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

References

• Adema AD, Floor K, Smid K, et al. (2014). Overexpression of MRP4 (ABCC4) and MRP5 (ABCC5) confer resistance to the nucleoside analogs cytarabine and troxacitabine, but not gemcitabine. SpringerPlus 3:732–743.
   PubMed Web of Science ®Google Scholar
• Ahlers J, Witte KE, Schwarze CP, et al. (2014). Therapy response correlates with ALDH activity in ALDH low-positive childhood acute lymphoblastic leukemias. Pediatr Hematol Oncol 31:303–310.
   PubMed Web of Science ®Google Scholar
• Akhdar H, Loyer P, Rauch C, et al. (2009). Involvement of Nrf2 activation in resistance to 5-fluorouracil in human colon cancer HT-29 cells. Eur J Cancer 45:2219–2227.
   PubMed Web of Science ®Google Scholar
• Androutsopoulos VP, Spyrou I, Ploumidis A, et al. (2013). Expression profile of CYP1A1 and CYP1B1 enzymes in colon and bladder tumors. PLoS One 8:e82487. doi: 10.1371/journal.pone.0082487.
   PubMed Web of Science ®Google Scholar
• Apopa PL, He X, Ma Q. (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.
   PubMed Web of Science ®Google Scholar
• Arai T, Miyoshi Y, Kim SJ, et al. (2008). Association of GSTP1 expression with resistance to docetaxel and paclitaxel in human breast cancers. Eur J Surg Oncol 34:734–738.
   PubMed Web of Science ®Google Scholar
• Arlt A, Sebens S, Krebs S, et al. (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.
   PubMed Web of Science ®Google Scholar
• Ax W, Soldan M, Koch L, et al. (2000). Development of daunorubicin resistance in tumour cells by induction of carbonyl reduction. Biochem Pharmacol 59:293–300.
   PubMed Web of Science ®Google Scholar
• Baird L, Dinkova-Kostova AT. (2011). The cytoprotective role of the Keap1-Nrf2 pathway. Arch Toxicol 85:241–272.
   PubMed Web of Science ®Google Scholar
• Ballatori N, Hammond CL, Cunningham JB, et al. (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.
   PubMed Web of Science ®Google Scholar
• Bao L-J, Jaramillo MC, Yi X-F, et al. (2014). Nrf2 induces cisplatin resistance through activation of autophagy in ovarian carcinoma. Int J Clin Exp Pathol 7:1502–1513.
   PubMed Web of Science ®Google Scholar
• Barr MP, Gray SG, Hoffmann AC, et al. (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.
   Web of Science ®Google Scholar
• Barrera LN, Rushworth SA, Bowles KM, et al. (2012). Bortezomib induces heme oxygenase-1 expression in multiple myeloma. Cell Cycle 11:2248–2252.
   PubMed Web of Science ®Google Scholar
• Basta PV, Bensen JT, Tse CK, et al. (2008). Genetic variation in transaldolase 1 and risk of squamous cell carcinoma of the head and neck. Cancer Detect Prev 32:200–208.
   PubMedGoogle Scholar
• Beall HD, Winski SI. (2000). Mechanisms of action of quinone-containing alkylating agents. I: NQO1-directed drug development. Front Biosci 5:639–648.
   PubMed Web of Science ®Google Scholar
• Benson AM, Hunkeler MJ, Talalay P. (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.
   PubMed Web of Science ®Google Scholar
• Bock KW. (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.
   PubMed Web of Science ®Google Scholar
• Brown SL, Sekhar KR, Rachakonda G, et al. (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.
   PubMed Web of Science ®Google Scholar
• Brufsky AM. (2014). Current approaches and emerging directions in HER2-resistant breast cancer. Breast Cancer (Auckl) 8:109–118.
   PubMedGoogle Scholar
• Bunting KD, Lindahl R, Townsend AJ. (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.
   PubMed Web of Science ®Google Scholar
• Bunting KD, Townsend AJ. (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.
   PubMed Web of Science ®Google Scholar
• Calatozzolo C, Gelati M, Ciusani E, et al. (2005). Expression of drug resistance proteins Pgp, MRP1, MRP3, MRP5 and GST-pi in human glioma. J Neurooncol 74:113–121.
   PubMed Web of Science ®Google Scholar
• Chan JY, Han XL, Kan YW. (1993). Cloning of Nrf1, an NF-E2-related transcription factor, by genetic selection in yeast. Proc Natl Acad Sci USA 90:11371–11375.
   PubMed Web of Science ®Google Scholar
• Chartoumpekis DV, Wakabayashi N, Kensler TW. (2015). Keap1/Nrf2 pathway in the frontiers of cancer and non-cancer cell metabolism. Biochem Soc Trans 43:639–644.
   PubMed Web of Science ®Google Scholar
• Chen Z, Ye X, Tang N, et al. (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.
   PubMed Web of Science ®Google Scholar
• Chen ZS, Furukawa T, Sumizawa T, et al. (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.
   PubMed Web of Science ®Google Scholar
• Chen ZS, Tiwari AK. (2011). Multidrug resistance proteins (MRPs/ABCCs) in cancer chemotherapy and genetic diseases. FEBS J 278:3226–3245.
   PubMed Web of Science ®Google Scholar
• Chian S, Li YY, Wang XJ, et al. (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.
   PubMed Web of Science ®Google Scholar
• Cho JM, Manandhar S, Lee HR, et al. (2008). Role of the Nrf2-antioxidant system in cytotoxicity mediated by anticancer cisplatin: implication to cancer cell resistance. Cancer Lett 260:96–108.
   PubMed Web of Science ®Google Scholar
• Choi HK, Yang JW, Roh SH, et al. (2007). Induction of multidrug resistance associated protein 2 in tamoxifen-resistant breast cancer cells. Endocr Relat Cancer 14:293–303.
   PubMed Web of Science ®Google Scholar
• Chowdhry S, Zhang Y, McMahon M, et al. (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.
   PubMed Web of Science ®Google Scholar
• Corominas-Faja B, Oliveras-Ferraros C, Cuyas E, et al. (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.
   PubMed Web of Science ®Google Scholar
• Cortes-Dericks L, Froment L, Boesch R, et al. (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.
   PubMed Web of Science ®Google Scholar
• Cortessis V, Siegmund K, Chen Q, et al. (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.
   PubMed Web of Science ®Google Scholar
• Cui Y, König J, Buchholz JK, et al. (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.
