Cited by 795Genomics, phytochemicals, and oxidative stressRedox biology and oxidative stressBioactive Compounds and Antitumor Agents

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Small Molecule Modulators of Keap1‐ Nrf2‐ ARE Pathway as Potential Preventive and Therapeutic Agents

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Magesh, Sadagopan, Chen, Yu, Hu, Longqin·2012·Medicinal Research Reviews

DOI 10.1002/med.21257PMC PMC3393814

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Abstract

Kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid 2-related factor 2 (Nrf2)-antioxidant response elements (ARE) pathway represents one of the most important cellular defense mechanisms against oxidative stress and xenobiotic damage. Activation of Nrf2 signaling induces the transcriptional regulation of ARE-dependent expression of various detoxifying and antioxidant defense enzymes and proteins. Keap1-Nrf2-ARE signaling has become an attractive target for the prevention and treatment of oxidative stress-related diseases and conditions including cancer, neurodegenerative, cardiovascular, metabolic, and inflammatory diseases. Over the last few decades, numerous Nrf2 inducers have been developed and some of them are currently undergoing clinical trials. Recently, overactivation of Nrf2 has been implicated in cancer progression as well as in drug resistance to cancer chemotherapy. Thus, Nrf2 inhibitors could potentially be used to improve the effectiveness of cancer therapy. Herein, we review the signaling mechanism of Keap1-Nrf2-ARE pathway, its disease relevance, and currently known classes of small molecule modulators. We also discuss several aspects of Keap1-Nrf2 interaction, Nrf2-based peptide inhibitor design, and the screening assays currently used for the discovery of direct inhibitors of Keap1-Nrf2 interaction.

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Retracted
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BackgroundInfluential
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BackgroundInfluential
Regulation of Heme Oxygenase-1 Expression through the Phosphatidylinositol 3-Kinase/Akt Pathway and the Nrf2 Transcription Factor in Response to the Antioxidant Phytochemical Carnosol
Martı́n, D., Rojo, A. I., Salinas, M., Díaz, R. G., Gallardo, G., Alam, J., de Galarreta, C. M. R., & Cuadrado, A. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m309660200 · Cited by 700
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Nrf2-mediated neuroprotection in the MPTP mouse model of Parkinson’s disease: Critical role for the astrocyte
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Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2
Ungvari, Z. I., Bagi, Z. A., Fehér, A., Recchia, F. A., Sonntag, W. E., Pearson, K. J., de Cabo, R., & Csiszár, A. (2010) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00260.2010 · Cited by 575
Mechanisms of cadmium carcinogenesis☆
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Scaffolding of Keap1 to the actin cytoskeleton controls the function of Nrf2 as key regulator of cytoprotective phase 2 genes
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Background
Nrf2, a multi‐organ protector?
Lee, J., Li, J., Johnson, D. A., Stein, T. D., Kraft, A. D., Calkins, M. J., Jakel, R. J., & Johnson, J. A. (2005) · The FASEB Journal · doi:10.1096/fj.04-2591hyp · Cited by 532
Nrf2-Deficient Mice Have an Increased Susceptibility to Dextran Sulfate Sodium–Induced Colitis
Khor, T. O., Huang, M., Kwon, K. H., Chan, J. Y., Reddy, B. S., & Kong, A. T. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-3562 · Cited by 530
Identification of a novel Nrf2-regulated antioxidant response element (ARE) in the mouse NAD(P)H:quinone oxidoreductase 1 gene: reassessment of the ARE consensus sequence
Nioi, P., McMahon, M. J., Itoh, K., Yamamoto, M. P., & Hayes, J. D. (2003) · Biochemical Journal · doi:10.1042/bj20030754 · Cited by 515 · cited 1×
“Dimercaptans, such as (±)-2,3-dimercapto-1-propanol (British antilewisite or BAL) (76),32, 49 1,2-ethanedithiol (77),49 and 2,3-dimercaptosuccinic acid (78),175 were shown to activate Nrf2.”
