Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2
Open accessAbstract
Drug resistance during chemotherapy is the major obstacle to the successful treatment of many cancers. Here, we report that inhibition of NF-E2-related factor 2 (Nrf2) may be a promising strategy to combat chemoresistance. Nrf2 is a critical transcription factor regulating a cellular protective response that defends cells against toxic insults from a broad spectrum of chemicals. Under normal conditions, the low constitutive amount of Nrf2 protein is maintained by the Kelch-like ECH-associated protein1 (Keap1)-mediated ubiquitination and proteasomal degradation system. Upon activation, this Keap1-dependent Nrf2 degradation mechanism is quickly inactivated, resulting in accumulation and activation of the antioxidant response element (ARE)-dependent cytoprotective genes. Since its discovery, Nrf2 has been viewed as a 'good' transcription factor that protects us from many diseases. In this study, we demonstrate the dark side of Nrf2: stable overexpression of Nrf2 resulted in enhanced resistance of cancer cells to chemotherapeutic agents including cisplatin, doxorubicin and etoposide. Inversely, downregulation of the Nrf2-dependent response by overexpression of Keap1 or transient transfection of Nrf2-small interfering RNA (siRNA) rendered cancer cells more susceptible to these drugs. Upregulation of Nrf2 by the small chemical tert-butylhydroquinone (tBHQ) also enhanced the resistance of cancer cells, indicating the feasibility of using small chemical inhibitors of Nrf2 as adjuvants to chemotherapy to increase the efficacy of chemotherapeutic agents. Furthermore, we provide evidence that the strategy of using Nrf2 inhibitors to increase efficacy of chemotherapeutic agents is not limited to certain cancer types or anticancer drugs and thus can be applied during the course of chemotherapy to treat many cancer types.
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Some somatic mutations give rise to hyperactive Nrf2, which causes enhanced antioxidant capacity and confers protection of cancer cells from ROS and cancer therapy, leading to cancer cell growth and proliferation, cancer progression, and cancer therapy resistance.
“Some somatic mutations give rise to hyperactive Nrf2, which causes enhanced antioxidant capacity and confers protection of cancer cells from ROS and cancer therapy, thereby leading to cancer cell growth and proliferation, cancer progression, and cancer therapy resistance (e.g., chemoresistance) (Figure 8) [161,162,163,164,165,166,167,168,169,170,171].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [165]
Upregulation of Nrf2-mediated antioxidant proteins renders cancer cells resistant to chemotherapeutic drugs (e.g., cisplatin, 5-fluorouracil, docetaxel, and bortezomib) and radiotherapy.
“The resultant upregulation of Nrf2-mediated antioxidant proteins renders cancer cells resistant to chemotherapeutic drugs (e.g., cisplatin, 5-fluorouracil, docetaxel, and bortezomib) and radiotherapy [47,161,165,178,179,180,181,182,183,184].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [165]
Cites
Itoh, K., Wakabayashi, N., Katoh, Y., Ishii, T., Igarashi, K., Engel, J. D., & Yamamoto, M. (1999) · Genes & Development · doi:10.1101/gad.13.1.76 · Cited by 3,634 · see citing works
Kobayashi, A., Kang, M.-I., Okawa, H., Ohtsuji, M., Zenke, Y., Chiba, T., Igarashi, K., & Yamamoto, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.16.7130-7139.2004 · Cited by 2,224 · see citing works
Keap1 Is a Redox-Regulated Substrate Adaptor Protein for a Cul3-Dependent Ubiquitin Ligase Complex
Zhang, D. D., Lo, S., Cross, J. V., Templeton, D. J., & Hannink, M. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.24.10941-10953.2004 · Cited by 1,262 · see citing works
Self-citation(2002) · PubMed · Cited by 1,190 · see citing works
Ramos-Gomez, M., Kwak, M.-K., Dolan, P. M., Itoh, K., Yamamoto, M., Talalay, P., & Kensler, T. W. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.051618798 · Cited by 1,102 · see citing works
Mechanistic Studies of the Nrf2-Keap1 Signaling Pathway