   PubMed Web of Science ®Google Scholar
• Cui Y, Nadiminty N, Liu C, et al. (2014). Upregulation of glucose metabolism by NF-κB2/p52 mediates enzalutamide resistance in castration-resistant prostate cancer cells. Endocr Relat Cancer 21:435–442.
   PubMed Web of Science ®Google Scholar
• Cullinan SB, Zhang D, Hannink M, et al. (2003). Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol 23:7198–7209.
   PubMed Web of Science ®Google Scholar
• Cummings J, Ethell BT, Jardine L, et al. (2003). Glucuronidation as a mechanism of intrinsic drug resistance in human colon cancer: reversal of resistance by food additives. Cancer Res 63:8443–8450.
   PubMed Web of Science ®Google Scholar
• Cummings J, Ethell BT, Jardine L, et al. (2006). Glucuronidation of SN-38 and NU/ICRF 505 in human colon cancer and adjacent normal colon. Anticancer Res 26:2189–2196.
   PubMed Web of Science ®Google Scholar
• Cummings J, Zelcer N, Allen JD, et al. (2004). Glucuronidation as a mechanism of intrinsic drug resistance in colon cancer cells: contribution of drug transport proteins. Biochem Pharmacol 67:31–39.
   PubMed Web of Science ®Google Scholar
• de Groote ML, Verschure PJ, Rots MG. (2012). Epigenetic Editing: targeted rewriting of epigenetic marks to modulate expression of selected target genes. Nucleic Acids Res 40:10596–10613.
   PubMed Web of Science ®Google Scholar
• Dempke WC, Suto T, Reck M. (2010). Targeted therapies for non-small cell lung cancer. Lung Cancer-J IASLC 67:257–274.
   PubMed Web of Science ®Google Scholar
• DeNicola GM, Karreth FA, Humpton TJ, et al. (2011). Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475:106–109.
   PubMed Web of Science ®Google Scholar
• Dhakshinamoorthy S, Jain AK, Bloom DA, et al. (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.
   PubMed Web of Science ®Google Scholar
• Dinkova-Kostova AT, Talalay P. (2010). NAD(P)H:quinone acceptor oxidoreductase 1 (NQO1), a multifunctional antioxidant enzyme and exceptionally versatile cytoprotector. Arch Biochem Biophys 501:116–123.
   PubMed Web of Science ®Google Scholar
• Doyle L, Ross DD. (2003). Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 22:7340–7358.
   PubMed Web of Science ®Google Scholar
• Doyle LA, Yang WK, Abruzzo LV, et al. (1998). A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA 95:15665–15670.
   PubMed Web of Science ®Google Scholar
• Dreger H, Westphal K, Wilck N, et al. (2010). Protection of vascular cells from oxidative stress by proteasome inhibition depends on Nrf2. Cardiovasc Res 85:395–403.
   PubMed Web of Science ®Google Scholar
• Duong HQ, Yi YW, Kang HJ, et al. (2014). Inhibition of NRF2 by PIK-75 augments sensitivity of pancreatic cancer cells to gemcitabine. Int J Oncol 44:959–969.
   PubMed Web of Science ®Google Scholar
• Ebert B, Kisiela M, Wsol V, et al. (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.
   PubMed Web of Science ®Google Scholar
• Faraonio R, Vergara P, Di Marzo D. (2006). p53 suppresses the Nrf2-dependent transcription of antioxidant response genes. J Biol Chem 281:39776–39784.
   PubMed Web of Science ®Google Scholar
• Fukutomi T, Takagi K, Mizushima T, et al. (2014). Kinetic, thermodynamic, and structural characterizations of the association between Nrf2-DLGex degron and Keap1. Mol Cell Biol 34:832–846.
   PubMed Web of Science ®Google Scholar
• Furfaro AL, Piras S, Passalacqua M, et al. (2014). HO-1 up-regulation: a key point in high-risk neuroblastoma resistance to bortezomib. Biochim Biophys Acta 1842:613–622.
   PubMed Web of Science ®Google Scholar
• Ganan-Gomez I, Wei Y, Yang H, et al. (2013). Oncogenic functions of the transcription factor Nrf2. Free Radic Biol Med 65:750–764.
   PubMed Web of Science ®Google Scholar
• Gao AM, Ke ZP, Shi F, et al. (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.
   PubMed Web of Science ®Google Scholar
• Gao AM, Ke ZP, Wang JN, et al. (2013b). Apigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway. Carcinogenesis 34:1806–1814.
   PubMed Web of Science ®Google Scholar
• Garofalo M, Croce CM. (2013). MicroRNAs as therapeutic targets in chemoresistance. Drug Resist Updates 16:47–59.
   PubMed Web of Science ®Google Scholar
• Gavelova M, Hladikova J, Vildova L, et al. (2008). Reduction of doxorubicin and oracin and induction of carbonyl reductase in human breast carcinoma MCF-7 cells. Chem Biol Interact 176:9–18.
   PubMed Web of Science ®Google Scholar
• Gonzalez B, Akman S, Doroshow J, et al. (1995). Protection against daunorubicin cytotoxicity by expression of a cloned human carbonyl reductase cDNA in K562 leukemia cells. Cancer Res 55:4646–4650.
   PubMed Web of Science ®Google Scholar
• Halon A, Materna V, Donizy P, et al. (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.
   Web of Science ®Google Scholar
• Hanada N, Takahata T, Zhou Q, et al. (2012). Methylation of the KEAP1 gene promoter region in human colorectal cancer. BMC Cancer 12:66. doi: 10.1186/1471-2407-12-66.
   PubMed Web of Science ®Google Scholar
• Hanneken A, Lin FF, Johnson J, et al. (2006). Flavonoids protect human retinal pigment epithelial cells from oxidative-stress-induced death. Invest Ophthalmol Vis Sci 47:3164–3177.
   PubMed Web of Science ®Google Scholar
• Hayden A, Douglas J, Sommerlad M, et al. (2014). The Nrf2 transcription factor contributes to resistance to cisplatin in bladder cancer. Urol Oncol 32:806–814.
   PubMed Web of Science ®Google Scholar
• Hayes JD, Chanas S,A. Henderson CJ, et al. (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.
   PubMed Web of Science ®Google Scholar
• Hayes JD, Dinkova-Kostova AT. (2014). The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci 39:199–218.
   PubMed Web of Science ®Google Scholar
• Hayes JD, Flanagan JU, Jowsey IR. (2005). Glutathione transferases. Annu Rev Pharmacol Toxicol 45:51–88.
