Emerging role of NRF2 in chemoresistance by regulating drug-metabolizing enzymes and efflux transporters

Drug Metabolism Reviews

Volumn 48, Issue 4, 2016, Pages 541-567

  Bai, Xupeng ^a   Chen, Yibei ^a   Hou, Xiangyu ^a   Huang, Min ^a   Jin, Jing ^a  

^a SUN YAT SEN UNIVERSITY   (China)

Author keywords

cancer; chemotherapy; drug; inhibitors; KEAP1; mutations; NRF2 signaling pathway; strategy

Indexed keywords

2 MORPHOLINO 8 PHENYLCHROMONE; 8 [4 (1 AMINOCYCLOBUTYL)PHENYL] 9 PHENYL 1,2,4 TRIAZOLO[3,4 F][1,6]NAPHTHYRIDIN 3(2H) ONE; ACTIVATING TRANSCRIPTION FACTOR 3; ALDEHYDE DEHYDROGENASE; ALDO KETO REDUCTASE; ANTINEOPLASTIC AGENT; BREAST CANCER RESISTANCE PROTEIN; CARBONYL REDUCTASE; CAVEOLIN 1; CYTOCHROME P450 1B1; DRUG METABOLIZING ENZYME; GLUCOSE 6 PHOSPHATE DEHYDROGENASE; GLUCURONOSYLTRANSFERASE; GLUTATHIONE TRANSFERASE; GLYCOGEN SYNTHASE KINASE 3; HEAT SHOCK PROTEIN; ISOCITRATE DEHYDROGENASE 1; KELCH LIKE ECH ASSOCIATED PROTEIN 1; MICROSOMAL EPOXIDE HYDROLASE; MULTIDRUG RESISTANCE PROTEIN; N BUTYL N (4 HYDROXYBUTYL)NITROSAMINE; PROTEIN BACH1; PROTEIN HO 1; PROTEIN P53; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE (PHOSPHATE) DEHYDROGENASE (QUINONE) 1; SHORT HAIRPIN RNA; SMALL INTERFERING RNA; TRANSCRIPTION FACTOR NRF2; UNCLASSIFIED DRUG; UVOMORULIN; CARRIER PROTEIN; NFE2L2 PROTEIN, HUMAN;

BLADDER CANCER; BREAST CANCER; CANCER CELL; COLORECTAL CANCER; DRUG RESISTANCE; DRUG TARGETING; ENZYME REGULATION; GENE; HEAD AND NECK CANCER; HUMAN; LEUKEMIA; LIVER CANCER; LUNG CANCER; ME1 GENE; NEUROBLASTOMA; NONHUMAN; OVARY CANCER; PANCREAS CANCER; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PROSTATE CANCER; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN STRUCTURE; PROTEIN TRANSPORT; REVIEW; STOMACH CANCER; TALDO1 GENE; TKT GENE; TRANSCRIPTION INITIATION; DRUG INACTIVATION; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; MUTATION;

ANTINEOPLASTIC AGENTS; DRUG RESISTANCE, NEOPLASM; GENE EXPRESSION REGULATION; HUMANS; INACTIVATION, METABOLIC; MEMBRANE TRANSPORT PROTEINS; MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS; MUTATION; NF-E2-RELATED FACTOR 2;

EID: 84991107767     PISSN: 03602532     EISSN: 10979883     Source Type: Journal    
DOI: 10.1080/03602532.2016.1197239     Document Type: Review

References (263)

1. A.D.Adema, K.Floor, K.Smid,. (2014). Overexpression of MRP4 (ABCC4) and MRP5 (ABCC5) confer resistance to the nucleoside analogs cytarabine and troxacitabine, but not gemcitabine. SpringerPlus 3:732–743.
2. J.Ahlers, K.E.Witte, C.P.Schwarze,. (2014). Therapy response correlates with ALDH activity in ALDH low-positive childhood acute lymphoblastic leukemias. Pediatr Hematol Oncol 31:303–310.
3. H.Akhdar, P.Loyer, C.Rauch,. (2009). Involvement of Nrf2 activation in resistance to 5-fluorouracil in human colon cancer HT-29 cells. Eur J Cancer 45:2219–2227.
4. V.P.Androutsopoulos, I.Spyrou, A.Ploumidis,. (2013). Expression profile of CYP1A1 and CYP1B1 enzymes in colon and bladder tumors. PLoS One 8:e82487. doi:10.1371/journal.pone.0082487.
5. P.L.Apopa, X.He, Q.Ma (2008). Phosphorylation of Nrf2 in the transcription activation domain by casein kinase 2 (CK2) is critical for the nuclear translocation and transcription activation function of Nrf2 in IMR-32 neuroblastoma cells. J Biochem Mol Toxicol 22:63–76.
6. T.Arai, Y.Miyoshi, S.J.Kim,. (2008). Association of GSTP1 expression with resistance to docetaxel and paclitaxel in human breast cancers. Eur J Surg Oncol 34:734–738.
7. A.Arlt, S.Sebens, S.Krebs,. (2013). Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. Oncogene 32:4825–4835.
8. W.Ax, M.Soldan, L.Koch,. (2000). Development of daunorubicin resistance in tumour cells by induction of carbonyl reduction. Biochem Pharmacol 59:293–300.
9. L.Baird, A.T.Dinkova-Kostova (2011). The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol 85:241–272.
10. N.Ballatori, C.L.Hammond, J.B.Cunningham,. (2005). Molecular mechanisms of reduced glutathione transport:role of the MRP/CFTR/ABCC and OATP/SLC21A families of membrane proteins. Toxicol Appl Pharmacol 204:238–255.
11. L.-J.Bao, M.C.Jaramillo, X.-F.Yi,. (2014). Nrf2 induces cisplatin resistance through activation of autophagy in ovarian carcinoma. Int J Clin Exp Pathol 7:1502–1513.
12. M.P.Barr, S.G.Gray, A.C.Hoffmann,. (2013). Generation and characterisation of cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature. PLoS One 8:e54193. doi:10.1371/journal.pone.0054193.
13. L.N.Barrera, S.A.Rushworth, K.M.Bowles,. (2012). Bortezomib induces heme oxygenase-1 expression in multiple myeloma. Cell Cycle 11:2248–2252.
14. P.V.Basta, J.T.Bensen, C.K.Tse,. (2008). Genetic variation in transaldolase 1 and risk of squamous cell carcinoma of the head and neck. Cancer Detect Prev 32:200–208.
15. H.D.Beall, S.I.Winski (2000). Mechanisms of action of quinone-containing alkylating agents. I:NQO1-directed drug development. Front Biosci 5:639–648.
16. A.M.Benson, M.J.Hunkeler, P.Talalay (1980). Increase of NAD(P)H:quinone reductase by dietary antioxidants:possible role in protection against carcinogenesis and toxicity. Proc Natl Acad Sci USA 77:5216–5220.
17. K.W.Bock (2010). Functions and transcriptional regulation of adult human hepatic UDP-glucuronosyl-transferases (UGTs):mechanisms responsible for interindividual variation of UGT levels. Biochem Pharmacol 80:771–777.
18. S.L.Brown, K.R.Sekhar, G.Rachakonda,. (2008). Activating transcription factor 3 is a novel repressor of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2)-regulated stress pathway. Cancer Res 68:364–368.
19. A.M.Brufsky (2014). Current approaches and emerging directions in HER2-resistant breast cancer. Breast Cancer (Auckl) 8:109–118.
