistance in human gastric cancer. Oncology Reports. 2015;33(3):1147–1154.
227. Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6(11):857–866.
228. Bao L, Hazari S, Mehra S, et al. Increased expression of P-glycoprotein and doxorubicin chemoresistance of metastatic breast cancer is regulated by miR-298. Am J Pathol. 2012;180(6):2490–2503.
229. Hong L, Han Y, Zhang H, et al. The prognostic and chemotherapeutic value of miR-296 in esophageal squamous cell carcinoma. Ann Surg. 2010;251(6):1056–1063.
230. Zhu H, Wu H, Liu X, et al. Role of microRNA miR-27a and miR-451 in the regulation of MDR1/P-glycoprotein expression in human cancer cells. Biochem Pharmacol. 2008;76(5):582–588.
231. Li W, Zhang H, Assaraf YG, et al. Overcoming ABC transporter-mediated multidrug resistance:molecular mechanisms and novel therapeutic drug strategies. Drug Resist Updat. 2016;27:14–29.
232. Abba M.L, Patil N, Leupold JH, et al. MicroRNAs as novel targets and tools in cancer therapy. Cancer letters, 2017;387:84–94.
233. Bar-Zeev M, Assaraf YG, Livney YD. β-Casein nanovehicles for oral delivery of chemotherapeutic drug combinations overcoming P-glycoprotein-mediated multidrug resistance in human gastric cancer cells. Oncotarget. 2016.
234. Livney YD, Assaraf YG. Rationally designed nanovehicles to overcome cancer chemoresistance. Adv Drug Deliv Rev. 2013;65(13):1716–1730.
235. Shapira A, Davidson I, Avni N, et al. β-Casein nanoparticle-based oral drug delivery system for potential treatment of gastric carcinoma:stability, target-activated release and cytotoxicity. Eur J Pharmaceutics Biopharmaceutics. 2012;80(2):298–305.
236. Sun T, Zhang YS, Pang B, et al. Engineered nanoparticles for drug delivery in cancer therapy. Angewandte Chemie Int Edit. 2014;53(46):12320–12364.
237. Yang X, Singh A, Choy E, et al. MDR1 siRNA loaded hyaluronic acid-based CD44 targeted nanoparticle systems circumvent paclitaxel resistance in ovarian cancer. Scientific reports, 2015;5:8509.
238. Zhang M, Akbulut M. Adsorption, desorption, and removal of polymeric nanomedicine on and from cellulose surfaces:effect of size. Langmuir. 2011;27(20):12550–12559.
239. Fang J, Nakamura H, Maeda H. The EPR effect:unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev. 2011;63(3):136–151.
240. Zhang -T-T, Li W, Meng G, et al. Strategies for transporting nanoparticles across the blood–brain barrier. Biomater Science. 2016;4(2):219–229.
241. Kapse-Mistry S., Govender T, Srivastava R, et al. Nanodrug delivery in reversing multidrug resistance in cancer cells. Front Pharmacol. 2014;5:159.
242. Li Z, Liu K, Sun P, et al. Poly (D, L-lactide-co-glycolide)/montmorillonite nanoparticles for improved oral delivery of exemestane. J Microencapsul. 2013;30(5):432–440.
243. Park JW. Liposome-based drug delivery in breast cancer treatment. Breast Cancer Res. 2002;4(3):1.
244. Ogawara K-I, Un K, Tanaka K-I, et al. In vivo anti-tumor effect of PEG liposomal doxorubicin (DOX) in DOX-resistant tumor-bearing mice:involvement of cytotoxic effect on vascular endothelial cells. J Control Release. 2009;133(1):4–10.
245. Krishna R, Mayer LD. Liposomal doxorubicin circumvents PSC 833-free drug interactions, resulting in effective therapy of multidrug-resistant solid tumors. Cancer Res. 1997;57(23):5246–5253.
246. Kaye SB. Reversal of drug resistance in ovarian cancer:where do we go from here? J Clin Oncol. 2008;26(16):2616–2618.
247. Shaffer BC, Gillet J-P, Patel C, et al. Drug resistance:still a daunting challenge to the successful treatment of AML. Drug Resist Updat. 2012;15(1–2):62–69.
248. Norman BH, Lander PA, Gruber JM, et al. Cyclohexyl-linked tricyclic isoxazoles are potent and selective modulators of the multidrug resistance protein (MRP1). Bioorg Med Chem Lett. 2005;15(24):5526–5530.
249. O’Connor R, O’Leary M, Ballot J, et al. A phase I clinical and pharmacokinetic study of the multi-drug resistance protein-1 (MRP-1) inhibitor sulindac, in combination with epirubicin in patients with advanced cancer. Cancer Chemother Pharmacol. 2007;59(1):79–87.
250. Kondratov RV, Komarov PG, Becker Y, et al. Small molecules that dramatically alter multidrug resistance phenotype by modulating the substrate specificity of P-glycoprotein. Proc Natl Acad Sci. 2001;98(24):14078–14083.
251. Dantzig AH, De Alwis DP, Burgess M. Considerations in the design and development of transport inhibitors as adjuncts to drug therapy. Adv Drug Deliv Rev. 2003;55(1):133–150.
252. Li Y, Revalde JL, Reid G, et al. Interactions of dietary phytochemicals with ABC transporters:possible implications for drug disposition and multidrug resistance in cancer. Drug Metab Rev. 2010;42(4):590–611.
253. Norman BH, Gruber JM, Hollinshead SP, et al. Tricyclic isoxazoles are novel inhibitors of the multidrug resistance protein (MRP1). Bioorg Med Chem Lett. 2002;12(6):883–886.
254. Ahmad J, Akhter S, Khan MA, et al. Engineered nanoparticles against MDR in cancer:the state of the art and its prospective. Curr Pharm Des. 2016;22(28):4360–4373.
255. Nakanishi T, Ross DD. Breast cancer resistance protein (BCRP/ABCG2):its role in multidrug resistance and regulation of its gene expression. Chin J Cancer. 2012;31(2):73–99.
256. Zhang Y-K, Wang Y-J, Gupta P, et al. Multidrug resistance proteins (MRPs) and cancer therapy. Aaps J. 2015;17(4):802–812.