Background
Physiological Significance of Reactive Cysteine Residues of Keap1 in Determining Nrf2 Activity
Yamamoto, T., Suzuki, T., Kobayashi, A., Wakabayashi, J., Maher, J. M., Motohashi, H., & Yamamoto, M. P. (2008) · Molecular and Cellular Biology · doi:10.1128/mcb.01704-07 · Cited by 515
BTB proteins are substrate-specific adaptors in an SCF-like modular ubiquitin ligase containing CUL-3
Xu, L., Yue, W., Reboul, J., Vaglio, P., Shin, T.-H., Vidal, M., Elledge, S. J., & Harper, J. W. (2003) · Nature · doi:10.1038/nature01985 · Cited by 500
Dimerization of Substrate Adaptors Can Facilitate Cullin-mediated Ubiquitylation of Proteins by a “Tethering” Mechanism
McMahon, M. J., Thomas, N., Itoh, K., Yamamoto, M. P., & Hayes, J. D. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601119200 · Cited by 495 · cited 2×
“Humans require varying amounts of heavy metals such as iron, cobalt, copper, and zinc, but excessive heavy metals can be dangerous, and some heavy metals, such as mercury, cadmium, gold, and lead, can be very toxic.247 A number of the heavy metals are known to induce the expression of ARE genes in the order of Hg > Cd…”
BackgroundInfluential
Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin
Tanigawa, S., Fujii, M., & Hou, D.-X. (2007) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2007.02.017 · Cited by 487
Nrf2: friend or foe for chemoprevention?
Kensler, T. W., & Wakabayashi, N. (2009) · Carcinogenesis · doi:10.1093/carcin/bgp231 · Cited by 487 · cited 1×
“Quercetin (48) is a plant-derived polyphenolic flavonoid antioxidant found in many fruits, vegetables, leaves, and grains.”
Background
The Nrf2 System as a Potential Target for the Development of Indirect Antioxidants
Jung, K.-A., & Kwak, M. (2010) · Molecules · doi:10.3390/molecules15107266 · Cited by 478
Modifying specific cysteines of the electrophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain Neh2
Eggler, A. L., Liu, G., Pezzuto, J. M., van Breemen, R. B., & Mesecar, A. D. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0502402102 · Cited by 476
Two-site substrate recognition model for the Keap1-Nrf2 system: A hinge and latch mechanism
Tong, K. I., Kobayashi, A., Katsuoka, F., & Yamamoto, M. (2006) · Biological Chemistry · doi:10.1515/bc.2006.164 · Cited by 473 · cited 2×
“Miscellaneous Inducers Other ARE inducers that have been shown to covalently modify Keap1 include those with a good leaving group that can react with sulfhydryl groups in a SN2 fashion such as dexamethasone-21-mesylate (88) and N-iodoacetyl-N-biotinylhexylenediamine (89).”
Background
The pathways and molecular mechanisms regulating Nrf2 activation in response to chemical stress
Nguyen, T., Yang, C. S., & Pickett, C. B. (2004) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2004.04.033 · Cited by 472 · cited 1×
“Sesquiterpenes such as zumberone (18)180 and isoalantolactone (19),181 and terpenoids containing α,β-unsaturated fragrant aldehydes182 such as perillaldehyde (20) and citral (21) were shown to induce Nrf2-mediated expression of detoxifying enzymes.”
Background
Different Electrostatic Potentials Define ETGE and DLG Motifs as Hinge and Latch in Oxidative Stress Response
Tong, K. I., Padmanabhan, B., Kobayashi, A., Shang, C., Hirotsu, Y., Yokoyama, S., & Yamamoto, M. P. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00753-07 · Cited by 459 · cited 1×
“67, 86 Recently, 1-cyano-2,3-epithiopropane (90), a thiirane degradation product of glucosinolates found in cabbage, was shown to induce ARE genes and confer protection of rodent hepatocytes against the genotoxicity of acrolein.”