Zhang, D. D. (2006) · Drug Metabolism Reviews · doi:10.1080/03602530600971974 · Cited by 1,091 · see citing works
Self-citationDysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer
Singh, A., Misra, V., Thimmulappa, R. K., Lee, H., Ames, S., Hoque, M. O., Herman, J. G., Baylin, S. B., Sidransky, D., Gabrielson, E., et al. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030420 · Cited by 1,060 · see citing works
Radjendirane, V., & Jaiswal, A. K. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.25.14960 · Cited by 1,034 · see citing works
Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke–induced emphysema in mice
Rangasamy, T., Cho, C. Y., Thimmulappa, R. K., Zhen, L., Srisuma, S., Kensler, T. W., Yamamoto, M. P., Petrache, I., Tuder, R. M., & Biswal, S. S. (2004) · Journal of Clinical Investigation · doi:10.1172/jci21146 · Cited by 993 · see citing works
Glutathione-Associated Enzymes In Anticancer Drug Resistance
Tew, K. D. (2016) · Cancer Research · doi:10.1158/0008-5472.can-15-3143 · Cited by 865 · see citing works
Kobayashi, M., & Yamamoto, M. P. (2006) · Advances in Enzyme Regulation · doi:10.1016/j.advenzreg.2006.01.007 · Cited by 855 · see citing works
Shih, A. Y., Johnson, D. A., Wong, G., Kraft, A. D., Jiang, L., Erb, H., Johnson, J. A., & Murphy, T. H. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-08-03394.2003 · Cited by 786 · see citing works
Lee, J., Calkins, M. J., Chan, K., Kan, Y. W., & Johnson, J. A. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211558200 · Cited by 783 · see citing works
Suh, J. H., Shenvi, S. V., Dixon, B. M., Liu, H., Jaiswal, A. K., Liu, R.-M., & Hagen, T. M. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0400282101 · Cited by 774 · see citing works
An important function of Nrf2 in combating oxidative stress: Detoxification of acetaminophen
Chan, K., Han, X.-D., & Kan, Y. W. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.081082098 · Cited by 766 · see citing works
Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer
Padmanabhan, B., Tong, K. I., Ohta, T., Nakamura, Y., Scharlock, M., Ohtsuji, M., Kang, M.-I., Kobayashi, A., Yokoyama, S., & Yamamoto, M. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.013 · Cited by 735 · see citing works
Enomoto, A. (2001) · Toxicological Sciences · doi:10.1093/toxsci/59.1.169 · Cited by 728 · see citing works
Kwak, M.-K., Wakabayashi, N., Itoh, K., Motohashi, H., Yamamoto, M. P., & Kensler, T. W. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m211898200 · Cited by 661 · see citing works
Regulation of γ-Glutamylcysteine Synthetase Subunit Gene Expression by the Transcription Factor Nrf2
Wild, A. C., Moinova, H., & Mulcahy, R. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.47.33627 · Cited by 595 · see citing works
Disruption of <i>Nrf2</i> enhances susceptibility to severe airway inflammation and asthma in mice
Rangasamy, T., Guo, J., Mitzner, W. A., Roman, J., Singh, A., Fryer, A. D., Yamamoto, M., Kensler, T. W., Tuder, R. M., Georas, S. N., et al. (2005) · The Journal of Experimental Medicine · doi:10.1084/jem.20050538 · Cited by 580 · see citing works
Sasaki, H., Sato, H., Kuriyama-Matsumura, K., Sato, K., Maebara, K., Wang, H., Tamba, M., Itoh, K., Yamamoto, M. P., & Bannai, S. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m208704200 · Cited by 544 · see citing works
Identification of Activating Transcription Factor 4 (ATF4) as an Nrf2-interacting Protein
He, C. H., Gong, P., Hu, B., Stewart, D., Choi, M. E., Choi, A. M. K., & Alam, J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m101198200 · Cited by 473 · see citing works
Nrf2 Defends the Lung from Oxidative Stress
Cho, H., Reddy, S. P., & Kleeberger, S. R. (2006) · Antioxidants and Redox Signaling · doi:10.1089/ars.2006.8.76 · Cited by 463 · see citing works
Braun, S., Hanselmann, C., Gassmann, M. G., auf dem Keller, U., Born-Berclaz, C., Chan, K., Kan, Y. W., & Werner, S. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.15.5492-5505.2002 · Cited by 410 · see citing works
Heme Oxygenase-1 in Tumors: Is It a False Friend?