20. K.D.Bunting, R.Lindahl, A.J.Townsend (1994). Oxazaphosphorine-specific resistance in human MCF-7 breast carcinoma cell lines expressing transfected rat class 3 aldehyde dehydrogenase. J Biol Chem 269:23197–23203.
21. K.D.Bunting, A.J.Townsend (1996). De novo expression of transfected human class 1 aldehyde dehydrogenase (ALDH) causes resistance to oxazaphosphorine anti-cancer alkylating agents in hamster V79 cell lines. Elevated class 1 ALDH activity is closely correlated with reduction in DNA interstrand cross-linking and lethality. J Biol Chem 271:11884–11890.
22. C.Calatozzolo, M.Gelati, E.Ciusani,. (2005). Expression of drug resistance proteins Pgp, MRP1, MRP3, MRP5 and GST-pi in human glioma. J Neurooncol 74:113–121.
23. J.Y.Chan, X.L.Han, Y.W.Kan (1993). Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast. Proc Natl Acad Sci USA 90:11371–11375.
24. D.V.Chartoumpekis, N.Wakabayashi, T.W.Kensler (2015). Keap1/Nrf2 pathway in the frontiers of cancer and non-cancer cell metabolism. Biochem Soc Trans 43:639–644.
25. Z.Chen, X.Ye, N.Tang,. (2014). The histone acetylranseferase hMOF acetylates Nrf2 and regulates anti-drug responses in human non-small cell lung cancer. Br J Pharmacol 171:3196–3211.
26. Z.S.Chen, T.Furukawa, T.Sumizawa,. (1999). ATP-dependent efflux of CPT-11 and SN-38 by the multidrug resistance protein (MRP) and its inhibition by PAK-104P. Mol Pharmacol 55:921–928.
27. Z.S.Chen, A.K.Tiwari (2011). Multidrug resistance proteins (MRPs/ABCCs) in cancer chemotherapy and genetic diseases. FEBS J 278:3226–3245.
28. S.Chian, Y.Y.Li, X.J.Wang,. (2014). Luteolin sensitizes two oxaliplatin-resistant colorectal cancer cell lines to chemotherapeutic drugs via inhibition of the Nrf2 pathway. Asian Pac J Cancer Prev 15:2911–2916.
29. J.M.Cho, S.Manandhar, H.R.Lee,. (2008). Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin:implication to cancer cell resistance. Cancer Lett 260:96–108.
30. H.K.Choi, J.W.Yang, S.H.Roh,. (2007). Induction of multidrug resistance associated protein 2 in tamoxifen-resistant breast cancer cells. Endocr Relat Cancer 14:293–303.
31. S.Chowdhry, Y.Zhang, M.McMahon,. (2013). Nrf2 is controlled by two distinct β-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. Oncogene 32:3765–3781.
32. B.Corominas-Faja, C.Oliveras-Ferraros, E.Cuyas,. (2013). Stem cell-like ALDH(bright) cellular states in EGFR-mutant non-small cell lung cancer:a novel mechanism of acquired resistance to erlotinib targetable with the natural polyphenol silibinin. Cell Cycle 12:3390–3404.
33. L.Cortes-Dericks, L.Froment, R.Boesch,. (2014). Cisplatin-resistant cells in malignant pleural mesothelioma cell lines show ALDH(high)CD44(+) phenotype and sphere-forming capacity. BMC Cancer 14:304. doi:10.1186/1471-2407-14.
34. V.Cortessis, K.Siegmund, Q.Chen,. (2001). A case-control study of microsomal epoxide hydrolase, smoking, meat consumption, glutathione S-transferase M3, and risk of colorectal adenomas. Cancer Res 61:2381–2385.
35. Y.Cui, J.König, J.K.Buchholz,. (1999). Drug resistance and ATP-dependent conjugate transport mediated by the apical multidrug resistance protein, MRP2, permanently expressed in human and canine cells. Mol Pharmacol 55:929–937.
36. Y.Cui, N.Nadiminty, C.Liu,. (2014). Upregulation of glucose metabolism by NF-κB2/p52 mediates enzalutamide resistance in castration-resistant prostate cancer cells. Endocr Relat Cancer 21:435–442.
37. S.B.Cullinan, D.Zhang, M.Hannink,. (2003). Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23:7198–7209.
38. J.Cummings, B.T.Ethell, L.Jardine,. (2003). Glucuronidation as a mechanism of intrinsic drug resistance in human colon cancer:reversal of resistance by food additives. Cancer Res 63:8443–8450.
39. J.Cummings, B.T.Ethell, L.Jardine,. (2006). Glucuronidation of SN-38 and NU/ICRF 505 in human colon cancer and adjacent normal colon. Anticancer Res 26:2189–2196.
40. J.Cummings, N.Zelcer, J.D.Allen,. (2004). Glucuronidation as a mechanism of intrinsic drug resistance in colon cancer cells:contribution of drug transport proteins. Biochem Pharmacol 67:31–39.
41. M.L.de Groote, P.J.Verschure, M.G.Rots (2012). Epigenetic Editing:targeted rewriting of epigenetic marks to modulate expression of selected target genes. Nucleic Acids Res 40:10596–10613.
42. W.C.Dempke, T.Suto, M.Reck (2010). Targeted therapies for non-small cell lung cancer. Lung Cancer-J IASLC 67:257–274.
43. G.M.DeNicola, F.A.Karreth, T.J.Humpton,. (2011). Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475:106–109.
44. S.Dhakshinamoorthy, A.K.Jain, D.A.Bloom,. (2005). Bach1 competes with Nrf2 leading to negative regulation of the antioxidant response element (ARE)-mediated NAD(P)H:quinone oxidoreductase 1 gene expression and induction in response to antioxidants. J Biol Chem 280:16891–16900.
45. A.T.Dinkova-Kostova, P.Talalay (2010). NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector. Arch Biochem Biophys 501:116–123.
46. L.Doyle, D.D.Ross (2003). Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 22:7340–7358.
47. L.A.Doyle, W.K.Yang, L.V.Abruzzo,. (1998). A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA 95:15665–15670.
48. H.Dreger, K.Westphal, N.Wilck,. (2010). Protection of vascular cells from oxidative stress by proteasome inhibition depends on Nrf2. Cardiovasc Res 85:395–403.
49. H.Q.Duong, Y.W.Yi, H.J.Kang,. (2014). Inhibition of NRF2 by PIK-75 augments sensitivity of pancreatic cancer cells to gemcitabine. Int J Oncol 44:959–969.
50. B.Ebert, M.Kisiela, V.Wsol,. (2011). Proteasome inhibitors MG-132 and bortezomib induce AKR1C1, AKR1C3, AKR1B1, and AKR1B10 in human colon cancer cell lines SW-480 and HT-29. Chem Biol Interact 191:239–249.
51. R.Faraonio, P.Vergara, D.Di Marzo (2006). p53 suppresses the Nrf2-dependent transcription of antioxidant response genes. J Biol Chem 281:39776–39784.
52. T.Fukutomi, K.Takagi, T.Mizushima,. (2014). Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1. Mol Cell Biol 34:832–846.
53. A.L.Furfaro, S.Piras, M.Passalacqua,. (2014). HO-1 up-regulation:a key point in high-risk neuroblastoma resistance to bortezomib. Biochim Biophys Acta 1842:613–622.
54. I.Ganan-Gomez, Y.Wei, H.Yang,. (2013). Oncogenic functions of the transcription factor Nrf2. Free Radic Biol Med 65:750–764.
