Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism
Open accessAbstract
The major obstacle in cancer treatment is the resistance of cancer cells to therapies. Nrf2 is a transcription factor that regulates a cellular defense response and is ubiquitously expressed at low basal levels in normal tissues due to Keap1-dependent ubiquitination and proteasomal degradation. Recently, Nrf2 has emerged as an important contributor to chemoresistance. High constitutive expression of Nrf2 was found in many types of cancers, creating an environment conducive for cancer cell survival. Here, we report the identification of brusatol as a unique inhibitor of the Nrf2 pathway that sensitizes a broad spectrum of cancer cells and A549 xenografts to cisplatin and other chemotherapeutic drugs. Mechanistically, brusatol selectively reduces the protein level of Nrf2 through enhanced ubiquitination and degradation of Nrf2. Consequently, expression of Nrf2-downstream genes is reduced and the Nrf2-dependent protective response is suppressed. In A549 xenografts, brusatol and cisplatin cotreatment induced apoptosis, reduced cell proliferation, and inhibited tumor growth more substantially when compared with cisplatin treatment alone. Additionally, A549-K xenografts, in which Nrf2 is expressed at very low levels due to ectopic expression of Keap1, do not respond to brusatol treatment, demonstrating that brusatol-mediated sensitization to cisplatin is Nrf2 dependent. Moreover, a decrease in drug detoxification and impairment in drug removal may be the primary mechanisms by which brusatol enhances the efficacy of chemotherapeutic drugs. Taken together, these results clearly demonstrate the effectiveness of using brusatol to combat chemoresistance and suggest that brusatol can be developed into an adjuvant chemotherapeutic drug.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Brusatol enhances the efficacy of chemotherapy by inhibiting Nrf2.
“brusatol has been shown to enhance the efficacy of chemotherapy by inhibiting Nrf2 [229,230].”
From Nrf2 and Oxidative Stress: A General Overview of Mechanisms and Implications in Human Disease (2022) · cites this paper as [229]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Cell Survival Responses to Environmental Stresses Via the Keap1-Nrf2-ARE Pathway
Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.46.120604.141046 · Cited by 3,630 · 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
Dinkova-Kostova, A. T., Holtzclaw, W. D., Cole, R. N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., & Talalay, P. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.172398899 · Cited by 1,947 · 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-citationRamos-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
Cullinan, S. B., Gordan, J. D., Jin, J., Harper, J. W., & Diehl, J. A. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.19.8477-8486.2004 · Cited by 986 · see citing works
NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer
Hayes, J. D., & McMahon, M. J. (2009) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2008.12.008 · Cited by 870 · see citing works
Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2
Wang, X.-J., Sun, Z., Villeneuve, N. F., Zhang, S., Zhao, F., Li, Y., Chen, W., Yi, X., Zheng, W., Wondrak, G. T., et al. (2008) · Carcinogenesis · doi:10.1093/carcin/bgn095 · Cited by 839 · see citing works
Self-citationFurukawa, M., & Xiong, Y. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.25.1.162-171.2005 · Cited by 746 · 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 · cited 1× · see citing works
“When Yamamoto’s team revealed the structure of the Nrf2–Keap1 interaction, they demonstrated that two different mutations in the Kelch domain of Keap1 in lung cancer disrupted the interaction between Nrf2 and Keap1, leading to hyperactivation of the Nrf2-mediated protective response (19).”
BackgroundShibata, T., Ohta, T., Tong, K. I., Kokubu, A., Odogawa, R., Tsuta, K., Asamura, H., Yamamoto, M., & Hirohashi, S. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806268105 · Cited by 728 · see citing works
LAU, A., VILLENEUVE, N., Sun, Z., Wong, P. K., & Zhang, D. (2008) · Pharmacological Research · doi:10.1016/j.phrs.2008.09.003 · Cited by 645 · see citing works
Self-citationDirect 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-citationLoss of Keap1 Function Activates Nrf2 and Provides Advantages for Lung Cancer Cell Growth
Ohta, T., Iijima, K., Miyamoto, M., Nakahara, I., Tanaka, H., Ohtsuji, M., Suzuki, T., Kobayashi, A., Yokota, J., Sakiyama, T., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5003 · Cited by 630 · see citing works
Discovery of the Negative Regulator of Nrf2, Keap1: A Historical Overview
Itoh, K., Mimura, J., & Yamamoto, M. P. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3222 · Cited by 513 · see citing works
Nrf2: friend or foe for chemoprevention?