Józkowicz, A., Waś, H., & Dulak, J. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1659 · Cited by 381 · see citing works
Iida, K., Itoh, K., Kumagai, Y., Oyasu, R., Hattori, K., Kawai, K., Shimazui, T., Akaza, H., & Yamamoto, M. P. (2004) · Cancer Research · doi:10.1158/0008-5472.can-04-1906 · Cited by 372 · see citing works
The transcription factor NRF2 protects against pulmonary fibrosis
Cho, H., Reddy, S. P., Yamamoto, M. P., & Kleeberger, S. R. (2004) · The FASEB Journal · doi:10.1096/fj.03-1127fje · Cited by 355 · see citing works
Nrf2‐deficient mice are highly susceptible to cigarette smoke‐induced emphysema
Iizuka, T., Ishii, Y., Itoh, K., Kiwamoto, T., Kimura, T., Matsuno, Y., Morishima, Y., Hegab, A. E., Homma, S., Nomura, A., et al. (2005) · Genes to Cells · doi:10.1111/j.1365-2443.2005.00905.x · Cited by 336 · see citing works
Sun, Z., Zhang, S., Chan, J. Y., & Zhang, D. D. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00630-07 · Cited by 332 · see citing works
Self-citationChan, J. Y., & Kwong, M. (2000) · Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression · doi:10.1016/s0167-4781(00)00238-4 · Cited by 317 · see citing works
Kensler, T. W., Chen, J., Egner, P. A., Fahey, J. W., Jacobson, L. P., Stephenson, K. K., Ye, L., Coady, J. L., Wang, J.-B., Wu, Y., et al. (2005) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-05-0368 · Cited by 317 · see citing works
Wang, X. J., Hayes, J. D., & Wolf, C. R. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-2298 · Cited by 317 · see citing works
Self-citationDoxorubicin-DNA Adducts Induce a Non-Topoisomerase II–Mediated Form of Cell Death
Swift, L. P., Rephaeli, A., Nudelman, A., Phillips, D. R., & Cutts, S. M. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3410 · Cited by 314 · see citing works
Selvakumaran, M., Pisarcik, D., Bao, R., et al. (2003) · PubMed · Cited by 314 · see citing works
Accelerated DNA adduct formation in the lung of the Nrf2 knockout mouse exposed to diesel exhaust
Aoki, Y., Sato, H., Nishimura, N., Takahashi, S., Itoh, K., & Yamamoto, M. (2001) · Toxicology and Applied Pharmacology · doi:10.1006/taap.2001.9176 · Cited by 297 · see citing works
DNA Repair: Enzymatic Mechanisms and Relevance to Drug Response
Chaney, S. G., & Sancar, A. (1996) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/88.19.1346 · Cited by 279 · see citing works
Shih, A. Y., Imbeault, S., Barakauskas, V., Erb, H., Jiang, L., Li, P., & Murphy, T. H. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m414635200 · Cited by 273 · see citing works
Hayashi, A., Suzuki, H., Itoh, K., Yamamoto, M. P., & Sugiyama, Y. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2003.09.086 · Cited by 267 · see citing works