Background
Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells
Kode, A., Rajendrasozhan, S., Caito, S., Yang, S.-R., Megson, I. L., & Rahman, I. (2008) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00361.2007 · Cited by 447
Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals
McMahon, M. J., Lamont, D. J., Beattie, K. A., & Hayes, J. D. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1007387107 · Cited by 445
Curcumin upregulates transcription factor Nrf2, HO-1 expression and protects rat brains against focal ischemia
Yang, C., Zhang, X., Fan, H., & Liu, Y. (2009) · Brain Research · doi:10.1016/j.brainres.2009.05.009 · Cited by 444
The Nrf2/ARE Pathway as a Potential Therapeutic Target in Neurodegenerative Disease
Calkins, M. J., Johnson, D. A., Townsend, J. A., Vargas, M. R., Dowell, J. A., Williamson, T. P., Kraft, A. D., Lee, J., Li, J., & Johnson, J. A. (2008) · Antioxidants and Redox Signaling · doi:10.1089/ars.2008.2242 · Cited by 441 · cited 1×
“22 Other triterpenoid natural products, such as avicin D (29)190 and gedunin (30),175 were also shown to increase the expression of certain cytoprotective enzymes via Nrf2 activation.”
Background
The Protective Role of Nrf2 in Streptozotocin-Induced Diabetic Nephropathy
Jiang, T., Huang, Z., Lin, Y., Zhang, Z., Fang, D., & Zhang, D. D. (2010) · Diabetes · doi:10.2337/db09-1342 · Cited by 440
Nrf2-induced antioxidant protection: A promising target to counteract ROS-mediated damage in neurodegenerative disease?
de Vries, H. E., Witte, M. E., Hondius, D., Rozemüller, A. J. M., Drukarch, B., Hoozemans, J. J. M., & van Horssen, J. (2008) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2008.09.001 · Cited by 436
Oxidative Stress and Antioxidants in Exercise
Leeuwenburgh, C., & Heinecke, J. W. (2001) · Current Medicinal Chemistry · doi:10.2174/0929867013372896 · Cited by 435 · cited 1×
“107, 166 A synthetic analogue of curcumin, salicylcurcuminoid (2) having ortho hydroxyl substitutions relative to the α,β-unsaturated ketone system, is much more potent (∼24-fold) than curcumin in inducing quinone reductase in murine hepatoma cells.”
Background
Molecular actions of Ebselen—an antiinflammatory antioxidant
SCHEWE, T. (1995) · General Pharmacology The Vascular System · doi:10.1016/0306-3623(95)00003-j · Cited by 431
Regulation of the Nrf2–Keap1 Antioxidant Response by the Ubiquitin Proteasome System: An Insight into Cullin-Ring Ubiquitin Ligases
Villeneuve, N. F., Lau, A., & Zhang, D. D. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3211 · Cited by 423 · cited 3×
“The restoration of imatinib sensitivity in KCL22/SR was at least partially due to ascorbic acid’s inhibition of Nrf2 activity.252 EGCG (53) was also shown to suppress Nrf2 activity and reduce HO-1 expression in A549 cells, although the concentrations of EGCG required for its inhibitory effect were high (>200 μM).253 A…”
BackgroundInfluential
Chemoprotection against cancer by induction of Phase 2 enzymes
Talalay, P. (2000) · BioFactors · doi:10.1002/biof.5520120102 · Cited by 421 · cited 1×
“A number of flavonoids have been reported to have ARE gene-induction properties; these include synthetic flavonoids such as 4-bromo flavone (13)178 and β-naphthoflavone (14),32 a natural isoflavone sappanone A (15),175 and flavonoids-like benzofuran-containing substituted aurones (16)177 and their corresponding indole…”
Background
The integrated antioxidant system
Jacob, R. A. (1995) · Nutrition Research · doi:10.1016/0271-5317(95)00041-g · Cited by 420 · cited 1×
“174 Some naturally occurring coumarin derivatives, such as 4-methyl daphnetin (9),175 imperatorin (10),176 auraptene (11),176 and poncimarin (12),177 are reported to have ARE-mediated enzyme induction activities via Keap1-Nrf2-ARE pathway.”
Background
Redox-regulated Turnover of Nrf2 Is Determined by at Least Two Separate Protein Domains, the Redox-sensitive Neh2 Degron and the Redox-insensitive Neh6 Degron
McMahon, M. J., Thomas, N., Itoh, K., Yamamoto, M. P., & Hayes, J. D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m403061200 · Cited by 419 · cited 3×
“233 Some lipophilic thioethers, such as DAS (69), diallyl disulfide (DADS, 70), and diallyl trisulfide (DATS, 71), have been shown to upregulate the expression of detoxifying enzymes with inducing strength in the order of DATS > DADS > DAS, but the mechanism underlying ARE-inducing activity is poorly understood.”