Kensler, T. W., & Wakabayashi, N. (2009) · Carcinogenesis · doi:10.1093/carcin/bgp231 · Cited by 487 · see citing works
Shibata, T., Kokubu, A., Gotoh, M., Ojima, H., Ohta, T., Yamamoto, M. P., & Hirohashi, S. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.06.082 · Cited by 470 · see citing works
Solis, L. M., Behrens, C., Dong, W., Suraokar, M. B., Ozburn, N. C., Moran, C. A., Corvalán, A. H., Biswal, S. S., Swisher, S. G., Bekele, B. N., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-3352 · Cited by 430 · see citing works
Nrf2 Enhances Cell Proliferation and Resistance to Anticancer Drugs in Human Lung Cancer
Homma, S., Ishii, Y., Morishima, Y., Yamadori, T., Matsuno, Y., Haraguchi, N., Kikuchi, N., Satoh, H., Sakamoto, T., Hizawa, N., et al. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-2822 · Cited by 417 · see citing works
The cancer chemopreventive actions of phytochemicals derived from glucosinolates
Hayes, J. D., Kelleher, M., & Eggleston, I. M. (2008) · European Journal of Nutrition · doi:10.1007/s00394-008-2009-8 · Cited by 404 · see citing works
Zhang, P., Singh, A., Yegnasubramanian, S., Esopi, D., Kombairaju, P., Bodas, M., Wu, H., Bova, G. S., & Biswal, S. S. (2010) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0589 · Cited by 376 · see citing works
Singh, A., Boldin‐Adamsky, S., Thimmulappa, R. K., Rath, S. K., Ashush, H., Coulter, J. B., Blackford, A. L., Goodman, S. N., Bunz, F., Watson, W. H., et al. (2008) · Cancer Research · doi:10.1158/0008-5472.can-08-1401 · Cited by 371 · see citing works
Nrf2: A Potential Molecular Target for Cancer Chemoprevention by Natural Compounds
Jeong, W., Jun, M., & Kong, A. T. (2006) · Antioxidants and Redox Signaling · doi:10.1089/ars.2006.8.99 · Cited by 371 · see citing works
Oncogenic NRF2 mutations in squamous cell carcinomas of oesophagus and skin
Kim, Y. R., Oh, J. E., Kim, M. S., Kang, M. R., Park, S. W., Han, J. Y., Eom, H., Yoo, N. J., & Lee, S. H. (2009) · The Journal of Pathology · doi:10.1002/path.2653 · Cited by 357 · see citing works
Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer
Khor, T. O., Huang, M.-T., Prawan, A., Liu, Y., Hao, X., Yu, S., Cheung, W. K. L., Chan, J. Y., Reddy, B. S., Yang, C. S., et al. (2008) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-08-0028 · Cited by 306 · see citing works
Zhang, D. D., Lo, S., Sun, Z., Habib, G. M., Lieberman, M. W., & Hannink, M. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m501279200 · Cited by 299 · see citing works
Self-citationHigh 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
Self-citationKim, S. K., Yang, J. W., Kim, M. R., Roh, S. H., Kim, H. G., Lee, K. Y., Jeong, H. G., & Kang, K. W. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.05.011 · Cited by 171 · see citing works
Signal transduction events elicited by cancer prevention compounds
Kong, A. T., Yu, R., Hebbar, V., Chen, C., Owuor, E. D., Hu, R., Ee, P. L. R., & Mandlekar, S. (2001) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/s0027-5107(01)00182-8 · Cited by 169 · 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
Current Standards of Care in Small-Cell and Non-Small-Cell Lung Cancer
Schiller, J. H. (2001) · Oncology · doi:10.1159/000055386 · Cited by 154 · 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
The Double-Edged Sword of Nrf2: Subversion of Redox Homeostasis during the Evolution of Cancer
Hayes, J. D., & McMahon, M. J. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.03.004 · Cited by 134 · see citing works
Shim, G.-S., Manandhar, S., Shin, D., Kim, T., & Kwak, M. (2009) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2009.09.006 · Cited by 132 · see citing works
Du, Y., Villeneuve, N. F., Wang, X., Sun, Z., Chen, W., Li, J., Lou, H., Wong, P. K., & Zhang, D. D. (2008) · Environmental Health Perspectives · doi:10.1289/ehp.11464 · Cited by 99 · see citing works
Self-citationNuclear Factor (Erythroid-Derived 2)-Like 2 Regulates Drug Resistance in Pancreatic Cancer Cells