Maher, J. M., Cheng, X., Slitt, A. L., Dieter, M. Z., & Klaassen, C. D. (2005) · Drug Metabolism and Disposition · doi:10.1124/dmd.105.003798 · Cited by 255 · see citing works
Ishii, Y., Itoh, K., Morishima, Y., Kimura, T., Kiwamoto, T., IIzuka, T., Hegab, A. E., Hosoya, T., Nomura, A., Sakamoto, T., et al. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.10.6968 · Cited by 248 · see citing works
Overexpression of Heme Oxygenase-1 in Murine Melanoma
Waś, H., Cichoń, T., Smolarczyk, R., Rudnicka, D., Stopa, M., Chevalier, C., Leger, J. J., Lackowska, B., Grochot‐Przeczek, A., Bojkowska, K., et al. (2006) · American Journal Of Pathology · doi:10.2353/ajpath.2006.051365 · Cited by 192 · see citing works
Heme oxygenase-1 protects tumor cells against photodynamic therapy-mediated cytotoxicity
Nowis, D., Legat, M., Grzela, T., Niderla, J., Wilczek, E., Wilczynski, G. M., Głodkowska‐Mrówka, E., Mrówka, P., Issat, T., Dulak, J., et al. (2006) · Oncogene · doi:10.1038/sj.onc.1209378 · Cited by 185 · see citing works
Cho, J., Manandhar, S., Lee, H., Park, H.-M., & Kwak, M. (2007) · Cancer Letters · doi:10.1016/j.canlet.2007.10.022 · Cited by 167 · see citing works
Induction of Mrp3 and Mrp4 transporters during acetaminophen hepatotoxicity is dependent on Nrf2
Aleksunes, L. M., Slitt, A. L., Maher, J. M., Augustine, L. M., Goedken, M. J., Chan, J. Y., Cherrington, N. J., Klaassen, C. D., & Manautou, J. E. (2007) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2007.08.022 · Cited by 152 · see citing works
A Two-drug Model for Etoposide Action against Human Topoisomerase IIα
Bromberg, K. D., Burgin, A. B., & Osheroff, N. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m212056200 · Cited by 145 · see citing works
Stacy, D., Ely, K., Massion, P. P., Yarbrough, W. G., Hallahan, D. E., Sekhar, K. R., & Freeman, M. L. (2006) · Head & Neck · doi:10.1002/hed.20430 · Cited by 136 · see citing works
Kim, Y., Yamaguchi, Y., Kondo, N., Masutani, H., & Yodoi, J. (2003) · Oncogene · doi:10.1038/sj.onc.1206369 · Cited by 130 · see citing works
Accelerated Ovarian Failure Induced by 4-Vinyl Cyclohexene Diepoxide in Nrf2 Null Mice
Hu, X., Roberts, J. R., Apopa, P. L., Kan, Y. W., & Ma, Q. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.3.940-954.2006 · Cited by 127 · see citing works
Kim, H.-R., Kim, S.-J., Kim, E., Park, J., Yang, S., Jeong, E., Park, C., Youn, M., So, H., & Park, R. (2007) · Lung Cancer · doi:10.1016/j.lungcan.2007.09.021 · Cited by 114 · see citing works
Nrf2 protects human bladder urothelial cells from arsenite and monomethylarsonous acid toxicity
Wang, X.-J., Sun, Z., Chen, W., Eblin, K. E., Gandolfi, J. A., & Zhang, D. D. (2007) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2007.07.016 · Cited by 98 · see citing works
Self-citationActivating transcription factor 4 increases the cisplatin resistance of human cancer cell lines.