   PubMed Web of Science ®Google Scholar
• Hayes JD, McMahon M. (2009). NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci 34:176–188.
   PubMed Web of Science ®Google Scholar
• Heasman SA, Zaitseva L, Bowles KM, et al. (2011). Protection of acute myeloid leukaemia cells from apoptosis induced by front-line chemotherapeutics is mediated by haem oxygenase-1. Oncotarget 2:658–668.
   PubMed Web of Science ®Google Scholar
• Higgins LG, Kelleher MO, Eggleston IM, et al. (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.
   PubMed Web of Science ®Google Scholar
• Hill DL, Laster WRJ, Struck RF. (1972). Enzymatic metabolism of cyclophosphamide and nicotine and production of a toxic cyclophosphamide metabolite. Cancer Res 32:658–665.
   PubMed Web of Science ®Google Scholar
• Hirotsu Y, Katsuoka F, Funayama R, et al. (2012). Nrf2-MafG heterodimers contribute globally to antioxidant and metabolic networks. Nucleic Acids Res 40:10228–10239.
   PubMed Web of Science ®Google Scholar
• Homma S, Ishii Y, Morishima Y, et al. (2009). Nrf2 enhances cell proliferation and resistance to anticancer drugs in human lung cancer. Clin Cancer Res 15:3423–3432.
   PubMed Web of Science ®Google Scholar
• Hong YB, Kang HJ, Kwon SY, et al. (2010). Nuclear factor (erythroid-derived 2)-like 2 regulates drug resistance in pancreatic cancer cells. Pancreas 39:463–472.
   PubMed Web of Science ®Google Scholar
• Hooijberg JH, Broxterman HJ, Kool M, et al. (1999). Antifolate resistance mediated by the multidrug resistance proteins MRP1 and MRP2. Cancer Res 59:2532–2535.
   PubMed Web of Science ®Google Scholar
• Hou X, Bai X, Gou X, et al. (2015). 3′, 4′, 5′, 5, 7-pentamethoxyflavone sensitizes cisplatin-resistant A549 cells to cisplatin by inhibition of Nrf2 pathway. Mol Cells 38:396–401.
   PubMed Web of Science ®Google Scholar
• Hu L, Miao W, Loignon M, et al. (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.
   PubMed Web of Science ®Google Scholar
• Hu XF, Yao J, Gao SG, et al. (2013). Nrf2 overexpression predicts prognosis and 5-FU resistance in gastric cancer. Asian Pac J Cancer Prev 14:5231–5235.
   PubMedGoogle Scholar
• Huang CP, Tsai MF, Chang TH, et al. (2013). ALDH-positive lung cancer stem cells confer resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Cancer Lett 328:144–151.
   PubMed Web of Science ®Google Scholar
• Huang HC, Nguyen T, Pickett CB. (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.
   PubMed Web of Science ®Google Scholar
• Huang J, Tan PH, Thiyagarajan J, et al. (2003). Prognostic significance of glutathione S-transferase-pi in invasive breast cancer. Mod Pathol 16:558–565.
   PubMed Web of Science ®Google Scholar
• Huang W, Ding L, Huang Q, et al. (2010). Carbonyl reductase 1 as a novel target of (−)-epigallocatechin gallate against hepatocellular carcinoma. Hepatology 52:703–714.
   PubMed Web of Science ®Google Scholar
• Huang Y, Sadee W. (2006). Membrane transporters and channels in chemoresistance and -sensitivity of tumor cells. Cancer Lett 239:168–182.
   PubMed Web of Science ®Google Scholar
• Iida K, Itoh K, Kumagai Y, et al. (2004). Nrf2 is essential for the chemopreventive efficacy of oltipraz against urinary bladder carcinogenesis. Cancer Res 64:6424–6431.
   PubMed Web of Science ®Google Scholar
• Ikeda R, Vermeulen LC, Lau E, et al. (2011). Isolation and characterization of gemcitabine-resistant human non-small cell lung cancer A549 cells. Int J Oncol 38:513–519.
   PubMed Web of Science ®Google Scholar
• Ito K, Oleschuk CJ, Westlake C, et al. (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.
   Web of Science ®Google Scholar
• Jang M, Kim Y, Won H, et al. (2012). Carbonyl reductase 1 offers a novel therapeutic target to enhance leukemia treatment by arsenic trioxide. Cancer Res 72:4214–4224.
   PubMed Web of Science ®Google Scholar
• Januchowski R, Wojtowicz K, Zabel M. (2013). The role of aldehyde dehydrogenase (ALDH) in cancer drug resistance. Biomed Pharmacother 67:669–680.
   PubMed Web of Science ®Google Scholar
• Jaramillo MC, Zhang DD. (2013). The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev 27:2179–2191.
   PubMed Web of Science ®Google Scholar
• Jeon WK, Hong HY, Seo WC, et al. (2012). Smad7 sensitizes A549 lung cancer cells to cisplatin-induced apoptosis through heme oxygenase-1 inhibition. Biochem Biophys Res Commun 420:288–292.
   PubMed Web of Science ®Google Scholar
• Jin Y, Penning TM. (2007). Aldo-keto reductases and bioactivation/detoxication. Annu Rev Pharmacol Toxicol 47:263–292.
   PubMed Web of Science ®Google Scholar
• Johansson K, Ahlen K, Rinaldi R, et al. (2007). Microsomal glutathione transferase 1 in anticancer drug resistance. Carcinogenesis 28:465–470.
   PubMed Web of Science ®Google Scholar
• Johansson K, Jarvliden J, Gogvadze V, et al. (2010). Multiple roles of microsomal glutathione transferase 1 in cellular protection: a mechanistic study. Free Radic Biol Med 49:1638–1645.
   PubMed Web of Science ®Google Scholar
• Jones DVJ, Winn RJ, Brown BW, et al. (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.
   PubMed Web of Science ®Google Scholar
• Kang HJ, Yi YW, Hong YB, et al. (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.
   Web of Science ®Google Scholar
• Kang KA, Piao MJ, Kim KC, et al. (2014b). Epigenetic modification of Nrf2 in 5-fluorouracil-resistant colon cancer cells: involvement of TET-dependent DNA demethylation. Cell Death Dis 5:e1183.
   PubMed Web of Science ®Google Scholar
• Katoh Y, Itoh K, Yoshida E, et al. (2001). Two domains of Nrf2 cooperatively bind CBP, a CREB binding protein, and synergistically activate transcription. Genes Cells 6:857–868.