55. A.M.Gao, Z.P.Ke, F.Shi,. (2013a). Chrysin enhances sensitivity of BEL-7402/ADM cells to doxorubicin by suppressing PI3K/Akt/Nrf2 and ERK/Nrf2 pathway. Chem Biol Interact 206:100–108.
56. A.M.Gao, Z.P.Ke, J.N.Wang,. (2013b). Apigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway. Carcinogenesis 34:1806–1814.
57. M.Garofalo, C.M.Croce (2013). MicroRNAs as therapeutic targets in chemoresistance. Drug Resist Updates 16:47–59.
58. M.Gavelova, J.Hladikova, L.Vildova,. (2008). Reduction of doxorubicin and oracin and induction of carbonyl reductase in human breast carcinoma MCF-7 cells. Chem Biol Interact 176:9–18.
59. B.Gonzalez, S.Akman, J.Doroshow,. (1995). Protection against daunorubicin cytotoxicity by expression of a cloned human carbonyl reductase cDNA in K562 leukemia cells. Cancer Res 55:4646–4650.
60. A.Halon, V.Materna, P.Donizy,. (2007). MRP2 (ABCC2, cMOAT) expression in nuclear envelope of primary fallopian tube cancer cells is a new unfavorable prognostic factor. Arch Gynecol Obstet 287:563–570.
61. N.Hanada, T.Takahata, Q.Zhou,. (2012). Methylation of the KEAP1 gene promoter region in human colorectal cancer. BMC Cancer 12:66. doi:10.1186/1471-2407-12-66.
62. A.Hanneken, F.F.Lin, J.Johnson,. (2006). Flavonoids protect human retinal pigment epithelial cells from oxidative-stress-induced death. Invest Ophthalmol Vis Sci 47:3164–3177.
63. A.Hayden, J.Douglas, M.Sommerlad,. (2014). The Nrf2 transcription factor contributes to resistance to cisplatin in bladder cancer. Urol Oncol 32:806–814.
64. J.D.Hayes, S.,.A.Chanas C.J.Henderson,. (2000). The Nrf2 transcription factor contributes both to the basal expression of glutathione S-transferases in mouse liver and to their induction by the chemopreventive synthetic antioxidants, butylated hydroxyanisole and ethoxyquin. Biochem Soc Trans 28:33–41.
65. J.D.Hayes, A.T.Dinkova-Kostova (2014). The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci 39:199–218.
66. J.D.Hayes, J.U.Flanagan, I.R.Jowsey (2005). Glutathione transferases. Annu Rev Pharmacol Toxicol 45:51–88.
67. J.D.Hayes, M.McMahon (2009). NRF2 and KEAP1 mutations:permanent activation of an adaptive response in cancer. Trends Biochem Sci 34:176–188.
68. S.A.Heasman, L.Zaitseva, K.M.Bowles,. (2011). Protection of acute myeloid leukaemia cells from apoptosis induced by front-line chemotherapeutics is mediated by haem oxygenase-1. Oncotarget 2:658–668.
69. L.G.Higgins, M.O.Kelleher, I.M.Eggleston,. (2009). Transcription factor Nrf2 mediates an adaptive response to sulforaphane that protects fibroblasts in vitro against the cytotoxic effects of electrophiles, peroxides and redox-cycling agents. Toxicol Appl Pharmacol 237:267–280.
70. D.L.Hill, W.R.J.Laster, R.F.Struck (1972). Enzymatic metabolism of cyclophosphamide and nicotine and production of a toxic cyclophosphamide metabolite. Cancer Res 32:658–665.
71. Y.Hirotsu, F.Katsuoka, R.Funayama,. (2012). Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks. Nucleic Acids Res 40:10228–10239.
72. S.Homma, Y.Ishii, Y.Morishima,. (2009). Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer. Clin Cancer Res 15:3423–3432.
73. Y.B.Hong, H.J.Kang, S.Y.Kwon,. (2010). Nuclear factor (erythroid-derived 2)-like 2 regulates drug resistance in pancreatic cancer cells. Pancreas 39:463–472.
74. J.H.Hooijberg, H.J.Broxterman, M.Kool,. (1999). Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Res 59:2532–2535.
75. X.Hou, X.Bai, X.Gou,. (2015). 3′, 4′, 5′, 5, 7-pentamethoxyflavone sensitizes cisplatin-resistant A549 cells to cisplatin by inhibition of Nrf2 pathway. Mol Cells 38:396–401.
76. L.Hu, W.Miao, M.Loignon,. (2010). Putative chemopreventive molecules can increase Nrf2-regulated cell defense in some human cancer cell lines, resulting in resistance to common cytotoxic therapies. Cancer Chemother Pharmacol 66:467–474.
77. X.F.Hu, J.Yao, S.G.Gao,. (2013). Nrf2 overexpression predicts prognosis and 5-FU resistance in gastric cancer. Asian Pac J Cancer Prev 14:5231–5235.
78. C.P.Huang, M.F.Tsai, T.H.Chang,. (2013). ALDH-positive lung cancer stem cells confer resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Cancer Lett 328:144–151.
79. H.C.Huang, T.Nguyen, C.B.Pickett (2000). Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2. Proc Natl Acad Sci USA 97:12475–12480.
80. J.Huang, P.H.Tan, J.Thiyagarajan,. (2003). Prognostic significance of glutathione S-transferase-pi in invasive breast cancer. Mod Pathol 16:558–565.
81. W.Huang, L.Ding, Q.Huang,. (2010). Carbonyl reductase 1 as a novel target of (−)-epigallocatechin gallate against hepatocellular carcinoma. Hepatology 52:703–714.
82. Y.Huang, W.Sadee (2006). Membrane transporters and channels in chemoresistance and -sensitivity of tumor cells. Cancer Lett 239:168–182.
83. K.Iida, K.Itoh, Y.Kumagai,. (2004). Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis. Cancer Res 64:6424–6431.
84. R.Ikeda, L.C.Vermeulen, E.Lau,. (2011). Isolation and characterization of gemcitabine-resistant human non-small cell lung cancer A549 cells. Int J Oncol 38:513–519.
85. K.Ito, C.J.Oleschuk, C.Westlake,. (2001). Mutation of Trp1254 in the multispecific organic anion transporter, multidrug resistance protein 2 (MRP2) (ABCC2), alters substrate specificity and results in loss of methotrexate transport activity. J Biol Chem 276:3810–38114.
86. M.Jang, Y.Kim, H.Won,. (2012). Carbonyl reductase 1 offers a novel therapeutic target to enhance leukemia treatment by arsenic trioxide. Cancer Res 72:4214–4224.
87. R.Januchowski, K.Wojtowicz, M.Zabel (2013). The role of aldehyde dehydrogenase (ALDH) in cancer drug resistance. Biomed Pharmacother 67:669–680.
88. M.C.Jaramillo, D.D.Zhang (2013). The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev 27:2179–2191.
89. W.K.Jeon, H.Y.Hong, W.C.Seo,. (2012). Smad7 sensitizes A549 lung cancer cells to cisplatin-induced apoptosis through heme oxygenase-1 inhibition. Biochem Biophys Res Commun 420:288–292.
90. Y.Jin, T.M.Penning (2007). Aldo-keto reductases and bioactivation/detoxication. Annu Rev Pharmacol Toxicol 47:263–292.
91. K.Johansson, K.Ahlen, R.Rinaldi,. (2007). Microsomal glutathione transferase 1 in anticancer drug resistance. Carcinogenesis 28:465–470.