Tanabe, M., Izumi, H., Ise, T., et al. (2003) · PubMed · Cited by 80 · see citing works
Nrf2 and p53 cooperatively protect against BBN-induced urinary bladder carcinogenesis
Iida, K., Itoh, K., Maher, J. M., Kumagai, Y., Oyasu, R., Mori, Y., Shimazui, T., Akaza, H., & Yamamoto, M. P. (2007) · Carcinogenesis · doi:10.1093/carcin/bgm146 · Cited by 79 · see citing works
Kim, H., So, H., Lee, J., Lee, J., Park, C., Park, S.-Y., Kim, Y., Youn, M., Kim, S.-J., Chung, S.-Y., et al. (2006) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2006.01.018 · Cited by 75 · see citing works
Active Efflux System for Cisplatin in Cisplatin‐resistant Human KB Cells
Fujii, R., Mutoh, M., Niwa, K., et al. (1994) · Japanese Journal of Cancer Research · doi:10.1111/j.1349-7006.1994.tb02376.x · Cited by 68 · see citing works
p53 Determines Multidrug Sensitivity of Childhood Neuroblastoma
Xue, C., Haber, M., Flemming, C. L., Marshall, G. M., Lock, R. B., MacKenzie, K. L., Gurova, K. V., Norris, M. D., & Gudkov, A. V. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4345 · Cited by 64 · see citing works
Chemopreventive promise of targeting the Nrf2 pathway
Yates, M. S., & Kensler, T. W. (2007) · Drug News & Perspectives · doi:10.1358/dnp.2007.20.2.1083437 · Cited by 51 · see citing works
Janus face of Nrf2–HO-1 axis in cancer—Friend in chemoprevention, foe in anticancer therapy
Łoboda, A., Waś, H., Józkowicz, A., & Dulak, J. (2007) · Lung Cancer · doi:10.1016/j.lungcan.2007.10.024 · Cited by 34 · see citing works
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Oxidative stress, inflammation, and cancer: How are they linked?
Reuter, S., Gupta, S. C., Chaturvedi, M. M., & Aggarwal, B. B. (2010) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2010.09.006 · Cited by 5,441 · see citing works
Sun, X., Ou, Z., Chen, R., Niu, X., Chen, D., Kang, R., & Tang, D. (2016) · Hepatology · doi:10.1002/hep.28251 · Cited by 2,012 · see citing works
NRF2 and the Hallmarks of Cancer
Rojo de la Vega, M., Chapman, E., & Zhang, D. D. (2018) · Cancer Cell · doi:10.1016/j.ccell.2018.03.022 · Cited by 1,672 · see citing works
Self-citationNrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease
Ngo, V., & Duennwald, M. L. (2022) · Antioxidants · doi:10.3390/antiox11122345 · Cited by 1,130 · see citing works
NRF2 and cancer: the good, the bad and the importance of context
Sporn, M. B., & Liby, K. T. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3278 · Cited by 1,067 · see citing works
Tebay, L. E., Robertson, H., Durant, S. T., Vitale, S. R., Penning, T. M., Dinkova-Kostova, A. T., & Hayes, J. D. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.021 · Cited by 837 · see citing works
Stress-activated cap’n’collar transcription factors in aging and human disease
Sykiotis, G. P., & Bohmann, D. (2010) · Science Signaling · doi:10.1126/scisignal.3112re3 · Cited by 776 · see citing works
Natural compounds for cancer treatment and prevention
Nobili, S., Lippi, D., Witort, E., Donnini, M., Bausi, L., Mini, E., & Capaccioli, S. (2009) · Pharmacological Research · doi:10.1016/j.phrs.2009.01.017 · Cited by 780 · see citing works
Magesh, S., Chen, Y., & Hu, L. (2012) · Medicinal Research Reviews · doi:10.1002/med.21257 · Cited by 760 · see citing works
Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism
Ren, D., Villeneuve, N. F., Jiang, T., Wu, T., Lau, A., Toppin, H. A., & Zhang, D. D. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1014275108 · Cited by 673 · see citing works