   PubMed Web of Science ®Google Scholar
• Kawai Y, Garduno L, Theodore M, et al. (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.
   PubMed Web of Science ®Google Scholar
• Kawasaki Y, Ishigami S, Arigami T, et al. (2015). Clinicopathological significance of nuclear factor (erythroid-2)-related factor 2 (Nrf2) expression in gastric cancer. BMC Cancer 15:5.
   PubMed Web of Science ®Google Scholar
• Kim HR, Kim S, Kim EJ, et al. (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.
   PubMed Web of Science ®Google Scholar
• Kim JH, Yu S, Chen JD, et al. (2013a). The nuclear cofactor RAC3/AIB1/SRC-3 enhances Nrf2 signaling by interacting with transactivation domains. Oncogene 32:514–527.
   PubMed Web of Science ®Google Scholar
• Kim SK, Kim H, Lee DH, et al. (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.
   Web of Science ®Google Scholar
• Kim SK, Yang JW, Kim MR, et al. (2008b). Increased expression of Nrf2/ARE-dependent anti-oxidant proteins in tamoxifen-resistant breast cancer cells. Free Radic Biol Med 45:537–546.
   PubMed Web of Science ®Google Scholar
• Kim WD, Kim YW, Cho IJ, et al. (2012). E-cadherin inhibits nuclear accumulation of Nrf2: implications for chemoresistance of cancer cells. J Cell Sci 125:1284–1295.
   PubMed Web of Science ®Google Scholar
• Konstantinopoulos PA, Fountzilas E, Pillay K, et al. (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.
   PubMed Web of Science ®Google Scholar
• Konstantinopoulos PA, Spentzos D, Fountzilas E, et al. (2011). Keap1 mutations and Nrf2 pathway activation in epithelial ovarian cancer. Cancer Res 71:5081–5089.
   PubMed Web of Science ®Google Scholar
• Kool M, van der Linden M, de Haas M, et al. (1999). MRP3, an organic anion transporter able to transport anti-cancer drugs. Proc Natl Acad Sci USA 96:6914–6919.
   PubMed Web of Science ®Google Scholar
• Krajka-Kuzniak V, Paluszczak J, Szaefer H, et al. (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.
   PubMed Web of Science ®Google Scholar
• Kunicka T, Soucek P. (2014). Importance of ABCC1 for cancer therapy and prognosis. Drug Metab Rev 46:325–342.
   PubMed Web of Science ®Google Scholar
• Kweon MH, Adhami VM, Lee JS, et al. (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.
   PubMed Web of Science ®Google Scholar
• Lau A, Villeneuve NF, Sun Z, et al. (2008). Dual roles of Nrf2 in cancer. Pharmacol Res 58:262–270.
   PubMed Web of Science ®Google Scholar
• Lazarus P, Sun D. (2010). Potential role of UGT pharmacogenetics in cancer treatment and prevention: focus on tamoxifen and aromatase inhibitors. Drug Metab Rev 42:182–194.
   PubMed Web of Science ®Google Scholar
• Lee BS, Heo J, Kim YM, et al. (2006). Carbon monoxide mediates heme oxygenase 1 induction via Nrf2 activation in hepatoma cells. Biochem Biophys Res Commun 343:965–972.
   PubMed Web of Science ®Google Scholar
• Leinonen HM, Ruotsalainen AK, Maatta AM, et al. (2012). Oxidative stress-regulated lentiviral TK/GCV gene therapy for lung cancer treatment. Cancer Res 72:6227–6235.
   PubMed Web of Science ®Google Scholar
• Lemmens KJA, Sthijns MMJPE ,van der Vijgh WJF, et al. (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.
   Google Scholar
• Leonardo CC, Dore S. (2011). Dietary flavonoids are neuroprotective through Nrf2-coordinated induction of endogenous cytoprotective proteins. Nutr Neurosci 14:226–236.
   PubMed Web of Science ®Google Scholar
• Lewis DF. (2004). 57 varieties: the human cytochromes P450. Pharmacogenomics 5:305–318.
   PubMed Web of Science ®Google Scholar
• Li D, Ma S, Ellis EM. (2014a). Nrf2-mediated adaptive response to methyl glyoxal in HepG2 cells involves the induction of AKR7A2. Chem Biol Interact 234:366–371.
   PubMed Web of Science ®Google Scholar
• Li M, Wang Z, Guo J, et al. (2014b). Clinical significance of UGT1A1 gene polymorphisms on irinotecan-based regimens as the treatment in metastatic colorectal cancer. Onco Targets Ther 7:1653–1661.
   PubMed Web of Science ®Google Scholar
• Li W, Liu H, Zhou JS, et al. (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.
   PubMed Web of Science ®Google Scholar
• Ji L, Wei Y, Jiang T, et al. (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.
   PubMed Web of Science ®Google Scholar
• Lim J, Lee SH, Cho S, et al. (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.
   PubMed Web of Science ®Google Scholar
• Lister A, Nedjadi T, Kitteringham NR, et al. (2011). Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy. Mol Cancer 10:37. doi: 10.1186/1476-4598-10-37.
   PubMed Web of Science ®Google Scholar
• Liu XM, Chapman GB, Peyton K, et al. (2002). Carbon monoxide inhibits apoptosis in vascular smooth muscle cells. Cardiovasc Res 55:396–405.
   PubMed Web of Science ®Google Scholar
• Lockhart AC, Tirona RG, Kim RB. (2003). Pharmacogenetics of ATP-binding cassette transporters in cancer and chemotherapy. Mol Cancer Ther 2:685–698.
   PubMed Web of Science ®Google Scholar
• Lorico A, Rappa G, Finch RA, et al. (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.
   PubMed Web of Science ®Google Scholar
• Lu CY, Yeh YS, Huang CW, et al. (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.
   PubMed Web of Science ®Google Scholar
• Ma J, Yang J, Wang C, et al. (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.
   PubMed Web of Science ®Google Scholar
• Ma Y, Wink M. (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.
   PubMed Web of Science ®Google Scholar
• Magesh S, Chen Y, Hu L. (2012). Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents. Med Res Rev 32:687–726.
   PubMed Web of Science ®Google Scholar
• Mahaffey CM, Mahaffey NC, Holland W, et al. (2012). Aberrant regulation of the MRP3 gene in non-small cell lung carcinoma. J Thorac Oncol 7:34–39.