92. K.Johansson, J.Jarvliden, V.Gogvadze,. (2010). Multiple roles of microsomal glutathione transferase 1 in cellular protection:a mechanistic study. Free Radic Biol Med 49:1638–1645.
93. D.V.J.Jones, R.J.Winn, B.W.Brown,. (1995). Randomized phase III study of 5-fluorouracil plus high dose folinic acid versus 5-fluorouracil plus folinic acid plus methyl-lomustine for patients with advanced colorectal cancer. Cancer 76:1709–1714.
94. H.J.Kang, Y.W.Yi, Y.B.Hong,. (2014a). HER2 confers drug resistance of human breast cancer cells through activation of NRF2 by direct interaction. Sci Rep 4:7201. doi:10.1038/srep07201:7201.
95. K.A.Kang, M.J.Piao, K.C.Kim,. (2014b). Epigenetic modification of Nrf2 in 5-fluorouracil-resistant colon cancer cells:involvement of TET-dependent DNA demethylation. Cell Death Dis 5:e1183.
96. Y.Katoh, K.Itoh, E.Yoshida,. (2001). Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells 6:857–868.
97. Y.Kawai, L.Garduno, M.Theodore,. (2011). Acetylation–deacetylation of the transcription factor Nrf2 (nuclear factor erythroid 2-related factor 2) regulates its transcriptional activity and nucleocytoplasmic localization. J Biol Chem 286:7629–7640.
98. Y.Kawasaki, S.Ishigami, T.Arigami,. (2015). Clinicopathological significance of nuclear factor (erythroid-2)-related factor 2 (Nrf2) expression in gastric cancer. BMC Cancer 15:5.
99. H.R.Kim, S.Kim, E.J.Kim,. (2008a). Suppression of Nrf2-driven heme oxygenase-1 enhances the chemosensitivity of lung cancer A549 cells toward cisplatin. Lung Cancer-J IASLC 60:47–56.
100. J.H.Kim, S.Yu, J.D.Chen,. (2013a). The nuclear cofactor RAC3/AIB1/SRC-3 enhances Nrf2 signaling by interacting with transactivation domains. Oncogene 32:514–527.
101. S.K.Kim, H.Kim, D.H.Lee,. (2013b). Reversing the intractable nature of pancreatic cancer by selectively targeting ALDH-high, therapy-resistant cancer cells. PLoS One 8:e78130. doi:10.1371/journal.pone.0078130.
102. S.K.Kim, J.W.Yang, M.R.Kim,. (2008b). Increased expression of Nrf2/ARE-dependent anti-oxidant proteins in tamoxifen-resistant breast cancer cells. Free Radic Biol Med 45:537–546.
103. W.D.Kim, Y.W.Kim, I.J.Cho,. (2012). E-cadherin inhibits nuclear accumulation of Nrf2:implications for chemoresistance of cancer cells. J Cell Sci 125:1284–1295.
104. P.A.Konstantinopoulos, E.Fountzilas, K.Pillay,. (2008). Carboplatin-induced gene expression changes in vitro are prognostic of survival in epithelial ovarian cancer. BMC Med Genomics 1:59. doi:10.1186/1755-8794-1.
105. P.A.Konstantinopoulos, D.Spentzos, E.Fountzilas,. (2011). Keap1 mutations and Nrf2 pathway activation in epithelial ovarian cancer. Cancer Res 71:5081–5089.
106. M.Kool, M.van der Linden, M.de Haas,. (1999). MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc Natl Acad Sci USA 96:6914–6919.
107. V.Krajka-Kuzniak, J.Paluszczak, H.Szaefer,. (2015). The activation of the Nrf2/ARE pathway in HepG2 hepatoma cells by phytochemicals and subsequent modulation of phase II and antioxidant enzyme expression. J Physiol Biochem 71:227–238.
108. T.Kunicka, P.Soucek (2014). Importance of ABCC1 for cancer therapy and prognosis. Drug Metab Rev 46:325–342.
109. M.H.Kweon, V.M.Adhami, J.S.Lee,. (2006). Constitutive overexpression of Nrf2-dependent heme oxygenase-1 in A549 cells contributes to resistance to apoptosis induced by epigallocatechin 3-gallate. J Biol Chem 281:33761–33772.
110. A.Lau, N.F.Villeneuve, Z.Sun,. (2008). Dual roles of Nrf2 in cancer. Pharmacol Res 58:262–270.
111. P.Lazarus, D.Sun (2010). Potential role of UGT pharmacogenetics in cancer treatment and prevention:focus on tamoxifen and aromatase inhibitors. Drug Metab Rev 42:182–194.
112. B.S.Lee, J.Heo, Y.M.Kim,. (2006). Carbon monoxide mediates heme oxygenase 1 induction via Nrf2 activation in hepatoma cells. Biochem Biophys Res Commun 343:965–972.
113. H.M.Leinonen, A.K.Ruotsalainen, A.M.Maatta,. (2012). Oxidative stress-regulated lentiviral TK/GCV gene therapy for lung cancer treatment. Cancer Res 72:6227–6235.
114. K.J.A.Lemmens, M.M.J.P.E.Sthijns,W.J.F.van der Vijgh,. (2014). The antioxidant flavonoid monoHER provides efficient protection and induces the innate Nrf2 mediated adaptation in endothelial cells subjected to oxidative stress. PharmaNutrition 2:69–74.
115. C.C.Leonardo, S.Dore (2011). Dietary flavonoids are neuroprotective through Nrf2-coordinated induction of endogenous cytoprotective proteins. Nutr Neurosci 14:226–236.
116. D.F.Lewis (2004). 57 varieties:the human cytochromes P450. Pharmacogenomics 5:305–318.
117. D.Li, S.Ma, E.M.Ellis (2014a). Nrf2-mediated adaptive response to methyl glyoxal in HepG2 cells involves the induction of AKR7A2. Chem Biol Interact 234:366–371.
118. M.Li, Z.Wang, J.Guo,. (2014b). Clinical significance of UGT1A1 gene polymorphisms on irinotecan-based regimens as the treatment in metastatic colorectal cancer. Onco Targets Ther 7:1653–1661.
119. W.Li, H.Liu, J.S.Zhou,. (2012). Caveolin-1 inhibits expression of antioxidant enzymes through direct interaction with nuclear erythroid 2 p45-related factor-2 (Nrf2). J Biol Chem 287:20922–20930.
120. L.Ji, Y.Wei, T.Jiang,. (2014). Correlation of Nrf2, NQO1, MRP1, cmyc and p53 in colorectal cancer and their relationships to clinicopathologic features and survival. Int J Clin Exp Pathol 7:1124–1131.
121. J.Lim, S.H.Lee, S.Cho,. (2013). 4-methoxychalcone enhances cisplatin-induced oxidative stress and cytotoxicity by inhibiting the Nrf2/ARE-mediated defense mechanism in A549 lung cancer cells. Mol Cells 36:340–346.
122. A.Lister, T.Nedjadi, N.R.Kitteringham,. (2011). Nrf2 is overexpressed in pancreatic cancer:implications for cell proliferation and therapy. Mol Cancer 10:37. doi:10.1186/1476-4598-10-37.
123. X.M.Liu, G.B.Chapman, K.Peyton,. (2002). Carbon monoxide inhibits apoptosis in vascular smooth muscle cells. Cardiovasc Res 55:396–405.