Background
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
Dhakshinamoorthy, S., Jain, A. K., Bloom, D. A., & Jaiswal, A. K. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m500166200 · Cited by 414 · cited 1×
“242, 243 Recently, an organoselenium compound, 3-selena-1-dethiacephem (82), was identified as an activator of Nrf2-ARE and as a direct ROS scavenger.”
Background
Identification of Sensor Cysteines in Human Keap1 Modified by the Cancer Chemopreventive Agent Sulforaphane
Hong, F., Freeman, M. L., & Liebler, D. C. (2005) · Chemical Research in Toxicology · doi:10.1021/tx0502138 · Cited by 404
Carnosic acid, a catechol‐type electrophilic compound, protects neurons both in vitro and in vivo through activation of the Keap1/Nrf2 pathway via S‐alkylation of targeted cysteines on Keap1
Satoh, T., Kosaka, K., Itoh, K., Kobayashi, A., Yamamoto, M. P., Shimojo, Y., Kitajima, C., Cui, J., Kamins, J., Okamoto, S., et al. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2007.05039.x · Cited by 399
Nrf2 signaling and cell survival
Niture, S. K., Kaspar, J. W., Shen, J., & Jaiswal, A. K. (2009) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.06.009 · Cited by 397
Activation of NRF2 by Nitrosative Agents and H2O2 Involves KEAP1 Disulfide Formation
Fourquet, S., Guérois, R., Biard, D. S. F., & Tolédano, M. B. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.051714 · Cited by 389
Induction of Cytoprotective Genes Through Nrf2 / Antioxidant Response Element Pathway: A New Therapeutic Approach for the Treatment of Inflammatory Diseases
Chen, X., & KUNSCH, C. A. (2004) · Current Pharmaceutical Design · doi:10.2174/1381612043452901 · Cited by 387 · cited 5×
“Mechanistically, thiol-selenide or selenol-sulfide exchange is well known due to the similar electronegativity of sulfur and selenium.239 Selenites and various organoselenium compounds are reported to have cytoprotective activities.240 Interestingly, SFN-isoSe (80), a selenium isostere of SFN (60) was found to have be…”
BackgroundInfluential
The Carboxy-Terminal Neh3 Domain of Nrf2 Is Required for Transcriptional Activation
Nioi, P., Nguyen, T., Sherratt, P. J., & Pickett, C. B. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.24.10895-10906.2005 · Cited by 383
FREE RADICALS, ANTIOXIDANTS, DISEASES AND PHYTOMEDICINES: CURRENT STATUS AND FUTURE PROSPECT
Sen, S., Chakraborty, R., Sridhar, C., Reddy, Y. S., & De, B. (2010) · Cited by 378
Arsenic toxicity, mutagenesis, and carcinogenesis – a health risk assessment and management approach
Tchounwou, P. B., Centeno, J. A., & Patlolla, A. K. (2003) · Molecular and Cellular Biochemistry · doi:10.1023/b:mcbi.0000007260.32981.b9 · Cited by 375
Redox Regulation by Keap1 and Nrf2 Controls Intestinal Stem Cell Proliferation in Drosophila
Hochmuth, C. E., Biteau, B., Bohmann, D., & Jasper, H. (2011) · Cell stem cell · doi:10.1016/j.stem.2010.12.006 · Cited by 374 · cited 4×
“184 The introduction of highly activated Michael acceptors (α,β-unsaturated α-cyano ketone) to the A and C rings of oleanolic acid scaffold resulted in potent Nrf2 inducers CDDO (23) and its methyl ester (24, also known as bardoxolone methyl or CDDO-Me).”
BackgroundInfluential
Inhibitory effects of caffeic acid phenethyl ester on the activity and expression of cyclooxygenase-2 in human oral epithelial cells and in a rat model of inflammation.