Hong, Y. B., Kang, H. J., Kwon, S. Y., Kim, H. J., Kwon, K. Y., Cho, C. H., Lee, J., Kallakury, B., & Bae, I. (2010) · Pancreas · doi:10.1097/mpa.0b013e3181c31314 · Cited by 91 · see citing works
Mata‐Greenwood, E., Cuendet, M., Sher, D., Gustin, D. M., Stock, W., & Pezzuto, J. (2002) · Leukemia · doi:10.1038/sj.leu.2402696 · Cited by 83 · see citing works
Hall, I. H., Lee, K. H., Elgebaly, S. A., Imakura, Y., Sumida, Y., & Wu, R.-Y. (1979) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600680726 · Cited by 54 · see citing works
Brusatol-induced HL-60 cell differentiation involves NF-κB activation
Cuendet, M., Gills, J. J., & Pezzuto, J. M. (2004) · Cancer Letters · doi:10.1016/j.canlet.2003.11.011 · Cited by 41 · see citing works
Mechanism of eukaryotic protein synthesis inhibition by brusatol
Willingham, W., Stafford, E. A., Reynolds, S. H., Chaney, S. G., Lee, K.-H., Okano, M., & Hall, I. H. (1981) · Biochimica et Biophysica Acta (BBA) - Nucleic Acids and Protein Synthesis · doi:10.1016/0005-2787(81)90168-4 · Cited by 36 · see citing works
Elgebaly, S. A., Hall, I. H., Lee, K. H., Sumida, Y., Imakura, Y., & Wu, R.-Y. (1979) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600680727 · Cited by 31 · see citing works
Lee, K., Okano, M., Hall, I. H., Brent, D. A., & Soltmann, B. (1982) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600710320 · Cited by 27 · see citing works
Hall, I. H., Liou, Y. F., Lee, K. H., Chaney, S. G., & Willingham, W. (1983) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600720612 · Cited by 25 · see citing works
Mata‐Greenwood, E., Daeuble, J. F., Grieco, P. A., Dou, J., McChesney, J. D., Mehta, R. G., Kinghorn, A. D., & Pezzuto, J. M. (2001) · Journal of Natural Products · doi:10.1021/np010212p · Cited by 24 · see citing works
Liou, Y. F., Hall, I. H., OKANO, M., Lee, K. H., & Chaney, S. G. (1982) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600710414 · Cited by 24 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
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
The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis
Yamamoto, M., Kensler, T. W., & Motohashi, H. (2018) · Physiological Reviews · doi:10.1152/physrev.00023.2017 · Cited by 1,968 · see citing works
Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases
Cuadrado, A., Rojo, A. I., Wells, G., Hayes, J. D., Cousin, S. P., Rumsey, W. L., Attucks, O. C., Franklin, S., Levonen, A., Kensler, T. W., et al. (2019) · Nature Reviews Drug Discovery · doi:10.1038/s41573-018-0008-x · Cited by 1,474 · see citing works
The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer
Kansanen, E., Kuosmanen, S. M., Leinonen, H., & Levonen, A.-L. (2013) · Redox Biology · doi:10.1016/j.redox.2012.10.001 · Cited by 1,313 · see citing works
The emerging role of the Nrf2–Keap1 signaling pathway in cancerPreprint
Jaramillo, M. C., & Zhang, D. D. (2013) · Genes & Development · doi:10.1101/gad.225680.113 · Cited by 1,304 · see citing works
Self-citationGlutathione metabolism in cancer progression and treatment resistance
Bansal, A., & Simon, M. C. (2018) · The Journal of Cell Biology · doi:10.1083/jcb.201804161 · Cited by 1,234 · see citing works
Role of Glutathione in Cancer Progression and Chemoresistance
Traverso, N., Ricciarelli, R., Nitti, M., Marengo, B., Furfaro, A. L., Pronzato, M. A., Marinari, U. M., & Domenicotti, C. (2013) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2013/972913 · Cited by 1,208 · see citing works
ROS homeostasis and metabolism: a dangerous liason in cancer cells
Panieri, E., & Santoro, M. M. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.105 · Cited by 1,156 · see citing works
Nrf2 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
The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity
Xie, Y., Zhu, S., Song, X., Sun, X., Fan, Y., Liu, J., Zhong, M., Yuan, H., Zhang, L., Billiar, T. R., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.07.055 · Cited by 952 · see citing works