   PubMed Web of Science ®Google Scholar
• Mahaffey CM, Zhang H, Rinna A, et al. (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.
   PubMed Web of Science ®Google Scholar
• Maher JM, Dieter MZ, Aleksunes LM, et al. (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.
   PubMed Web of Science ®Google Scholar
• Malhotra D, Portales-Casamar E, Singh A, et al. (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.
   PubMed Web of Science ®Google Scholar
• Maliepaard M, van Gastelen MA, Tohgo A, et al. (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.
   PubMed Web of Science ®Google Scholar
• Malloy MT, McIntosh DJ, Walters TS, et al. (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.
   PubMed Web of Science ®Google Scholar
• Mani M, Khaghani S, Gol Mohammadi T, et al. (2013). Activation of Nrf2-antioxidant response element mediated glutamate cysteine ligase expression in hepatoma cell line by homocysteine. Hepat Mon 13:e8394.
   PubMed Web of Science ®Google Scholar
• Martinez VG, O'connor R, Liang Y, et al. (2008). CYP1B1 expression is induced by docetaxel: effect on cell viability and drug resistance. Br J Cancer 98:564–570.
   PubMed Web of Science ®Google Scholar
• Marzec JM, Christie JD, Reddy SP, et al. (2007). Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury. FASEB J 21:2237–2246.
   PubMed Web of Science ®Google Scholar
• Materna V, Liedert B, Thomale J, et al. (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.
   PubMed Web of Science ®Google Scholar
• Matsunaga T, Yamane Y, Iida K, et al. (2011). Involvement of the aldo-keto reductase, AKR1B10, in mitomycin-c resistance through reactive oxygen species-dependent mechanisms. Anticancer Drugs 22:402–408.
   PubMed Web of Science ®Google Scholar
• Mayerhofer M, Florian S, Krauth MT, et al. (2004). Identification of heme oxygenase-1 as a novel BCR/ABL-dependent survival factor in chronic myeloid leukemia. Cancer Res 64:3148–3154.
   PubMed Web of Science ®Google Scholar
• Mayerhofer M, Gleixner KV, Mayerhofer J, et al. (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.
   PubMed Web of Science ®Google Scholar
• McAleer MA, Breen MA, White NL, et al. (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.
   PubMed Web of Science ®Google Scholar
• McFadyen MC, McLeod HL, Jackson FC, et al. (2001). Cytochrome P450 CYP1B1 protein expression: a novel mechanism of anticancer drug resistance. Biochem Pharmacol 62:207–212.
   PubMed Web of Science ®Google Scholar
• McMahon M, Thomas N, Itoh K, et al. (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.
   PubMed Web of Science ®Google Scholar
• Meng E, Mitra A, Tripathi K, et al. (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.
   Web of Science ®Google Scholar
• Mitsuishi Y, Taguchi K, Kawatani Y, et al. (2012). Nrf2 redirects glucose and glutamine into anabolic pathways in metabolic reprogramming. Cancer Cell 22:66–79.
   PubMed Web of Science ®Google Scholar
• Miura S, Shibazaki M, Kasai S, et al. (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.
   PubMed Web of Science ®Google Scholar
• Miyazaki T, Kirino Y, Takeno M, et al. (2010). Expression of heme oxygenase-1 in human leukemic cells and its regulation by transcriptional repressor Bach1. Cancer Sci 101:1409–1416.
   PubMed Web of Science ®Google Scholar
• Moi P, Chan K, Asunis I, et al. (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.
   PubMed Web of Science ®Google Scholar
• Moinova HR, Mulcahy RT. (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.
   PubMed Web of Science ®Google Scholar
• Moon EJ, Giaccia A. (2014). Dual roles of NRF2 in tumor prevention and progression: possible implications in cancer treatment. Free Radic Biol Med 79:292–299.
   PubMed Web of Science ®Google Scholar
• Murray GI, Patimalla S, Stewart KN, et al. (2010). Profiling the expression of cytochrome P450 in breast cancer. Histopathology 57:202–211.
   PubMed Web of Science ®Google Scholar
• Muscarella LA, Parrella P, D’alessandro V, et al. (2014). Frequent epigenetics inactivation of KEAP1 gene in non-small cell lung cancer. Epigenetics 6:710–719.
   Web of Science ®Google Scholar
• Muzio G, Maggiora M, Paiuzzi E, et al. (2012). Aldehyde dehydrogenases and cell proliferation. Free Radic Biol Med 52:735–746.
   PubMed Web of Science ®Google Scholar
• Nagai T, Kikuchi S, Ohmine K, et al. (2008). Hemin reduces cellular sensitivity to imatinib and anthracyclins via Nrf2. J Cell Biochem 104:680–691.
   PubMed Web of Science ®Google Scholar
• Nagashima S, Soda H, Oka M, et al. (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.
   PubMed Web of Science ®Google Scholar
• Nebert DW, Vasiliou V. (2004). Analysis of the glutathione S-transferase (GST) gene family. Hum Genom 1:460–464.
   PubMedGoogle Scholar
• Nebert DW, Wikvall K, Miller WL. (2013). Human cytochromes P450 in health and disease. Philos Trans R Soc Lond B Biol Sci 368:20120431.
   PubMed Web of Science ®Google Scholar
• Ni Z, Bikadi Z, Rosenberg MF, et al. (2010). Structure and function of the human breast cancer resistance protein (BCRP/ABCG2). Curr Drug Metab 11:603–617.
   PubMed Web of Science ®Google Scholar
• Nioi P, Nguyen T. (2007). A mutation of Keap1 found in breast cancer impairs its ability to repress Nrf2 activity. Biochem Biophys Res Commun 362:816–821.
   PubMed Web of Science ®Google Scholar
• Nishikawa S, Konno M, Hamabe A, et al. (2013). Aldehyde dehydrogenase high gastric cancer stem cells are resistant to chemotherapy. Int J Oncol 42:1437–1442.
   PubMed Web of Science ®Google Scholar
• Niture SK, Khatri R, Jaiswal AK. (2014). Regulation of Nrf2 – an update. Free Radic Biol Med 66:36–44.
   PubMed Web of Science ®Google Scholar
• No JH, Kim YB, Song YS. (2014). Targeting nrf2 signaling to combat chemoresistance. J Cancer Prev 19:111–117.
   PubMedGoogle Scholar
• Noda E, Maeda K, Inoue T, et al. (2012). Predictive value of expression of ERCC 1 and GST-p for 5-fluorouracil/oxaliplatin chemotherapy in advanced colorectal cancer. Hepatogastroenterology 59:130–133.