Michaluart, P., Masferrer, J. L., Carothers, A. M., Subbaramaiah, K., Zweifel, B. S., Koboldt, C. M., MESTRE, J. R., Grünberger, D., Sacks, P. G., Tanabe, T., et al. (1999) · PubMed · Cited by 374
Thiol-Based Redox Switches and Gene Regulation
Antelmann, H., & Helmann, J. D. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3400 · Cited by 373
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
The Keap1 BTB/POZ dimerization function is required to sequester Nrf2 in cytoplasm
Zipper, L. M., & Mulcahy, R. T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m206530200 · Cited by 366 · cited 2×
“229 D3T and other synthetic substituted derivatives, such as ADT (66) and oltipraz (67), have been shown to induce the expression of cytoprotective genes through the Keap1-Nrf2 signaling pathway.”
Background
Molecular Targets of Dietary Phenethyl Isothiocyanate and Sulforaphane for Cancer Chemoprevention
Cheung, K. L., & Kong, A. T. (2009) · The AAPS Journal · doi:10.1208/s12248-009-9162-8 · Cited by 365
Identification of the interactive interface and phylogenic conservation of the Nrf2‐Keap1 system
Kobayashi, M., Itoh, K., Suzuki, T., Osanai, H., Nishikawa, K., Katoh, Y., Takagi, Y., & Yamamoto, M. P. (2002) · Genes to Cells · doi:10.1046/j.1365-2443.2002.00561.x · Cited by 340
Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury
Marzec, J. M., Christie, J. D., Reddy, S. P., Jedlicka, A., Vuong, H., Lanken, P. N., Aplenc, R., Yamamoto, T., Yamamoto, M. P., Cho, H., et al. (2007) · The FASEB Journal · doi:10.1096/fj.06-7759com · Cited by 340
Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs
Tang, X., Wang, H., Fan, L., Wu, X., Xin, A., Ren, H.-Y., & Wang, X. J. (2011) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2011.03.008 · Cited by 336
Vascular NAD(P)H oxidase activation in diabetes: a double-edged sword in redox signalling
Gao, L., & Mann, G. E. (2009) · Cardiovascular Research · doi:10.1093/cvr/cvp031 · Cited by 333
Keap1 Controls Postinduction Repression of the Nrf2-Mediated Antioxidant Response by Escorting Nuclear Export of Nrf2
Sun, Z., Zhang, S., Chan, J. Y., & Zhang, D. D. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00630-07 · Cited by 332 · cited 1×
“A quassinoid compound purified from the extract of plant Brucea javanica, brusatol (93), was found to enhance the degradation of Nrf2 in a Keap1-dependent manner and inhibit the Nrf2-mediated stress response and tumor growth.”
Background
Safety, Tolerance, and Metabolism of Broccoli Sprout Glucosinolates and Isothiocyanates: A Clinical Phase I Study
Shapiro, T. A., Fahey, J. W., Dinkova‐Kostova, A. T., Holtzclaw, W. D., Stephenson, K. K., Wade, K. L., Ye, L., & Talalay, P. (2006) · Nutrition and Cancer · doi:10.1207/s15327914nc5501_7 · Cited by 330 · cited 1×
“200, 201 In presence of oxygen and transition metals, tBHQ (42) was oxidized to tBQ (43) and rapidly underwent Michael addition with Keap1 protein and activated ARE-dependent transcription.”
Method
Pharmacological Targeting of the Transcription Factor Nrf2 at the Basal Ganglia Provides Disease Modifying Therapy for Experimental Parkinsonism
Jaźwa, A., Rojo, A. I., Innamorato, N. G., Hesse, M., Fernández‐Ruíz, J., & Cuadrado, A. (2011) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3731 · Cited by 329
Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast
Cornblatt, B. S., Ye, L., Dinkova‐Kostova, A. T., Erb, M., Fahey, J. W., Singh, N., Chen, M.-S. A., Stierer, T. L., Garrett-Mayer, E. S., Argani, P., et al. (2007) · Carcinogenesis · doi:10.1093/carcin/bgm049 · Cited by 323
Specific Patterns of Electrophile Adduction Trigger Keap1 Ubiquitination and Nrf2 Activation
Hong, F., Sekhar, K. R., Freeman, M. L., & Liebler, D. C. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m503346200 · Cited by 316 · cited 1×
“Low levels of H2O2 and organic peroxides, such as tert-butyl hydroperoxide (85) and cumol hydroperoxide (86), can act as inducers of ARE genes through the oxidation of sulfhydryl groups in Keap1 leading to the activation of Nrf2 and ARE genes.”