124. A.C.Lockhart, R.G.Tirona, R.B.Kim (2003). Pharmacogenetics of ATP-binding cassette transporters in cancer and chemotherapy. Mol Cancer Ther 2:685–698.
125. A.Lorico, G.Rappa, R.A.Finch,. (1997). Disruption of the murine MRP (multidrug resistance protein) gene leads to increased sensitivity to etoposide (VP-16) and increased levels of glutathione. Cancer Res 57:5238–5242.
126. C.Y.Lu, Y.S.Yeh, C.W.Huang,. (2014). FOLFIRI and regorafenib combination therapy with dose escalation of irinotecan as fourth-line treatment for patients with metastatic colon cancer according to UGT1A1 genotyping. Onco Targets Ther 7:2143–2146.
127. J.Ma, J.Yang, C.Wang,. (2014). Emodin augments cisplatin cytotoxicity in platinum-resistant ovarian cancer cells via ROS-dependent MRP1 downregulation. Biomed Res Int 2014:107671. doi:10.1155/2014/107671:107671.
128. Y.Ma, M.Wink (2010). The beta-carboline alkaloid harmine inhibits BCRP and can reverse resistance to the anticancer drugs mitoxantrone and camptothecin in breast cancer cells. Phytother Res 24:146–149.
129. S.Magesh, Y.Chen, L.Hu (2012). Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents. Med Res Rev 32:687–726.
130. C.M.Mahaffey, N.C.Mahaffey, W.Holland,. (2012). Aberrant regulation of the MRP3 gene in non-small cell lung carcinoma. J Thorac Oncol 7:34–39.
131. C.M.Mahaffey, H.Zhang, A.Rinna,. (2009). Multidrug-resistant protein-3 gene regulation by the transcription factor Nrf2 in human bronchial epithelial and non-small-cell lung carcinoma. Free Radic Biol Med 46:1650–1657.
132. J.M.Maher, M.Z.Dieter, L.M.Aleksunes,. (2007). Oxidative and electrophilic stress induces multidrug resistance-associated protein transporters via the nuclear factor-E2-related factor-2 transcriptional pathway. Hepatology 46:1597–1610.
133. D.Malhotra, E.Portales-Casamar, A.Singh,. (2010). Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis. Nucleic Acids Res 38:5718–5734.
134. M.Maliepaard, M.A.van Gastelen, A.Tohgo,. (2001). Circumvention of breast cancer resistance protein (BCRP)-mediated resistance to camptothecins in vitro using non-substrate drugs or the BCRP inhibitor GF1209181. Clin Cancer Res 7:935–941.
135. M.T.Malloy, D.J.McIntosh, T.S.Walters,. (2013). Trafficking of the transcription factor Nrf2 to promyelocytic leukemia-nuclear bodies:implications for degradation of NRF2 in the nucleus. J Biol Chem 288:14569–14583.
136. M.Mani, S.Khaghani, T.Gol Mohammadi,. (2013). Activation of Nrf2-antioxidant response element mediated glutamate cysteine ligase expression in hepatoma cell line by homocysteine. Hepat Mon 13:e8394.
137. V.G.Martinez, R.O'connor, Y.Liang,. (2008). CYP1B1 expression is induced by docetaxel:effect on cell viability and drug resistance. Br J Cancer 98:564–570.
138. J.M.Marzec, J.D.Christie, S.P.Reddy,. (2007). Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury. FASEB J 21:2237–2246.
139. V.Materna, B.Liedert, J.Thomale,. (2005). Protection of platinum-DNA adduct formation and reversal of cisplatin resistance by anti-MRP2 hammerhead ribozymes in human cancer cells. Int J Cancer 115:393–402.
140. T.Matsunaga, Y.Yamane, K.Iida,. (2011). Involvement of the aldo-keto reductase, AKR1B10, in mitomycin-c resistance through reactive oxygen species-dependent mechanisms. Anticancer Drugs 22:402–408.
141. M.Mayerhofer, S.Florian, M.T.Krauth,. (2004). Identification of heme oxygenase-1 as a novel BCR/ABL-dependent survival factor in chronic myeloid leukemia. Cancer Res 64:3148–3154.
142. M.Mayerhofer, K.V.Gleixner, J.Mayerhofer,. (2008). Targeting of heat shock protein 32 (Hsp32)/heme oxygenase-1 (HO-1) in leukemic cells in chronic myeloid leukemia:a novel approach to overcome resistance against imatinib. Blood 111:2200–2210.
143. M.A.McAleer, M.A.Breen, N.L.White,. (1999). pABC11 (also known as MOAT-C and MRP5), a member of the ABC family of proteins, has anion transporter activity but does not confer multidrug resistance when overexpressed in human embryonic kidney 293 cells. J Biol Chem 274:23541–23548.
144. M.C.McFadyen, H.L.McLeod, F.C.Jackson,. (2001). Cytochrome P450 CYP1B1 protein expression:a novel mechanism of anticancer drug resistance. Biochem Pharmacol 62:207–212.
145. M.McMahon, N.Thomas, K.Itoh,. (2006). Dimerization of substrate adaptors can facilitate cullin-mediated ubiquitylation of proteins by a “tethering” mechanism:a two-site interaction model for the Nrf2-Keap1. J Biol Chem 281:24756–24768.
146. E.Meng, A.Mitra, K.Tripathi,. (2014). ALDH1A1 maintains ovarian cancer stem cell-like properties by altered regulation of cell cycle checkpoint and DNA repair network signaling. PLoS One 9:e107142. doi:10.1371/journal.pone.0107142.
147. Y.Mitsuishi, K.Taguchi, Y.Kawatani,. (2012). Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22:66–79.
148. S.Miura, M.Shibazaki, S.Kasai,. (2014). A somatic mutation of the KEAP1 gene in malignant melanoma is involved in aberrant NRF2 activation and an increase in intrinsic drug resistance. J Invest Dermatol 134:553–556.
149. T.Miyazaki, Y.Kirino, M.Takeno,. (2010). Expression of heme oxygenase-1 in human leukemic cells and its regulation by transcriptional repressor Bach1. Cancer Sci 101:1409–1416.
150. P.Moi, K.Chan, I.Asunis,. (1994). Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proc Natl Acad Sci USA 91:9926–9930.
151. H.R.Moinova, R.T.Mulcahy (1999). Up-regulation of the human gamma-glutamylcysteine synthetase regulatory subunit gene involves binding of Nrf-2 to an electrophile responsive element. Biochem Biophys Res Commun 261:661–668.
152. E.J.Moon, A.Giaccia (2014). Dual roles of NRF2 in tumor prevention and progression:possible implications in cancer treatment. Free Radic Biol Med 79:292–299.
153. G.I.Murray, S.Patimalla, K.N.Stewart,. (2010). Profiling the expression of cytochrome P450 in breast cancer. Histopathology 57:202–211.
154. L.A.Muscarella, P.Parrella, V.D’alessandro,. (2014). Frequent epigenetics inactivation of KEAP1 gene in non-small cell lung cancer. Epigenetics 6:710–719.
155. G.Muzio, M.Maggiora, E.Paiuzzi,. (2012). Aldehyde dehydrogenases and cell proliferation. Free Radic Biol Med 52:735–746.
156. T.Nagai, S.Kikuchi, K.Ohmine,. (2008). Hemin reduces cellular sensitivity to imatinib and anthracyclins via Nrf2. J Cell Biochem 104:680–691.