Shen, D.-W., Pouliot, L. M., Hall, M. D., & Gottesman, M. M. (2012) · Pharmacological Reviews · doi:10.1124/pr.111.005637 · Cited by 955 · see citing works
Regulated cell death (RCD) in cancer: key pathways and targeted therapies
Peng, F., Liao, M., Qin, R., Zhu, S., Peng, C. Y., Fu, L., Chen, Y., & Han, B. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01110-y · Cited by 850 · see citing works
Cragg, G. M. L., & Pezzuto, J. M. (2015) · Medical Principles and Practice · doi:10.1159/000443404 · Cited by 807 · see citing works
The Keap1–Nrf2–ARE Pathway As a Potential Preventive and Therapeutic Target: An Update
Lu, M., Ji, J., Jiang, Z., & You, Q. (2016) · Medicinal Research Reviews · doi:10.1002/med.21396 · Cited by 801 · see citing works
Magesh, S., Chen, Y., & Hu, L. (2012) · Medicinal Research Reviews · doi:10.1002/med.21257 · Cited by 760 · see citing works
Nrf2, the Master Regulator of Anti-Oxidative Responses
Vomund, S., Schäfer, A., Parnham, M., Brüne, B., & Von Knethen, A. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18122772 · Cited by 752 · see citing works
Metallothionein‐1G facilitates sorafenib resistance through inhibition of ferroptosis
Sun, X., Niu, X., Chen, R., He, W., Chen, D., Kang, R., & Tang, D. (2016) · Hepatology · doi:10.1002/hep.28574 · Cited by 707 · see citing works
Toward clinical application of the Keap1-Nrf2 pathway
Suzuki, T., Motohashi, H., & Yamamoto, M. (2013) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2013.04.005 · Cited by 680 · see citing works
Jordan, E. J., Kim, H. R., Arcila, M. E., Barron, D., Chakravarty, D., Gao, J., Chang, M. T., Ni, A., Kundra, R., Jonsson, P., et al. (2017) · Cancer Discovery · doi:10.1158/2159-8290.cd-16-1337 · Cited by 643 · see citing works
p62 links autophagy and Nrf2 signaling
Jiang, T., Harder, B. G., de la Vega, M. R., Wong, P. K., Chapman, E., & Zhang, D. D. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.014 · Cited by 642 · 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
Transcription Factor NRF2 as a Therapeutic Target for Chronic Diseases: A Systems Medicine Approach
Cuadrado, A., Manda, G., Hassan, A., Alcaraz, M. J., Barbas, C., Daiber, A., Ghezzi, P., León, R., López, M. G., Oliva, B., et al. (2018) · Pharmacological Reviews · doi:10.1124/pr.117.014753 · Cited by 632 · see citing works
Singh, A., Venkannagari, S., Oh, K. H., Zhang, Y., Rohde, J. M., Liu, L., Nimmagadda, S., Sudini, K. R., Brimacombe, K. R., Gajghate, S., et al. (2016) · ACS Chemical Biology · doi:10.1021/acschembio.6b00651 · Cited by 624 · see citing works
Activators and Inhibitors of NRF2: A Review of Their Potential for Clinical Development
Robledinos-Antón, N., Fernández-Ginés, R., Manda, G., & Cuadrado, A. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/9372182 · Cited by 608 · see citing works
NRF2 controls iron homeostasis and ferroptosis through HERC2 and VAMP8
Anandhan, A., Dodson, M. B., Shakya, A., Chen, J., Liu, P., Wei, Y., Tan, H., Wang, Q., Jiang, Z., Yang, K. B., et al. (2023) · Science Advances · doi:10.1126/sciadv.ade9585 · Cited by 531 · see citing works
Self-citationModulating NRF2 in Disease: Timing Is Everything
Dodson, M. B., de la Vega, M. R., Cholanians, A. B., Schmidlin, C. J., Chapman, E., & Zhang, D. D. (2018) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-010818-021856 · Cited by 540 · see citing works
Self-citationThe KEAP1–NRF2 System in Cancer
Taguchi, K., & Yamamoto, M. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00085 · Cited by 527 · see citing works
Therapeutic Potential of Nrf2 Activators in Streptozotocin-Induced Diabetic Nephropathy
Zheng, H., Whitman, S. A., Wu, W., Wondrak, G. T., Wong, P. K., Fang, D., & Zhang, D. D. (2011) · Diabetes · doi:10.2337/db11-0807 · Cited by 507 · see citing works
Self-citationTargeting antioxidants for cancer therapy