Background
New Synthetic Triterpenoids: Potent Agents for Prevention and Treatment of Tissue Injury Caused by Inflammatory and Oxidative Stress
Sporn, M. B., Liby, K. T., Yore, M. M., Fu, L., Lopchuk, J. M., & Gribble, G. W. (2011) · Journal of Natural Products · doi:10.1021/np100826q · Cited by 312
Modification of Keap1 Cysteine Residues by Sulforaphane
Hu, C., Eggler, A. L., Mesecar, A. D., & van Breemen, R. B. (2011) · Chemical Research in Toxicology · doi:10.1021/tx100389r · Cited by 312
Multiple molecular targets in cancer chemoprevention by curcumin
Thangapazham, R. L., Sharma, A. K., & Maheshwari, R. K. (2006) · The AAPS Journal · doi:10.1208/aapsj080352 · Cited by 310
Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha
Wang, X. J., Hayes, J. D., Henderson, C. J., & Wolf, C. R. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709483104 · Cited by 310
Targeting NRF2 signaling for cancer chemoprevention
Kwak, M.-K., & Kensler, T. W. (2009) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.08.028 · Cited by 306
Characterization of the cancer chemopreventive NRF2-dependent gene battery in human keratinocytes: demonstration that the KEAP1–NRF2 pathway, and not the BACH1–NRF2 pathway, controls cytoprotection against electrophiles as well as redox-cycling compounds
MacLeod, A. K., McMahon, M. J., Plummer, S. M., Higgins, L. G., Penning, T. M., Igarashi, K., & Hayes, J. D. (2009) · Carcinogenesis · doi:10.1093/carcin/bgp176 · Cited by 305 · cited 3×
“(R)-Lipoic acid (79) is found in almost all foods, but slightly more in spinach and broccoli, and it is also produced endogenously.”
BackgroundInfluential
Nrf2 is essential for cholesterol crystal-induced inflammasome activation and exacerbation of atherosclerosis
Freigang, S., Ampenberger, F., Spohn, G., Heer, S., Shamshiev, A. T., Kisielow, J., Hersberger, M., Yamamoto, M., Bachmann, M. F., & Kopf, M. (2011) · European Journal of Immunology · doi:10.1002/eji.201041316 · Cited by 300
Ubiquitination of Keap1, a BTB-Kelch Substrate Adaptor Protein for Cul3, Targets Keap1 for Degradation by a Proteasome-independent Pathway
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 · cited 1×
“Low levels of H2O2 and organic peroxides, such as tert-butyl hydroperoxide (85) and cumol hydroperoxide (86), can act as inducers of ARE genes through the oxidation of sulfhydryl groups in Keap1 leading to the activation of Nrf2 and ARE genes.”
Background
Genetic Evidence that Small Maf Proteins Are Essential for the Activation of Antioxidant Response Element-Dependent Genes
Katsuoka, F., Motohashi, H., Ishii, T., Aburatani, H., Engel, J. D., & Yamamoto, M. P. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.18.8044-8051.2005 · Cited by 289
Emerging Role of Nrf2 in Protecting Against Hepatic and Gastrointestinal Disease
Aleksunes, L. M., & Manautou, J. E. (2007) · Toxicologic Pathology · doi:10.1080/01926230701311344 · Cited by 288
Down-Regulated NF-E2–Related Factor 2 in Pulmonary Macrophages of Aged Smokers and Patients with Chronic Obstructive Pulmonary Disease
Suzuki, M., Betsuyaku, T., Ito, Y., Nagai, K., Nasuhara, Y., Kaga, K., Kondo, S., & Nishimura, M. (2008) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2007-0424oc · Cited by 286
Anti-inflammatory Triterpenoid Blocks Immune Suppressive Function of MDSCs and Improves Immune Response in Cancer
Nagaraj, S., Youn, J., Weber, H., Iclozan, C., Lu, L. D., Cotter, M. J., Meyer, C. J., Becerra, C. R., Fishman, M., Antonia, S. J., et al. (2010) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-09-3272 · Cited by 286 · cited 2×
“Polyphenolic compounds are able to directly quench free radical species and were used as antioxidants, even before Keap1-Nrf2-ARE signaling pathway was indentified.196 In late 1970s, a prototypic phenolic antioxidant BHA (40) was found to induce the expression of cytoprotective enzymes.197, 198 Structural modification…”
Background
Role of oxidative stress in rheumatoid arthritis: insights from the Nrf2-knockout mice
Wruck, C. J., Fragoulis, A., Gurzynski, A., Brandenburg, L., Kan, Y. W., Chan, K., Hassenpflug, J., Freitag‐Wolf, S., Varoga, D. J., Lippross, S., et al. (2010) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2010.132720 · Cited by 283
Ageing, oxidative stress and cancer: paradigms in parallax
Benz, C. C., & Yau, C. S. F. (2008) · Nature reviews. Cancer · doi:10.1038/nrc2522 · Cited by 279 · cited 2×
“Isoliquiritigenin (7) is a licorice chalconoid, majorly found in the root of Glycyrrhiza glabra.”