157. S.Nagashima, H.Soda, M.Oka,. (2006). BCRP/ABCG2 levels account for the resistance to topoisomerase I inhibitors and reversal effects by gefitinib in non-small cell lung cancer. Cancer Chemother Pharmacol 58:594–600.
158. D.W.Nebert, V.Vasiliou (2004). Analysis of the glutathione S-transferase (GST) gene family. Hum Genom 1:460–464.
159. D.W.Nebert, K.Wikvall, W.L.Miller (2013). Human cytochromes P450 in health and disease. Philos Trans R Soc Lond B Biol Sci 368:20120431.
160. Z.Ni, Z.Bikadi, M.F.Rosenberg,. (2010). Structure and function of the human breast cancer resistance protein (BCRP/ABCG2). Curr Drug Metab 11:603–617.
161. P.Nioi, T.Nguyen (2007). A mutation of Keap1 found in breast cancer impairs its ability to repress Nrf2 activity. Biochem Biophys Res Commun 362:816–821.
162. S.Nishikawa, M.Konno, A.Hamabe,. (2013). Aldehyde dehydrogenase high gastric cancer stem cells are resistant to chemotherapy. Int J Oncol 42:1437–1442.
163. S.K.Niture, R.Khatri, A.K.Jaiswal (2014). Regulation of Nrf2 – an update. Free Radic Biol Med 66:36–44.
164. J.H.No, Y.B.Kim, Y.S.Song (2014). Targeting nrf2 signaling to combat chemoresistance. J Cancer Prev 19:111–117.
165. E.Noda, K.Maeda, T.Inoue,. (2012). Predictive value of expression of ERCC 1 and GST-p for 5-fluorouracil/oxaliplatin chemotherapy in advanced colorectal cancer. Hepatogastroenterology 59:130–133.
166. D.Nowis, M.Bugajski, M.Winiarska,. (2008). Zinc protoporphyrin IX, a heme oxygenase-1 inhibitor, demonstrates potent antitumor effects but is unable to potentiate antitumor effects of chemotherapeutics in mice. BMC Cancer 8:197.
167. F.Oesch (1973). Mammalian epoxide hydrases:inducible enzymes catalysing the inactivation of carcinogenic and cytotoxic metabolites derived from aromatic and olefinic compounds. Xenobiotica 3:305–340.
168. T.Ogura, K.I.Tong, K.Mio,. (2010). Keap1 is a forked-stem dimer structure with two large spheres enclosing the intervening, double glycine repeat, and C-terminal domains. Proc Natl Acad Sci USA 107:2842–2847.
169. T.Oguri, T.Isobe, K.Fujitaka,. (2001). Association between expression of the MRP3 gene and exposure to platinum drugs in lung cancer. Int J Cancer 93:584–589.
170. T.Oguri, T.Isobe, T.Suzuki,. (2000). Increased expression of the MRP5 gene is associated with exposure to platinum drugs in lung cancer. Int J Cancer 86:95–100.
171. T.Ohta, K.Iijima, M.Miyamoto,. (2008). Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res 68:1303–1309.
172. Y.Okano, U.Nezu, Y.Enokida,. (2013). SNP (–617C.A) in ARE-like loci of the NRF2 gene:a new biomarker for prognosis of lung adenocarcinoma in Japanese non-smoking women. PLoS Med 8:e73794. doi:10.1371/journal.pone.0073794.
173. A.Ooi, J.C.Wong, D.Petillo,. (2011). An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20:511–523.
174. S.Ota, G.Ishii, K.Goto,. (2009). Immunohistochemical expression of BCRP and ERCC1 in biopsy specimen predicts survival in advanced non-small-cell lung cancer treated with cisplatin-based chemotherapy. Lung Cancer-J IASLC 64:98–104.
175. B.Padmanabhan, K.I.Tong, T.Ohta,. (2006). Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell 21:689–700.
176. K.C.Patra, N.Hay (2014). The pentose phosphate pathway and cancer. Trends Biochem Sci 39:347–354.
177. H.Piotrowska, M.Kucinska, M.Murias (2013). Expression of CYP1A1, CYP1B1 and MnSOD in a panel of human cancer cell lines. Mol Cell Biochem 383:95–102.
178. M.Plebuch, M.Soldan, C.Hungerer,. (2007). Increased resistance of tumor cells to daunorubicin after transfection of cDNAs coding for anthracycline inactivating enzymes. Cancer Lett 255:49–56.
179. V.Pullarkat, Z.Meng, S.M.Tahara,. (2014). Proteasome inhibition induces both antioxidant and hb f responses in sickle cell disease via the nrf2 pathway. Hemoglobin 38:188–195.
180. P.Rada, A.I.Rojo, S.Chowdhry,. (2011). SCF/β-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Mol Cell Biol 31:1121–1133.
181. P.Rada, A.I.Rojo, N.Evrard-Todeschi,. (2012). Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP axis. Mol Cell Biol 32:3486–3499.
182. M.Ramos-Gomez, M.K.Kwak, P.M.Dolan,. (2001). Sensitivity to carcinogenesis is increased and chemoprotective efficacy of enzyme inducers is lost in nrf2 transcription factor-deficient mice. Proc Natl Acad Sci USA 98:3410–3415.
183. D.Ren, N.F.Villeneuve, T.Jiang,. (2011). Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci USA 108:1433–1438.
184. R.W.Robey, W.Y.Medina-Pérez, K.Nishiyama,. (2001). Overexpression of the ATP-binding cassette half-transporter, ABCG2 (MXR/BCRP/ABCP1), in flavopiridol-resistant human breast cancer cells. Clin Cancer Res 7:145–152.
185. R.W.Robey, O.Polgar, J.Deeken,. (2007). ABCG2:determining its relevance in clinical drug resistance. Cancer Metastasis Rev 26:39–57.
186. B.Rochat, J.M.Morsman, G.I.Murray,. (2001). Human CYP1B1 and anticancer agent metabolism:mechanism for tumor-specific drug inactivation? J Pharmacol Exp Ther 296:537–541.
187. A.Romero-Lorca, A.Novillo, M.Gaibar,. (2015). Impacts of the glucuronidase genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on tamoxifen metabolism in breast cancer patients. PLoS One 10:e0132269. doi:10.1371/journal.pone.0132269.
188. D.Ross, J.K.Kepa, S.L.Winski,. (2000). NAD(P)H:quinone oxidoreductase 1 (NQO1):chemoprotection, bioactivation, gene regulation and genetic polymorphisms. Chem Biol Interact 129:77–97.
189. S.A.Rushworth, K.M.Bowles, D.J.MacEwan (2011). High basal nuclear levels of Nrf2 in acute myeloid leukemia reduces sensitivity to proteasome inhibitors. Cancer Res 71:1999–2009.
190. S.A.Rushworth, D.J.MacEwan (2011). The role of nrf2 and cytoprotection in regulating chemotherapy resistance of human leukemia cells. Cancers (Basel) 3:1605–1621.
191. S.A.Rushworth, L.Zaitseva, M.Y.Murray,. (2012). The high Nrf2 expression in human acute myeloid leukemia is driven by NF-κB and underlies its chemo-resistance. Blood 120:5188–5198.
192. I.G.Ryoo, B.H.Choi, M.K.Kwak (2015). Activation of NRF2 by p62 and proteasome reduction in sphere-forming breast carcinoma cells. Oncotarget 6:8167–8184.
193. H.Sasaki, M.Shitara, K.Yokota,. (2012). MRP3 gene expression correlates with NRF2 mutations in lung squamous cell carcinomas. Mol Med Rep 6:705–708.