Glasauer, A., & Chandel, N. S. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.07.017 · Cited by 502 · see citing works
Nrf2 in cancers: A double‐edged sword
Wu, S., Lu, H., & Bai, Y. (2019) · Cancer Medicine · doi:10.1002/cam4.2101 · Cited by 473 · see citing works
A dual role for autophagy in a murine model of lung cancer
Rao, S., Tortola, L., Perlot, T., Wirnsberger, G., Novatchkova, M., Nitsch, R., Sykacek, P., Frank, L., Schramek, D., Komnenovic, V., et al. (2014) · Nature Communications · doi:10.1038/ncomms4056 · Cited by 444 · see citing works
Paradoxical Roles of Antioxidant Enzymes: Basic Mechanisms and Health Implications
Lei, X. G., Zhu, J., Cheng, W.-H., Bao, Y., Ho, Y.-S., Reddi, A. R., Holmgren, A., & Arnér, E. S. J. (2015) · Physiological Reviews · doi:10.1152/physrev.00010.2014 · Cited by 437 · see citing works
Phosphoinositide 3-Kinase/Akt Signaling and Redox Metabolism in Cancer
Koundouros, N., & Poulogiannis, G. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00160 · Cited by 420 · see citing works
Genomic alterations in lung adenocarcinoma
Devarakonda, S. H. K., Morgensztern, D., & Govindan, R. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00077-7 · Cited by 398 · see citing works
The Keap1–Nrf2 system in cancers: stress response and anabolic metabolism
Mitsuishi, Y., Motohashi, H., & Yamamoto, M. P. (2012) · Frontiers in Oncology · doi:10.3389/fonc.2012.00200 · Cited by 394 · see citing works
Say no to DMSO: dimethylsulfoxide inactivates cisplatin, carboplatin, and other platinum complexes
Hall, M. D., Telma, K. A., Chang, K.-E., Lee, T. D., Madigan, J. P., Lloyd, J. R., Goldlust, I. S., Hoeschele, J. D., & Gottesman, M. M. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0247 · Cited by 377 · see citing works
Natural product-derived pharmacological modulators of Nrf2/ARE pathway for chronic diseases
Kumar, H., Kim, I., More, S. V., Kim, B.-W., & Choi, D. (2013) · Natural Product Reports · doi:10.1039/c3np70065h · Cited by 334 · see citing works
Abed, D. A., Goldstein, M., Albanyan, H., Jin, H., & Hu, L. (2015) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2015.05.008 · Cited by 330 · see citing works
NRF2 as a regulator of cell metabolism and inflammation in cancer
He, F., Antonucci, L., & Karin, M. (2020) · Carcinogenesis · doi:10.1093/carcin/bgaa039 · Cited by 318 · see citing works
Molecular Basis of Electrophilic and Oxidative Defense: Promises and Perils of Nrf2
Ma, Q., & He, X. (2012) · Pharmacological Reviews · doi:10.1124/pr.110.004333 · Cited by 317 · see citing works
ROS-modulated therapeutic approaches in cancer treatment
Raza, M. H., Siraj, S., Arshad, A., Waheed, U., Aldakheel, F. M., Alduraywish, S. A., & Arshad, M. M. U. D. (2017) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-017-2464-9 · Cited by 301 · see citing works
The KEAP1-NRF2 pathway: Targets for therapy and role in cancer
Adinolfi, S., Patinen, T., Deen, A. J., Pitkänen, S., Härkönen, J., Kansanen, E., Küblbeck, J., & Levonen, A. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102726 · Cited by 301 · see citing works
The Nrf2/HO‐1 Axis in Cancer Cell Growth and Chemoresistance
Furfaro, A. L., Traverso, N., Domenicotti, C., Piras, S., Moretta, L., Marinari, U. M., Pronzato, M. A., & Nitti, M. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/1958174 · Cited by 295 · 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-citationKrajka‐Kuźniak, V., Paluszczak, J., & Baer‐Dubowska, W. (2016) · Pharmacological Reports · doi:10.1016/j.pharep.2016.12.011 · Cited by 288 · see citing works
Ge, M., Tian, H., Mao, L., Li, D., Lin, J., Hu, H., Huang, S., Zhang, C., & Mei, X. (2021) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13657 · Cited by 269 · see citing works
Lin, D., Wang, M., & Koeffler, H. P. (2017) · Gastroenterology · doi:10.1053/j.gastro.2017.06.066 · Cited by 249 · 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-citationThe genomic landscape of hepatoblastoma and their progenies with HCC-like features