   PubMed Web of Science ®Google Scholar
• Nowis D, Bugajski M, Winiarska M, et al. (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.
   PubMed Web of Science ®Google Scholar
• Oesch F. (1973). Mammalian epoxide hydrases: inducible enzymes catalysing the inactivation of carcinogenic and cytotoxic metabolites derived from aromatic and olefinic compounds. Xenobiotica 3:305–340.
   PubMed Web of Science ®Google Scholar
• Ogura T, Tong KI, Mio K, et al. (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.
   PubMed Web of Science ®Google Scholar
• Oguri T, Isobe T, Fujitaka K, et al. (2001). Association between expression of the MRP3 gene and exposure to platinum drugs in lung cancer. Int J Cancer 93:584–589.
   PubMed Web of Science ®Google Scholar
• Oguri T, Isobe T, Suzuki T, et al. (2000). Increased expression of the MRP5 gene is associated with exposure to platinum drugs in lung cancer. Int J Cancer 86:95–100.
   PubMed Web of Science ®Google Scholar
• Ohta T, Iijima K, Miyamoto M, et al. (2008). Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res 68:1303–1309.
   PubMed Web of Science ®Google Scholar
• Okano Y, Nezu U, Enokida Y, et al. (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.
   Web of Science ®Google Scholar
• Ooi A, Wong JC, Petillo D, et al. (2011). An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell 20:511–523.
   PubMed Web of Science ®Google Scholar
• Ota S, Ishii G, Goto K, et al. (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.
   PubMed Web of Science ®Google Scholar
• Padmanabhan B, Tong KI, Ohta T, et al. (2006). Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell 21:689–700.
   PubMed Web of Science ®Google Scholar
• Patra KC, Hay N. (2014). The pentose phosphate pathway and cancer. Trends Biochem Sci 39:347–354.
   PubMed Web of Science ®Google Scholar
• Piotrowska H, Kucinska M, Murias M. (2013). Expression of CYP1A1, CYP1B1 and MnSOD in a panel of human cancer cell lines. Mol Cell Biochem 383:95–102.
   PubMed Web of Science ®Google Scholar
• Plebuch M, Soldan M, Hungerer C, et al. (2007). Increased resistance of tumor cells to daunorubicin after transfection of cDNAs coding for anthracycline inactivating enzymes. Cancer Lett 255:49–56.
   PubMed Web of Science ®Google Scholar
• Pullarkat V, Meng Z, Tahara SM, et al. (2014). Proteasome inhibition induces both antioxidant and hb f responses in sickle cell disease via the nrf2 pathway. Hemoglobin 38:188–195.
   PubMed Web of Science ®Google Scholar
• Rada P, Rojo AI, Chowdhry S, et al. (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.
   PubMed Web of Science ®Google Scholar
• Rada P, Rojo AI, Evrard-Todeschi N, et al. (2012). Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP axis. Mol Cell Biol 32:3486–3499.
   PubMed Web of Science ®Google Scholar
• Ramos-Gomez M, Kwak MK, Dolan PM, et al. (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.
   PubMed Web of Science ®Google Scholar
• Ren D, Villeneuve NF, Jiang T, et al. (2011). Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci USA 108:1433–1438.
   PubMed Web of Science ®Google Scholar
• Robey RW, Medina-Pérez WY, Nishiyama K, et al. (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.
   PubMed Web of Science ®Google Scholar
• Robey RW, Polgar O, Deeken J, et al. (2007). ABCG2: determining its relevance in clinical drug resistance. Cancer Metastasis Rev 26:39–57.
   PubMed Web of Science ®Google Scholar
• Rochat B, Morsman JM, Murray GI, et al. (2001). Human CYP1B1 and anticancer agent metabolism: mechanism for tumor-specific drug inactivation? J Pharmacol Exp Ther 296:537–541.
   PubMed Web of Science ®Google Scholar
• Romero-Lorca A, Novillo A, Gaibar M, et al. (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.
   PubMed Web of Science ®Google Scholar
• Ross D, Kepa JK, Winski SL, et al. (2000). NAD(P)H:quinone oxidoreductase 1 (NQO1): chemoprotection, bioactivation, gene regulation and genetic polymorphisms. Chem Biol Interact 129:77–97.
   PubMed Web of Science ®Google Scholar
• Rushworth SA, Bowles KM, MacEwan DJ. (2011). High basal nuclear levels of Nrf2 in acute myeloid leukemia reduces sensitivity to proteasome inhibitors. Cancer Res 71:1999–2009.
   PubMed Web of Science ®Google Scholar
• Rushworth SA, MacEwan DJ. (2011). The role of nrf2 and cytoprotection in regulating chemotherapy resistance of human leukemia cells. Cancers (Basel) 3:1605–1621.
   PubMedGoogle Scholar
• Rushworth SA, Zaitseva L, Murray MY, et al. (2012). The high Nrf2 expression in human acute myeloid leukemia is driven by NF-κB and underlies its chemo-resistance. Blood 120:5188–5198.
   PubMed Web of Science ®Google Scholar
• Ryoo IG, Choi BH, Kwak MK. (2015). Activation of NRF2 by p62 and proteasome reduction in sphere-forming breast carcinoma cells. Oncotarget 6:8167–8184.
   PubMed Web of Science ®Google Scholar
• Sasaki H, Shitara M, Yokota K, et al. (2012). MRP3 gene expression correlates with NRF2 mutations in lung squamous cell carcinomas. Mol Med Rep 6:705–708.
   PubMed Web of Science ®Google Scholar
• Satoh H, Moriguchi T, Taguchi K, et al. (2010). Nrf2-deficiency creates a responsive microenvironment for metastasis to the lung. Carcinogenesis 31:1833–1843.
   PubMed Web of Science ®Google Scholar
• Schafer A, Teufel J, Ringel F, et al. (2012). Aldehyde dehydrogenase 1A1-a new mediator of resistance to temozolomide in glioblastoma. Neuro-oncology 14:1452–1464.
   PubMed Web of Science ®Google Scholar
• Schaupp CM, White CC, Merrill GF, et al. (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.
   PubMed Web of Science ®Google Scholar
• Schiff R, Reddy P, Ahotupa M, et al. (2000). Oxidative stress and AP-1 activity in tamoxifen-resistant breast tumors in vivo. J Natl Cancer Inst 92:1926–1934.