Background
Enhancing Expression of Nrf2-Driven Genes Protects the Blood–Brain Barrier after Brain Injury
Zhao, J., Moore, A. N., Redell, J. B., & Dash, P. K. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.1683-07.2007 · Cited by 274
Cellular Stress Response: A Novel Target for Chemoprevention and Nutritional Neuroprotection in Aging, Neurodegenerative Disorders and Longevity
Calabrese, V., Cornelius, C., Mancuso, C., Pennisi, G., Calafato, S., Bellia, F., Bates, T. E., Stella, A. M. G., Schapira, T., Dinkova‐Kostova, A. T., et al. (2008) · Neurochemical Research · doi:10.1007/s11064-008-9775-9 · Cited by 273
On the mechanisms of induction of cancer-protective enzymes: a unifying proposal.
Prochaska, H. J., Long, M. J., & Talalay, P. (1985) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.82.23.8232 · Cited by 260
Crystal Structure of the Kelch Domain of Human Keap1
Li, X., Zhang, D., Hannink, M., & Beamer, L. J. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m410073200 · Cited by 256
Phenolic antioxidants from herbs and spices
Nakatani, N. (2000) · BioFactors · doi:10.1002/biof.5520130123 · Cited by 254
Nrf2 is critical in defense against high glucose-induced oxidative damage in cardiomyocytes
He, X., Kan, H. J., Cai, L., & Ma, Q. (2008) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2008.10.007 · Cited by 250
Constitutive Overexpression of Nrf2-dependent Heme Oxygenase-1 in A549 Cells Contributes to Resistance to Apoptosis Induced by Epigallocatechin 3-Gallate
Kweon, M., Adhami, V. M., Lee, J., & Mukhtar, H. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m604748200 · Cited by 250
Relation of structure of curcumin analogs to their potencies as inducers of Phase 2 detoxification enzymes
Dinkova‐Kostova, A. T., & Talalay, P. (1999) · Carcinogenesis · doi:10.1093/carcin/20.5.911 · Cited by 249
Nrf2, a Guardian of Healthspan and Gatekeeper of Species Longevity
Lewis, K. N., Mele, J., Hayes, J. D., & Buffenstein, R. (2010) · Integrative and Comparative Biology · doi:10.1093/icb/icq034 · Cited by 249
Nrf2 protects against airway disorders
Cho, H., & Kleeberger, S. R. (2009) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2009.07.024 · Cited by 238
A Review of Natural and Synthetic Antioxidants Important for Health and Longevity
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Transcription Factor Nrf2 Protects the Brain From Damage Produced by Intracerebral Hemorrhage
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Green Tea: Nature's Defense against Malignancies
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Nrf2: control of sensitivity to carcinogens
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Method
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Curcumin induces heme oxygenase 1 through generation of reactive oxygen species, p38 activation and phosphatase inhibition
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“Recently, a cyclopentane analogue CPDT (68) has emerged as a promising ARE inducer in this class.”