Eichenmüller, M., Trippel, F., Kreuder, M., Beck, A., Schwarzmayr, T., Häberle, B., Cairo, S., Leuschner, I., von Schweinitz, D., Strom, T. M., et al. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.08.009 · Cited by 250 · see citing works
Ji, S., Li, Z., Song, W., Wang, Y., Liang, W., Li, K., Tang, S., Wang, Q., Qiao, X., Zhou, D., et al. (2016) · Journal of Natural Products · doi:10.1021/acs.jnatprod.5b00877 · Cited by 242 · see citing works
Inhibition of cancer antioxidant defense by natural compounds
Sznarkowska, A., Kostecka, A., Meller, K., & Bielawski, K. P. (2016) · Oncotarget · doi:10.18632/oncotarget.13723 · Cited by 241 · see citing works
Olayanju, A., Copple, I. M., Bryan, H. K., Edge, G. T., Sison, R. L., Wong, M. W., Lai, Z.-Q., Lin, Z.-X., Dunn, K., Sanderson, C. M., et al. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.11.003 · Cited by 232 · see citing works
Arsenic Inhibits Autophagic Flux, Activating the Nrf2-Keap1 Pathway in a p62-Dependent Manner
Lau, A., Zheng, Y., Tao, S., Wang, H., Whitman, S. A., White, E., & Zhang, D. D. (2013) · Molecular and Cellular Biology · doi:10.1128/mcb.01748-12 · Cited by 229 · see citing works
Self-citationMolecular and Chemical Regulation of the Keap1-Nrf2 Signaling Pathway
Keum, Y., & Choi, B. Y. (2014) · Molecules · doi:10.3390/molecules190710074 · Cited by 224 · see citing works
Nrf2: control of sensitivity to carcinogens
Slocum, S. L., & Kensler, T. W. (2011) · Archives of Toxicology · doi:10.1007/s00204-011-0675-4 · Cited by 219 · see citing works
Oxidative Stress, Inflammation and Colorectal Cancer: An Overview
Bardelčíková, A., Šoltýs, J., & Mojžíš, J. (2023) · Antioxidants · doi:10.3390/antiox12040901 · Cited by 222 · see citing works
Targeting SOD1 reduces experimental non–small-cell lung cancer
Glasauer, A., Sena, L. A., Diebold, L. P., Mazar, A. P., & Chandel, N. S. (2013) · Journal of Clinical Investigation · doi:10.1172/jci71714 · Cited by 212 · see citing works
Oncogenic functions of the transcription factor Nrf2
Gañán‐Gómez, I., Wei, Y., Yang, H., Boyano-Adánez, M. C., & Garcia‐Manero, G. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.06.041 · Cited by 200 · see citing works
The KEAP1–NRF2 System as a Molecular Target of Cancer Treatment
Taguchi, K., & Yamamoto, M. (2020) · Cancers · doi:10.3390/cancers13010046 · Cited by 195 · see citing works
Emerging role of NRF2 in ROS-mediated tumor chemoresistance
Xue, D., Zhou, X., & Qiu, J. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110676 · Cited by 191 · see citing works
Gao, A.-M., Ke, Z., Fang, S., Sun, G., & Chen, H. (2013) · Chemico-Biological Interactions · doi:10.1016/j.cbi.2013.08.008 · Cited by 190 · see citing works
The Keap1–Nrf2 system as an in vivo sensor for electrophiles
Uruno, A., & Motohashi, H. (2011) · Nitric Oxide · doi:10.1016/j.niox.2011.02.007 · Cited by 187 · see citing works
NRF2: KEAPing Tumors Protected
Pillai, R., Hayashi, M., Zavitsanou, A.-M., & Papagiannakopoulos, T. Y. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0922 · Cited by 187 · see citing works
NRF2 Activation in Cancer: From DNA to Protein
Cloer, E. W., Goldfarb, D., Schrank, T. P., Weissman, B. E., & Major, M. B. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-2723 · Cited by 182 · see citing works
The transcription factor NF‐E2‐related Factor 2 (Nrf2): a protooncogene?
Shelton, P. M., & Jaiswal, A. K. (2012) · The FASEB Journal · doi:10.1096/fj.12-217257 · Cited by 185 · see citing works
Potential Applications of NRF2 Inhibitors in Cancer Therapy
Panieri, E., & Saso, L. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/8592348 · Cited by 185 · see citing works
Lee, D., Xu, M., Chiu, D. K., Leibold, J., Tse, A. P., Bao, M. H., Yuen, V. W., Chan, C. Y., Lai, R. K., Chin, D. W., et al. (2018) · Hepatology · doi:10.1002/hep.30467 · Cited by 178 · see citing works
The Keap1–Nrf2 Cell Defense Pathway – A Promising Therapeutic Target?