Self-citationRoh, J.-L., Kim, E. H., Jang, H., & Shin, D. (2017) · Redox Biology · doi:10.1016/j.redox.2016.12.010 · Cited by 662 · see citing works
Direct Interaction between Nrf2 and p21Cip1/WAF1 Upregulates the Nrf2-Mediated Antioxidant Response
Chen, W., Sun, Z., Wang, X.-J., Jiang, T., Huang, Z., Fang, D., & Zhang, D. D. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.04.029 · Cited by 638 · see citing works
Self-citationThe Dual Roles of NRF2 in Cancer
Menegon, S., Columbano, A., & Giordano, S. (2016) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.05.002 · Cited by 633 · see citing works
Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities
Wondrak, G. T. (2009) · Antioxidants & Redox Signaling · doi:10.1089/ars.2009.2541 · Cited by 462 · see citing works
Self-citationThe multifaceted role of reactive oxygen species in tumorigenesis
Kirtonia, A., Sethi, G., & Garg, M. (2020) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-020-03536-5 · Cited by 452 · see citing works
Transcription factor NRF2 regulates miR-1 and miR-206 to drive tumorigenesis
Singh, A., Happel, C., Manna, S. K., Acquaah-Mensah, G., Carrerero, J., Kumar, S., Nasipuri, P., Krausz, K. W., Wakabayashi, N., Dewi, R., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci66353 · Cited by 333 · see citing works
Nrf2 mediates redox adaptations to exercise
Done, A. J., & Traustadóttir, T. (2016) · Redox Biology · doi:10.1016/j.redox.2016.10.003 · Cited by 308 · see citing works
Oncogenic KRAS Confers Chemoresistance by Upregulating NRF2
Tao, S., Wang, S., Moghaddam, S. J., Ooi, A., Chapman, E., Wong, P. K., & Zhang, D. D. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-1439 · Cited by 291 · see citing works
Self-citationGalan-Cobo, A., Sitthideatphaiboon, P., Qu, X., Poteete, A., Pisegna, M. A., Tong, P., Chen, P.-H., Boroughs, L. K., Rodriguez, M. L. M., Zhang, W., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-3527 · Cited by 292 · see citing works
High Levels of Nrf2 Determine Chemoresistance in Type II Endometrial Cancer
Jiang, T., Chen, N., Zhao, F., Wang, X.-J., Kong, B., Zheng, W., & Zhang, D. D. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0713 · Cited by 286 · see citing works
Thirty years of NRF2: advances and therapeutic challenges.
Zhang, D. D. (2025) · Nature Reviews Drug Discovery · doi:10.1038/s41573-025-01145-0 · Cited by 282 · see citing works
Self-citationKeap Calm, and Carry on Covalently
Wilson, A. J., Kerns, J. K., Callahan, J. F., & Moody, C. J. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm400224q · Cited by 171 · see citing works
The Oncogenic Action of NRF2 Depends on De-glycation by Fructosamine-3-Kinase
Sanghvi, V. R., Leibold, J., Mina, M., Mohan, P., Berishaj, M., Li, Z., Miele, M. M., Lailler, N., Zhao, C., de Stanchina, E., et al. (2019) · Cell · doi:10.1016/j.cell.2019.07.031 · Cited by 155 · see citing works
KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer
Krall, E. B., Wang, B., Munoz, D. M., Ilic, N., Raghavan, S., Niederst, M. J., Yu, K., Ruddy, D. A., Aguirre, A. J., Kim, J. W., et al. (2017) · eLife · doi:10.7554/elife.18970 · Cited by 160 · see citing works
Electrophiles in Foods: The Current Status of Isothiocyanates and Their Chemical Biology
NAKAMURA, Y., & MIYOSHI, N. (2010) · Bioscience, Biotechnology, and Biochemistry · doi:10.1271/bbb.90731 · Cited by 143 · see citing works
Role of p62/SQSTM1 in liver physiology and pathogenesis