   PubMed Web of Science ®Google Scholar
• Scotlandi K, Remondini D, Castellani G, et al. (2009). Overcoming resistance to conventional drugs in Ewing sarcoma and identification of molecular predictors of outcome. J Clin Oncol 27:2209–2216.
   PubMed Web of Science ®Google Scholar
• Shatalova EG, Klein-Szanto AJ, Devarajan K, et al. (2011). Estrogen and cytochrome P450 1B1 contribute to both early- and late-stage head and neck carcinogenesis. Cancer Prev Res (Phila) 4:107–115.
   PubMed Web of Science ®Google Scholar
• Shi L, Chen ZG, Wu LL, et al. (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.
   PubMedGoogle Scholar
• Shibata T, Kokubu A, Gotoh M, et al. (2008). Genetic alteration of Keap1 confers constitutive Nrf2 activation and resistance to chemotherapy in gallbladder cancer. Gastroenterology 135:1358–1368.
   PubMed Web of Science ®Google Scholar
• Shim GS, Manandhar S, Shin DH, et al. (2009). Acquisition of doxorubicin resistance in ovarian carcinoma cells accompanies activation of the NRF2 pathway. Free Radic Biol Med 47:1619–1631.
   PubMed Web of Science ®Google Scholar
• Shiozawa K, Oka M, Soda H, et al. (2004). Reversal of breast cancer resistance protein (BCRP/ABCG2)-mediated drug resistance by novobiocin, a coumermycin antibiotic. Int J Cancer 108:146–151.
   PubMed Web of Science ®Google Scholar
• Siegel D, Ross D. (2000). Immunodetection of NAD(P)H:quinone oxidoreductase 1 (NQO1) in human tissues. Free Radic Biol Med 29:246–253.
   PubMed Web of Science ®Google Scholar
• Siegel D, Yan C, Ross D. (2012). NAD(P)H:quinone oxidoreductase 1 (NQO1) in the sensitivity and resistance to antitumor quinones. Biochem Pharmacol 83:1033–1040.
   PubMed Web of Science ®Google Scholar
• Singh A, Misra V, Thimmulappa RK, et al. (2006). Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med 3:1865–1876
   Web of Science ®Google Scholar
• Singh A, Wu H, Zhang P, et al. (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.
   PubMed Web of Science ®Google Scholar
• Singh S, Brocker C, Koppaka V, et al. (2013). Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress. Free Radic Biol Med 56:89–101.
   PubMed Web of Science ®Google Scholar
• Sjöblom T, Jones S, Wood LD, et al. (2006). The consensus coding sequences of human breast and colorectal cancers. Science 314:268–274.
   PubMed Web of Science ®Google Scholar
• Soini Y, Eskelinen M, Juvonen P, et al. (2014). Nuclear Nrf2 expression is related to a poor survival in pancreatic adenocarcinoma. Pathol Res Pract 210:35–39.
   PubMed Web of Science ®Google Scholar
• Solis LM, Behrens C, Dong W, et al. (2010). Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features. Clin Cancer Res 16:3743–3753.
   PubMed Web of Science ®Google Scholar
• Sporn MB, Liby KT. (2012). NRF2 and cancer: the good, the bad and the importance of context. Nat Rev Cancer 12:564–571.
   PubMed Web of Science ®Google Scholar
• Strassburg A, Strassburg CP, Manns MP, et al. (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.
   PubMed Web of Science ®Google Scholar
• Su F, Hu X, Jia W, et al. (2003). Glutathion s transferase pi indicates chemotherapy resistance in breast cancer. J Surg Res 113:102–108.
   PubMed Web of Science ®Google Scholar
• Suh DH, Kim MK, No JH, et al. (2011). Metabolic approaches to overcoming chemoresistance in ovarian cancer. Ann N Y Acad Sci 1229:53–60.
   PubMed Web of Science ®Google Scholar
• Sun Z, Zhang S, Chan JY, et al. (2007). Keap1 controls postinduction repression of the Nrf2-mediated antioxidant response by escorting nuclear export of Nrf2. Mol Cell Biol 27:6334–6349.
   PubMed Web of Science ®Google Scholar
• Taguchi K, Motohashi H, Yamamoto M. (2011). Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution. Genes Cells 16:123–140.
   PubMed Web of Science ®Google Scholar
• Tak E, Lee S, Lee J, et al. (2011). Human carbonyl reductase 1 upregulated by hypoxia renders resistance to apoptosis in hepatocellular carcinoma cells. J Hepatol 54:328–339.
   PubMed Web of Science ®Google Scholar
• Takahashi T, Sonobe M, Menju T, et al. (2010). Mutations in Keap1 are a potential prognostic factor in resected non-small cell lung cancer. J Surg Oncol 101:500–506.
   PubMed Web of Science ®Google Scholar
• Tang X, Wang H, Fan L, et al. (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.
   PubMed Web of Science ®Google Scholar
• Tarumoto T, Nagai T, Ohmine K, et al. (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.
   PubMed Web of Science ®Google Scholar
• Tebay LE, Robertson H, Durant ST, et al. (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.
   PubMed Web of Science ®Google Scholar
• Tong KI, Katoh Y, Kusunoki H, et al. (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.
   PubMed Web of Science ®Google Scholar
• Urbschat A, Paulus P, von Quernheim QF, et al. (2013). Vitamin D hydroxylases CYP2R1, CYP27B1 and CYP24A1 in renal cell carcinoma. Eur J Clin Invest 43:1282–1290.
   PubMed Web of Science ®Google Scholar
• van der Wijst MG, Brown R, Rots MG. (2014). Nrf2, the master redox switch: the Achilles' heel of ovarian cancer? Biochim Biophys Acta 1846:494–509.
   PubMed Web of Science ®Google Scholar
• Varatharajan S, Abraham A, Zhang W, et al. (2012). Carbonyl reductase 1 expression influences daunorubicin metabolism in acute myeloid leukemia. Eur J Clin Pharmacol 68:1577–1586.
   PubMed Web of Science ®Google Scholar
• Venkatraman G, Benesch MG, Tang X, et al. (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.
   PubMed Web of Science ®Google Scholar
• Venugopal R, Jaiswal AK. (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.
   PubMed Web of Science ®Google Scholar
• Venugopal R, Jaiswal AK. (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.
   PubMed Web of Science ®Google Scholar
• Vollrath V, Wielandt AM, Iruretagoyena M, et al. (2006). Role of Nrf2 in the regulation of the Mrp2 (ABCC2) gene. Biochem J 395:599–609.