Copple, I. M. (2012) · Advances in pharmacology · doi:10.1016/b978-0-12-398339-8.00002-1 · Cited by 172 · see citing works
Gounder, S. S., Kannan, S., Devadoss, D., Miller, C. J., Whitehead, K. S., Odelberg, S. J., Firpo, M. A., Paine, R., Hoidal, J. R., Abel, E. D., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0045697 · Cited by 171 · see citing works
An update of Nrf2 activators and inhibitors in cancer prevention/promotion
Pouremamali, F., Pouremamali, A., Dadashpour, M., Soozangar, N., & Jeddi, F. (2022) · Cell Communication and Signaling · doi:10.1186/s12964-022-00906-3 · Cited by 172 · see citing works
Harder, B. G., Jiang, T., Wu, T., Tao, S., de la Vega, M. R., Tian, W., Chapman, E., & Zhang, D. D. (2015) · Biochemical Society Transactions · doi:10.1042/bst20150020 · Cited by 171 · see citing works
Self-citationBrucea javanica derived exosome-like nanovesicles deliver miRNAs for cancer therapy
Yan, G., Xiao, Q., Zhao, J., Chen, H., Xu, Y., Tan, M., & Peng, L. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.01.060 · Cited by 174 · see citing works
Gao, A.-M., Ke, Z., Wang, J., Yang, J., Chen, S., & Chen, H. (2013) · Carcinogenesis · doi:10.1093/carcin/bgt108 · Cited by 169 · see citing works
Targeting NRF2 and Its Downstream Processes: Opportunities and Challenges
Torrente, L., & DeNicola, G. M. (2021) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev-pharmtox-052220-104025 · Cited by 168 · see citing works
Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation
Tsuchida, K., Tsujita, T., Hayashi, M., Ojima, A., Keleku-Lukwete, N., Katsuoka, F., Otsuki, A., Kikuchi, H., Oshima, Y., Suzuki, M., et al. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.12.041 · Cited by 167 · see citing works
Aldo-keto reductases protect metastatic melanoma from ER stress-independent ferroptosis
Gagliardi, M., Cotella, D., Santoro, C., Corà, D., Barlev, N. A., Piacentini, M., & Corazzari, M. (2019) · Cell Death and Disease · doi:10.1038/s41419-019-2143-7 · Cited by 166 · see citing works
Potential Applications of NRF2 Modulators in Cancer Therapy
Panieri, E., Djordjević, A. B., Telkoparan‐Akillilar, P., Cevik, D., Kouretas, D., Veskoukis, A. S., Skaperda, Z., Tsatsakis, A. M., Wallace, D., Süzen, S., et al. (2020) · Antioxidants · doi:10.3390/antiox9030193 · Cited by 165 · see citing works
Zhu, J., Wang, H., Chen, F., Fu, J., Xu, Y., Hou, Y., Kou, H. H., Zhai, C., Nelson, M. B., Zhang, Q., et al. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.09.010 · Cited by 162 · see citing works
Dual roles of NRF2 in tumor prevention and progression: Possible implications in cancer treatment
Moon, E. J., & Giaccia, A. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.11.009 · Cited by 160 · see citing works
Bai, X., Chen, Y., Hou, X., Huang, M., & Jin, J. (2016) · Drug Metabolism Reviews · doi:10.1080/03602532.2016.1197239 · Cited by 159 · see citing works
Role of the Keap1–Nrf2 Pathway in Cancer
Leinonen, H. M., Kansanen, E., Pölönen, P., Heinäniemi, M., & Levonen, A. (2014) · Advances in cancer research · doi:10.1016/b978-0-12-420117-0.00008-6 · Cited by 158 · see citing works
Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo
Chian, S., Thapa, R., Chi, Z., Wang, X. J., & Tang, X. (2014) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2014.04.039 · Cited by 157 · see citing works
AMPK and NRF2: Interactive players in the same team for cellular homeostasis?