Background
Curcumin Activates Defensive Genes and Protects Neurons Against Oxidative Stress
Scapagnini, G., Colombrita, C., Amadio, M., D’Agata, V., Arcelli, E., Sapienza, M. A., Quattrone, A., & Calabrese, V. (2006) · Antioxidants and Redox Signaling · doi:10.1089/ars.2006.8.395 · Cited by 189
The Nrf2/ARE Pathway: A Promising Target to Counteract Mitochondrial Dysfunction in Parkinson's Disease
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The Keap1–Nrf2 system as an in vivo sensor for electrophiles
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Background
Dietary curcumin modulates transcriptional regulators of phase I and phase II enzymes in benzo[ a ]pyrene-treated mice: mechanism of its anti-initiating action
Garg, R., Gupta, S., & Maru, G. B. (2008) · Carcinogenesis · doi:10.1093/carcin/bgn064 · Cited by 185
Impaired Redox Signaling and Antioxidant Gene Expression in Endothelial Cells in Diabetes: A Role for Mitochondria and the Nuclear Factor-E2-Related Factor 2-Kelch-Like ECH-Associated Protein 1 Defense Pathway
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Disruption of Nrf2, a Key Inducer of Antioxidant Defenses, Attenuates ApoE-Mediated Atherosclerosis in Mice
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Cul3-mediated Nrf2 ubiquitination and antioxidant response element (ARE) activation are dependent on the partial molar volume at position 151 of Keap1
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“A recent study investigated the ARE-inducing activity of lycopene (83), a red carotenoid pigment mainly found in tomatoes, and its potential oxidation metabolite, 10,10′-diapocarotene-10,10′-dial (84).”
Background
Ethyl Ferulate, a Lipophilic Polyphenol, Induces HO-1 and Protects Rat Neurons Against Oxidative Stress
Scapagnini, G., Butterfield, D. A., Colombrita, C., Rukhsana Sultana, A., Pascale, A., & Calabrese, V. (2004) · Antioxidants and Redox Signaling · doi:10.1089/ars.2004.6.811 · Cited by 175
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Background
Electrophilic tuning of the chemoprotective natural product sulforaphane
Ahn, Y., Hwang, Y., Liu, H., Wang, X. J., Zhang, Y., Stephenson, K. K., Boronina, T. N., Cole, R. N., Dinkova‐Kostova, A. T., Talalay, P., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1004104107 · Cited by 170
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“As a result, the long term application of the Keap1/Nrf2 inhibitors results in the accumulation of the active Nrf2, which may trigger other problems like cancer(178) Therefore, finding non-covalent small molecules that directly interfere with the Keap–Nrf2 interaction, dissociating the two and exerting antioxidant def…”
Background
The Keap1–Nrf2–ARE Pathway As a Potential Preventive and Therapeutic Target: An Update
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Authors: Magesh, S., Chen, Y., & Hu, L.
Affiliations: Rutgers, The State University of New Jersey (US)
Corresponding author: Hu, Longqin
ORCID: Chen, Yu
Hu, Longqin
Venue: Medicinal Research Reviews
Publisher: Wiley
Published: 2012-05
Volume: 32
Issue: 4
Pages: 687-726
ISSN: 0198-6325 (ISSN-L)
1098-1128
DOI: 10.1002/med.21257
PMC: PMC3393814
OpenAlex: W1767659454
Cited by: 760
References: 275
Citations by year: 2026: 30 · 2025: 39 · 2024: 52 · 2023: 61 · 2022: 69 · 2021: 58 · 2020: 85 · 2019: 81 · 2018: 54 · 2017: 63 · 2016: 41 · 2015: 56 · 2014: 42 · 2013: 28 · 2012: 1
FWCI: 3.79
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Medicinal Research Reviews (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Funders: National Institutes of Health (CA133791, CA125868, MH093197)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Toxicology › Bioactive Compounds and Antitumor Agents
Keywords: Nrf2/Keap1 pathway, Nrf2, Keap1, antioxidant response element, small molecule modulators, Nrf2 inducers, Nrf2 inhibitors, oxidative stress, xenobiotic detoxification, antioxidant defense, cancer chemotherapy resistance, peptide inhibitors, Keap1-Nrf2 interaction
MeSH terms: Animals, Anti-Inflammatory Agents, Antineoplastic Agents, Antioxidants, Humans, Hypoglycemic Agents, Signal Transduction, Oxidative Stress, Neuroprotective Agents, Response Elements, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2

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Small Molecule Modulators of Keap1‐ Nrf2‐ ARE Pathway as Potential Preventive and Therapeutic Agents

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