   PubMed Web of Science ®Google Scholar
• von Dippe P, Amoui M, Stellwagen RH, et al. (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.
   PubMed Web of Science ®Google Scholar
• Wang B, Zhu X, Kim Y, et al. (2012). Histone deacetylase inhibition activates transcription factor Nrf2 and protects against cerebral ischemic damage. Free Radic Biol Med 52:928–936.
   PubMed Web of Science ®Google Scholar
• Wang H, Liu K, Geng M, et al. (2013). RXRα inhibits the NRF2-ARE signaling pathway through a direct interaction with the Neh7 domain of NRF2. Cancer Res 73:3097–3108. RXRalpha
   PubMed Web of Science ®Google Scholar
• Wang J, Zhang J, Zhang L, et al. (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.
   PubMed Web of Science ®Google Scholar
• Wang R, An J, Ji F, et al. (2008a). Hypermethylation of the Keap1 gene in human lung cancer cell lines and lung cancer tissues. Biochem Biophys Res Commun 373:151–154.
   PubMed Web of Science ®Google Scholar
• Wang XJ, Hayes JD, Henderson CJ, et al. (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.
   PubMed Web of Science ®Google Scholar
• Wang XJ, Hayes JD, Wolf CR. (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.
   PubMed Web of Science ®Google Scholar
• Wang XJ, Li Y, Luo L, et al. (2014). Oxaliplatin activates the Keap1/Nrf2 antioxidant system conferring protection against the cytotoxicity of anticancer drugs. Free Radic Biol Med 70:68–77.
   PubMed Web of Science ®Google Scholar
• Wang XJ, Sun Z, Villeneuve NF, et al. (2008b). Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis 29:1235–1243.
   PubMed Web of Science ®Google Scholar
• Wang Z, Liang S, Lian X, et al. (2015). Identification of proteins responsible for adriamycin resistance in breast cancer cells using proteomics analysis. Sci Rep 5:9301. doi: 10.1038/srep09301.
   PubMed Web of Science ®Google Scholar
• Wijnholds J, Mol CA, van Deemter L, et al. (2000). Multidrug-resistance protein 5 is a multispecific organic anion transporter able to transport nucleotide analogs. Proc Natl Acad Sci USA 97:7476–7481.
   PubMed Web of Science ®Google Scholar
• Wu G, Xu G, Schulman BA, et al. (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.
   PubMed Web of Science ®Google Scholar
• Wu TY, Khor TO, Lee JH, et al. (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.
   PubMed Web of Science ®Google Scholar
• Xia C, Bai X, Hou X, et al. (2015). Cryptotanshinone reverses cisplatin resistance of human lung carcinoma A549 cells through down-regulating Nrf2 pathway. Cell Physiol Biochem 37:816–824.
   PubMed Web of Science ®Google Scholar
• Xu X, Zhang Y, Li W, et al. (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.
   PubMed Web of Science ®Google Scholar
• Yin Y, Liu Q, Wang B, et al. (2012). Expression and function of heme oxygenase-1 in human gastric cancer. Exp Biol Med (Maywood) 237:362–371.
   PubMed Web of Science ®Google Scholar
• Yoo NJ, Kim HR, Kim YR, et al. (2012). Somatic mutations of the KEAP1 gene in common solid cancers. Histopathology 60:943–952.
   PubMed Web of Science ®Google Scholar
• Yoo NJ, Kim YR, Lee SH. (2010). Expression of NRF2, a cytoprotective protein, in gastric carcinomas. APMIS 118:613–614.
   PubMed Web of Science ®Google Scholar
• Young LC, Campling BG, Cole SP, et al. (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.
   PubMed Web of Science ®Google Scholar
• Yri OE, Ekstrom PO, Hilden V, et al. (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.
   PubMed Web of Science ®Google Scholar
• Yuan J, Lv H, Peng B, et al. (2009). Role of BCRP as a biomarker for predicting resistance to 5-fluorouracil in breast cancer. Cancer Chemother Pharmacol 63:1103–1110.
   PubMed Web of Science ®Google Scholar
• Yuan JH, Cheng JQ, Jiang LY, et al. (2008). Breast cancer resistance protein expression and 5-fluorouracil resistance. Biomed Environ Sci 21:290–295.
   PubMed Web of Science ®Google Scholar
• Zelcer N, Saeki T, Reid G, et al. (2001). Characterization of drug transport by the human multidrug resistance protein 3 (ABCC3). J Biol Chem 276:46400–46407.
   PubMed Web of Science ®Google Scholar
• Zhang DD. (2010). The Nrf2-Keap1-ARE signaling pathway: the regulation and dual function of Nrf2 in cancer. Antioxid Redox Signal 13:1623–1626.
   PubMed Web of Science ®Google Scholar
• Zhang J, Hosoya T, Maruyama A, et al. (2007). Nrf2 Neh5 domain is differentially utilized in the transactivation of cytoprotective genes. Biochem J 404:459–466.
   PubMed Web of Science ®Google Scholar
• Zhang L, Fang CH, Fan YF. (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.
   Google Scholar
• Zhang M, Chai YD, Brumbaugh J, et al. (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.
   PubMed Web of Science ®Google Scholar
• Zhang P, Singh A, Yegnasubramanian S, et al. (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.
   PubMed Web of Science ®Google Scholar
• Zhang YH, Wu Q, Xiao XY, et al. (2010b). Silencing MRP4 by small interfering RNA reverses acquired DDP resistance of gastric cancer cell. Cancer Lett 291:76–82.
   PubMed Web of Science ®Google Scholar
• Zhong L, Shen H, Huang C, et al. (2011). AKR1B10 induces cell resistance to daunorubicin and idarubicin by reducing C13 ketonic group. Toxicol Appl Pharmacol 255:40–47.
   PubMed Web of Science ®Google Scholar
• Zhong Y, Zhang F, Sun Z, et al. (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.
   PubMed Web of Science ®Google Scholar
• Zhou S, Starkov A, Froberg MK, et al. (2001). Cumulative and irreversible cardiac mitochondrial dysfunction induced by doxorubicin. Cancer Res 61:771–777.
   PubMed Web of Science ®Google Scholar
• Zhu Z, Mu Y, Qi C, et al. (2015). CYP1B1 enhances the resistance of epithelial ovarian cancer cells to paclitaxel in vivo and in vitro. Int J Mol Med 35:340–348.
   PubMed Web of Science ®Google Scholar