194. H.Satoh, T.Moriguchi, K.Taguchi,. (2010). Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung. Carcinogenesis 31:1833–1843.
195. A.Schafer, J.Teufel, F.Ringel,. (2012). Aldehyde dehydrogenase 1A1-a new mediator of resistance to temozolomide in glioblastoma. Neuro-oncology 14:1452–1464.
196. C.M.Schaupp, C.C.White, G.F.Merrill,. (2014). Metabolism of doxorubicin to the cardiotoxic metabolite doxorubicinol is increased in a mouse model of chronic glutathione deficiency:a potential role for carbonyl reductase 3. Chem Biol Interact 234:154–161.
197. R.Schiff, P.Reddy, M.Ahotupa,. (2000). Oxidative stress and AP-1 activity in tamoxifen-resistant breast tumors in vivo. J Natl Cancer Inst 92:1926–1934.
198. K.Scotlandi, D.Remondini, G.Castellani,. (2009). Overcoming resistance to conventional drugs in Ewing sarcoma and identification of molecular predictors of outcome. J Clin Oncol 27:2209–2216.
199. E.G.Shatalova, A.J.Klein-Szanto, K.Devarajan,. (2011). Estrogen and cytochrome P450 1B1 contribute to both early- and late-stage head and neck carcinogenesis. Cancer Prev Res (Phila) 4:107–115.
200. L.Shi, Z.G.Chen, L.L.Wu,. (2014). miR-340 reverses cisplatin resistance of hepatocellular carcinoma cell lines by targeting Nrf2-dependent antioxidant pathway. Asian Pac J Cancer Prev 15:10439–10444.
201. T.Shibata, A.Kokubu, M.Gotoh,. (2008). Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer. Gastroenterology 135:1358–1368.
202. G.S.Shim, S.Manandhar, D.H.Shin,. (2009). Acquisition of doxorubicin resistance in ovarian carcinoma cells accompanies activation of the NRF2 pathway. Free Radic Biol Med 47:1619–1631.
203. K.Shiozawa, M.Oka, H.Soda,. (2004). Reversal of breast cancer resistance protein (BCRP/ABCG2)-mediated drug resistance by novobiocin, a coumermycin antibiotic. Int J Cancer 108:146–151.
204. D.Siegel, D.Ross (2000). Immunodetection of NAD(P)H:quinone oxidoreductase 1 (NQO1) in human tissues. Free Radic Biol Med 29:246–253.
205. D.Siegel, C.Yan, D.Ross (2012). NAD(P)H:quinone oxidoreductase 1 (NQO1) in the sensitivity and resistance to antitumor quinones. Biochem Pharmacol 83:1033–1040.
206. A.Singh, V.Misra, R.K.Thimmulappa,. (2006). Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med 3:1865–1876
207. A.Singh, H.Wu, P.Zhang,. (2010). Expression of ABCG2 (BCRP) is regulated by Nrf2 in cancer cells that confers side population and chemoresistance phenotype. Mol Cancer Ther 9:2365–2376.
208. S.Singh, C.Brocker, V.Koppaka,. (2013). Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress. Free Radic Biol Med 56:89–101.
209. T.Sjöblom, S.Jones, L.D.Wood,. (2006). The consensus coding sequences of human breast and colorectal cancers. Science 314:268–274.
210. Y.Soini, M.Eskelinen, P.Juvonen,. (2014). Nuclear Nrf2 expression is related to a poor survival in pancreatic adenocarcinoma. Pathol Res Pract 210:35–39.
211. L.M.Solis, C.Behrens, W.Dong,. (2010). Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features. Clin Cancer Res 16:3743–3753.
212. M.B.Sporn, K.T.Liby (2012). NRF2 and cancer:the good, the bad and the importance of context. Nat Rev Cancer 12:564–571.
213. A.Strassburg, C.P.Strassburg, M.P.Manns,. (2002). Differential gene expression of NAD(P)H:quinone oxidoreductase and NRH:quinone oxidoreductase in human hepatocellular and biliary tissue. Mol Pharmacol 61:320–325.
214. F.Su, X.Hu, W.Jia,. (2003). Glutathion s transferase pi indicates chemotherapy resistance in breast cancer. J Surg Res 113:102–108.
215. D.H.Suh, M.K.Kim, J.H.No,. (2011). Metabolic approaches to overcoming chemoresistance in ovarian cancer. Ann N Y Acad Sci 1229:53–60.
216. Z.Sun, S.Zhang, J.Y.Chan,. (2007). Keap1 controls postinduction repression of the Nrf2-mediated antioxidant response by escorting nuclear export of Nrf2. Mol Cell Biol 27:6334–6349.
217. K.Taguchi, H.Motohashi, M.Yamamoto (2011). Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes Cells 16:123–140.
218. E.Tak, S.Lee, J.Lee,. (2011). Human carbonyl reductase 1 upregulated by hypoxia renders resistance to apoptosis in hepatocellular carcinoma cells. J Hepatol 54:328–339.
219. T.Takahashi, M.Sonobe, T.Menju,. (2010). Mutations in Keap1 are a potential prognostic factor in resected non-small cell lung cancer. J Surg Oncol 101:500–506.
220. X.Tang, H.Wang, L.Fan,. (2011). Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs. Free Radic Biol Med 50:1599–1609.
221. T.Tarumoto, T.Nagai, K.Ohmine,. (2004). Ascorbic acid restores sensitivity to imatinib via suppression of Nrf2-dependent gene expression in the imatinib-resistant cell line. Exp Hematol 32:375–381.
222. L.E.Tebay, H.Robertson, S.T.Durant,. (2015). Mechanisms of activation of the transcription factor Nrf2 by redox stressors, nutrient cues, and energy status and the pathways through which it attenuates degenerative disease. Free Radic Biol Med 88:108–146.
223. K.I.Tong, Y.Katoh, H.Kusunoki,. (2006). Keap1 recruits Neh2 through binding to ETGE and DLG motifs:characterization of the two-site molecular recognition model. Mol Cell Biol 26:2887–2900.
224. A.Urbschat, P.Paulus, Q.F.von Quernheim,. (2013). Vitamin D hydroxylases CYP2R1, CYP27B1 and CYP24A1 in renal cell carcinoma. Eur J Clin Invest 43:1282–1290.
225. M.G.van der Wijst, R.Brown, M.G.Rots (2014). Nrf2, the master redox switch:the Achilles' heel of ovarian cancer? Biochim Biophys Acta 1846:494–509.
226. S.Varatharajan, A.Abraham, W.Zhang,. (2012). Carbonyl reductase 1 expression influences daunorubicin metabolism in acute myeloid leukemia. Eur J Clin Pharmacol 68:1577–1586.
227. G.Venkatraman, M.G.Benesch, X.Tang,. (2014). Lysophosphatidate signaling stabilizes Nrf2 and increases the expression of genes involved in drug resistance and oxidative stress responses:implications for cancer treatment. FASEB J 29:772–785.
228. R.Venugopal, A.K.Jaiswal (1996). Nrf1 and Nrf2 positively and c-Fos and Fra1 negatively regulate the human antioxidant response element-mediated expression of NAD(P)H:quinone oxidoreductase1 gene. Proc Natl Acad Sci USA 93:14960–14965.
229. R.Venugopal, A.K.Jaiswal (1998). Nrf2 and Nrf1 in association with Jun proteins regulate antioxidant response element-mediated expression and coordinated induction of genes encoding detoxifying enzymes. Oncogene 17:3145–3156.