Petsouki, E., Cabrera, S. N. S., & Heiß, E. H. (2022) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2022.07.014 · Cited by 157 · see citing works
Yamadori, T., Ishii, Y., Homma, S., Morishima, Y., Kurishima, K., Itoh, K., Yamamoto, M. P., Minami, Y., Noguchi, M., & Hizawa, N. (2012) · Oncogene · doi:10.1038/onc.2011.628 · Cited by 151 · see citing works
Role of Nrf2 in the pathogenesis of atherosclerosis
Mimura, J., & Itoh, K. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.019 · Cited by 150 · see citing works
Xu, X., Li, H., Hou, X., Li, D., He, S., Wan, C., Yin, P., Liu, M., Liu, F., & Xu, J. (2015) · Mediators of Inflammation · doi:10.1155/2015/380218 · Cited by 149 · see citing works
Bekele, R., Venkatraman, G., Liu, R., Tang, X., Mi, S., Benesch, M. G. K., Mackey, J. R., Godbout, R., Curtis, J. M., McMullen, T. P. W., et al. (2016) · Scientific Reports · doi:10.1038/srep21164 · Cited by 146 · see citing works
Mirzaei, S., Mohammadi, A. T., Gholami, M. H., Hashemi, F., Zarrabi, A., Zabolian, A., Hushmandi, K., Makvandi, P., Samec, M., Líšková, A., et al. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105575 · Cited by 151 · see citing works
Targeting Nrf2 Signaling to Combat Chemoresistance
No, J. H., Kim, Y.-B., & Song, Y. S. (2014) · Journal of Cancer Prevention · doi:10.15430/jcp.2014.19.2.111 · Cited by 144 · see citing works
Brusatol, an NRF2 inhibitor for future cancer therapeutic
Cai, S. J., Liu, Y., Han, S., & Yang, C. (2019) · Cell & Bioscience · doi:10.1186/s13578-019-0309-8 · Cited by 142 · see citing works
Triptolide suppresses IDH1-mutated malignancy via Nrf2-driven glutathione metabolism
Yu, D., Liu, Y., Zhou, Y., Ruiz‐Rodado, V., Larion, M., Xu, G., & Yang, C. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1913633117 · Cited by 142 · see citing works
Lee, J. H., Mohan, C. D., Deivasigamani, A., Jung, Y. Y., Rangappa, S., Basappa, B., Chinnathambi, A., Alahmadi, T. A., Alharbi, S. A., Garg, M., et al. (2020) · Journal of Advanced Research · doi:10.1016/j.jare.2020.07.004 · Cited by 142 · see citing works
Phytochemicals As Chemosensitizers: From Molecular Mechanism to Clinical Significance
Balachandran, V., Maliekal, T. T., & Anto, R. J. (2012) · Antioxidants and Redox Signaling · doi:10.1089/ars.2012.4573 · Cited by 139 · see citing works
Arsenic‐Mediated Activation of the Nrf2‐Keap1 Antioxidant Pathway
Lau, A., Whitman, S. A., Jaramillo, M. C., & Zhang, D. D. (2012) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.21463 · Cited by 139 · see citing works
Self-citationBrusatol overcomes chemoresistance through inhibition of protein translation
Harder, B. G., Tian, W., Clair, J. J. L., Tan, A. C., Ooi, A., Chapman, E., & Zhang, D. D. (2016) · Molecular Carcinogenesis · doi:10.1002/mc.22609 · Cited by 137 · see citing works
Self-citationCo-delivery with nano-quercetin enhances doxorubicin-mediated cytotoxicity against MCF-7 cells
Minaei, A., Sabzichi, M., Ramezani, F., Hamishehkar, H., & Samadi, N. (2016) · Molecular Biology Reports · doi:10.1007/s11033-016-3942-x · Cited by 136 · see citing works
Tao, S., de la Vega, M. R., Chapman, E., Ooi, A., & Zhang, D. D. (2017) · Molecular Carcinogenesis · doi:10.1002/mc.22745 · Cited by 136 · see citing works
Self-citationTurpaev, K. T. (2013) · Biochemistry (Moscow) · doi:10.1134/s0006297913020016 · Cited by 135 · see citing works
Redox Modulating NRF2: A Potential Mediator of Cancer Stem Cell Resistance
Ryoo, I.-G., Lee, S.-H., & Kwak, M.-K. (2015) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2016/2428153 · Cited by 133 · see citing works
- Authors
- Ren, D., Villeneuve, N. F., Jiang, T., Wu, T., Lau, A., Toppin, H. A., & Zhang, D. D.
- Affiliations
- Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721;
- University of Arizona (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-01-04
- Volume
- 108
- Issue
- 4
- Pages
- 1433-1438
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3029730
- OpenAlex
- W2077950988
- Cited by
- 673
- References
- 47
- Citations by year
- 2026: 41 · 2025: 43 · 2024: 42 · 2023: 48 · 2022: 59 · 2021: 47 · 2020: 65 · 2019: 48 · 2018: 44 · 2017: 52 · 2016: 48 · 2015: 38 · 2014: 36 · 2013: 34 · 2012: 21
- FWCI
- 12.45
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (ES006694)
- National Institute of Environmental Health Sciences (ES-006694, R01ES015010, P30ES006694)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- brusatol, Nrf2, chemoresistance, cisplatin, Keap1, ubiquitination, proteasomal degradation, apoptosis, A549 xenograft, drug detoxification, adjuvant chemotherapy, lung cancer
- MeSH terms
- Animals, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Cisplatin, Drug Synergism, Glutathione, HeLa Cells, Humans, Lung Neoplasms, Mice, Nude, Immunoblotting, Molecular Structure, Signal Transduction, Apoptosis, Xenograft Model Antitumor Assays, Quassins, Intracellular Space, Cell Line, Tumor, Cell Proliferation, NF-E2-Related Factor 2, Mice, Ubiquitination
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
