The DOI matches its Crossref record; 47 of the 47 references it cites were found in a registry or an index.
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.
Overview
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
Verification
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?
In the citing paper
“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.
Citations
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
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
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
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 1,284
Self-citationMechanistic Studies of the Nrf2-Keap1 Signaling Pathway
Zhang, D. D. (2006) · Drug Metabolism Reviews · doi:10.1080/03602530600971974 · Cited by 1,105
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
Dysfunctional 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
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
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
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
Self-citationFurukawa, M., & Xiong, Y. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.25.1.162-171.2005 · Cited by 759
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×
“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
LAU, A., VILLENEUVE, N., Sun, Z., Wong, P. K., & Zhang, D. (2008) · Pharmacological Research · doi:10.1016/j.phrs.2008.09.003 · Cited by 653
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
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
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 521
Nrf2: friend or foe for chemoprevention?
Kensler, T. W., & Wakabayashi, N. (2009) · Carcinogenesis · doi:10.1093/carcin/bgp231 · Cited by 487
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 476
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
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
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
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
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
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
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
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
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
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
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 174
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 170
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
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
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
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
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 131
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
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
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
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
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
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
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
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
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
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
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
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
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
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 1,510
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
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 1,326
Self-citation
Metadata
- 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