230. V.Vollrath, A.M.Wielandt, M.Iruretagoyena,. (2006). Role of Nrf2 in the regulation of the Mrp2 (ABCC2) gene. Biochem J 395:599–609.
231. P.von Dippe, M.Amoui, R.H.Stellwagen,. (1996). The functional expression of sodium-dependent bile acid transport in Madin-Darby canine kidney cells transfected with the cDNA for microsomal epoxide hydrolase. J Biol Chem 271:18176–18180.
232. B.Wang, X.Zhu, Y.Kim,. (2012). Histone deacetylase inhibition activates transcription factor Nrf2 and protects against cerebral ischemic damage. Free Radic Biol Med 52:928–936.
233. H.Wang, K.Liu, M.Geng,. (2013). RXRα inhibits the NRF2-ARE signaling pathway through a direct interaction with the Neh7 domain of NRF2. Cancer Res 73:3097–3108. RXRalpha
234. J.Wang, J.Zhang, L.Zhang,. (2011). Expression of P-gp, MRP, LRP, GST-π and TopoIIα and intrinsic resistance in human lung cancer cell lines. Oncol Rep 26:1081–1089.
235. R.Wang, J.An, F.Ji,. (2008a). Hypermethylation of the Keap1 gene in human lung cancer cell lines and lung cancer tissues. Biochem Biophys Res Commun 373:151–154.
236. X.J.Wang, J.D.Hayes, C.J.Henderson,. (2007). Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha. Proc Natl Acad Sci USA 104:19589–19594.
237. X.J.Wang, J.D.Hayes, C.R.Wolf (2006). Generation of a stable antioxidant response element-driven reporter gene cell line and its use to show redox-dependent activation of nrf2 by cancer chemotherapeutic agents. Cancer Res 66:10983–10994.
238. X.J.Wang, Y.Li, L.Luo,. (2014). Oxaliplatin activates the Keap1/Nrf2 antioxidant system conferring protection against the cytotoxicity of anticancer drugs. Free Radic Biol Med 70:68–77.
239. X.J.Wang, Z.Sun, N.F.Villeneuve,. (2008b). Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis 29:1235–1243.
240. Z.Wang, S.Liang, X.Lian,. (2015). Identification of proteins responsible for adriamycin resistance in breast cancer cells using proteomics analysis. Sci Rep 5:9301. doi:10.1038/srep09301.
241. J.Wijnholds, C.A.Mol, L.van Deemter,. (2000). Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc Natl Acad Sci USA 97:7476–7481.
242. G.Wu, G.Xu, B.A.Schulman,. (2003). Structure of a beta-TrCP1-Skp1-beta-catenin complex:destruction motif binding and lysine specificity of the SCF(beta-TrCP1) ubiquitin ligase. Mol Cell 11:1445–1456.
243. T.Y.Wu, T.O.Khor, J.H.Lee,. (2013). Pharmacogenetics, pharmacogenomics and epigenetics of Nrf2-regulated xenobiotic-metabolizing enzymes and transporters by dietary phytochemical and cancer chemoprevention. Curr Drug Metab 14:688–694.
244. C.Xia, X.Bai, X.Hou,. (2015). Cryptotanshinone reverses cisplatin resistance of human lung carcinoma A549 cells through down-regulating Nrf2 pathway. Cell Physiol Biochem 37:816–824.
245. X.Xu, Y.Zhang, W.Li,. (2014). Wogonin reverses multi-drug resistance of human myelogenous leukemia K562/A02 cells via downregulation of MRP1 expression by inhibiting Nrf2/ARE signaling pathway. Biochem Pharmacol 92:220–234.
246. Y.Yin, Q.Liu, B.Wang,. (2012). Expression and function of heme oxygenase-1 in human gastric cancer. Exp Biol Med (Maywood) 237:362–371.
247. N.J.Yoo, H.R.Kim, Y.R.Kim,. (2012). Somatic mutations of the KEAP1 gene in common solid cancers. Histopathology 60:943–952.
248. N.J.Yoo, Y.R.Kim, S.H.Lee (2010). Expression of NRF2, a cytoprotective protein, in gastric carcinomas. APMIS 118:613–614.
249. L.C.Young, B.G.Campling, S.P.Cole,. (2001). Multidrug resistance proteins MRP3, MRP1, and MRP2 in lung cancer:correlation of protein levels with drug response and messenger RNA levels. Clin Cancer Res 7:1798–1804.
250. O.E.Yri, P.O.Ekstrom, V.Hilden,. (2012). Polymorphisms in genes encoding interleukin-10 and drug metabolizing enzymes GSTP1, GSTT1, GSTA1 and UGT1A1 influence risk and outcome in Hodgkin lymphoma. Leuk Lymphoma 53:1934–1944.
251. J.Yuan, H.Lv, B.Peng,. (2009). Role of BCRP as a biomarker for predicting resistance to 5-fluorouracil in breast cancer. Cancer Chemother Pharmacol 63:1103–1110.
252. J.H.Yuan, J.Q.Cheng, L.Y.Jiang,. (2008). Breast cancer resistance protein expression and 5-fluorouracil resistance. Biomed Environ Sci 21:290–295.
253. N.Zelcer, T.Saeki, G.Reid,. (2001). Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). J Biol Chem 276:46400–46407.
254. D.D.Zhang (2010). The Nrf2-Keap1-ARE signaling pathway:the regulation and dual function of Nrf2 in cancer. Antioxid Redox Signal 13:1623–1626.
255. J.Zhang, T.Hosoya, A.Maruyama,. (2007). Nrf2 Neh5 domain is differentially utilized in the transactivation of cytoprotective genes. Biochem J 404:459–466.
256. L.Zhang, C.H.Fang, Y.F.Fan (2008). Detection of multidrug resistance-associated proteins MRP2, MRP3, and MRP5 mRNA expressions in hepatocarcinoma cells using SYBR real-time PCR. J South Med Univ 28:219–221.
257. M.Zhang, Y.D.Chai, J.Brumbaugh,. (2014). Oral cancer cells may rewire alternative metabolic pathways to survive from siRNA silencing of metabolic enzymes. BMC Cancer 14:223. doi:10.1186/1471-2407-14-223.
258. P.Zhang, A.Singh, S.Yegnasubramanian,. (2010a). Loss of Kelch-like ECH-associated protein 1 function in prostate cancer cells causes chemoresistance and radioresistance and promotes tumor growth. Mol Cancer Ther 9:336–346.
259. Y.H.Zhang, Q.Wu, X.Y.Xiao,. (2010b). Silencing MRP4 by small interfering RNA reverses acquired DDP resistance of gastric cancer cell. Cancer Lett 291:76–82.
260. L.Zhong, H.Shen, C.Huang,. (2011). AKR1B10 induces cell resistance to daunorubicin and idarubicin by reducing C13 ketonic group. Toxicol Appl Pharmacol 255:40–47.
261. Y.Zhong, F.Zhang, Z.Sun,. (2013). Drug resistance associates with activation of Nrf2 in MCF-7/DOX cells, and Wogonin reverses it by down-regulating Nrf2-mediated cellular defense response. Mol Carcinog 52:824–834.
262. S.Zhou, A.Starkov, M.K.Froberg,. (2001). Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Res 61:771–777.
263. Z.Zhu, Y.Mu, C.Qi,. (2015). CYP1B1 enhances the resistance of epithelial ovarian cancer cells to paclitaxel in vivo and in vitro. Int J Mol Med 35:340–348.