Manley, S., Williams, J. A., & Ding, W.-X. (2013) · Experimental Biology and Medicine · doi:10.1177/1535370213489446 · Cited by 135 · see citing works
Tao, S., Justiniano, R., Zhang, D. D., & Wondrak, G. T. (2013) · Redox Biology · doi:10.1016/j.redox.2013.10.004 · Cited by 103 · see citing works
Self-citationMutations in Keap1 are a potential prognostic factor in resected non-small cell lung cancer
Takahashi, T., Sonobe, M., Menju, T., Nakayama, E., Mino, N., Iwakiri, S., Nagai, S., Sato, K., Miyahara, R., Okubo, K., et al. (2010) · Journal of Surgical Oncology · doi:10.1002/jso.21520 · Cited by 78 · see citing works
Rojo de la Vega, M., Krajisnik, A., Zhang, D., & Wondrak, G. (2017) · Nutrients · doi:10.3390/nu9121371 · Cited by 77 · see citing works
Self-citationTargeting Nrf2 with wogonin overcomes cisplatin resistance in head and neck cancer
Kim, E. H., Jang, H., Shin, D., Baek, S. H., & Roh, J.-L. (2016) · APOPTOSIS · doi:10.1007/s10495-016-1284-8 · Cited by 77 · see citing works
Roles of the KEAP1-NRF2 system in mammalian skin exposed to UV radiation
Ikehata, H., & Yamamoto, M. (2018) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2018.09.038 · Cited by 73 · see citing works
Renken, S., Nakajima, T., Magalhaes, I., Mattsson, J., Lundqvist, A., Arnér, E. S. J., Kiessling, R., & Wickström, S. L. (2022) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2021-004458 · Cited by 67 · see citing works
Manandhar, S., Choi, B.-H., Jung, K.-A., Ryoo, I.-G., Song, M., Kang, S. J., Choi, H.-G., Kim, J.-A., Park, P.-H., & Kwak, M.-K. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.02.031 · Cited by 45 · see citing works
NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy
Sanghvi, V. R., Mohan, P., Singh, K., Cao, L., Berishaj, M., Wolfe, A. L., Schatz, J. H., Lailler, N., de Stanchina, E., Viale, A., et al. (2021) · Cancers · doi:10.3390/cancers13040639 · Cited by 27 · see citing works
Zhou, S., Ye, W., Duan, X., Zhang, M., & Wang, J. (2013) · Digestive Diseases and Sciences · doi:10.1007/s10620-012-2537-1 · Cited by 18 · see citing works
Retracted
- Authors
- Wang, X.-J., Sun, Z., Villeneuve, N. F., Zhang, S., Zhao, F., Li, Y., Chen, W., Yi, X., Zheng, W., Wondrak, G. T., Wong, P. K., & Zhang, D. D.
- Affiliations
- University of Arizona (US)
- Corresponding author
- Zhang, D. D.
- Venue
- Carcinogenesis
- Publisher
- Oxford University Press (OUP)
- Published
- 2008-04-15
- Volume
- 29
- Issue
- 6
- Pages
- 1235-1243
- ISSN
- 0143-3334 (ISSN-L)
- 1460-2180
- PMC
- PMC3312612
- OpenAlex
- W2104718696
- Cited by
- 839
- References
- 57
- Citations by year
- 2026: 30 · 2025: 39 · 2024: 66 · 2023: 47 · 2022: 57 · 2021: 62 · 2020: 61 · 2019: 53 · 2018: 45 · 2017: 63 · 2016: 54 · 2015: 58 · 2014: 50 · 2013: 46 · 2012: 37
- FWCI
- 9.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Carcinogenesis (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Environmental Health Sciences (R01ES015010, ES 015010-01, T32ES007091, P30ES006694)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Keywords
- Nrf2, chemoresistance, Keap1, cisplatin, doxorubicin, etoposide, tert-butylhydroquinone, Nrf2 inhibitors, antioxidant response element, cancer chemotherapy, siRNA knockdown
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Antineoplastic Agents, Humans, Neoplasms, RNA, Messenger, Transfection, Immunoblotting, Gene Expression, Drug Resistance, Neoplasm, Reverse Transcriptase Polymerase Chain Reaction, RNA, Small Interfering, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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