Skip to main content
SpringerLink
Log in

Perspectives on the Clinical Development of NRF2-Targeting Drugs

  • Chapter
  • First Online:
Reactive Oxygen Species

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 264))

Abstract

The transcription factor NRF2 (nuclear factor erythroid 2-related factor 2) triggers homeostatic responses against a plethora of environmental or endogenous deviations in redox metabolism, inflammation, proteostasis, etc. Therefore, pharmacological activation of NRF2 is a promising therapeutic strategy for several chronic diseases that are underlined by low-grade oxidative inflammation and dysregulation of redox metabolism, such as neurodegenerative, cardiovascular, and metabolic diseases. While NRF2 activation is useful in inhibiting carcinogenesis, its inhibition is needed in constituted tumors where NRF2 provides a survival advantage in the challenging tumor niche. This review describes the electrophilic and non-electrophilic NRF2 activators with clinical projection in various chronic diseases. We also analyze the status of NRF2 inhibitors, which are for the moment in a proof-of-concept stage. Advanced in silico screening and medicinal chemistry are expected to provide new or repurposing small molecules with increased potential for fostering the development of targeted NRF2 modulators.

Graphical Abstract

The nuclear factor erythroid 2 (NFE2)-related factor 2 (NRF2) is rapidly degraded by proteasomes under a basal condition in a Keap1-dependent manner. ROS oxidatively modifies Keap1 to release NRF2 and allow its nuclear translocation. Here it binds to the antioxidant response element to regulate gene transcription. An alternative mechanism controlling NRF2 stability is glycogen synthase kinase 3 (GSK-3)-induced phosphorylation. Indicated in blue are NRF2-activating and NRF2-inhibiting drugs.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

AD:

Alzheimer’s disease

AHR:

Aryl hydrocarbon receptor

BACH1:

BTB domain and CNC homolog 1

BTB:

Broad complex, tramtrack, bric-a-brac

CUL3:

Cullin 3

DMF:

Dimethyl fumarate

DRG:

Double glycine repeat

GSH:

Glutathione

GSK-3:

Glycogen synthase kinase

IVR:

Intervening region

KEAP1:

Kelch-like ECH-associated protein 1

MMF:

Monomethyl fumarate

MS:

Multiple sclerosis

NFE2L2 :

Gene encoding NRF2

NRF2:

Nuclear factor erythroid 2-related factor 2

PD:

Parkinson’s disease

PPI:

Protein-protein interaction

RBX1:

RING-box protein 1

ROS:

Reactive oxygen species

SFN:

Sulforaphane

SQSTM1:

Sequestosome 1

XRE:

Xenobiotic response element

β-TrCP:

Beta-transducin repeat containing E3 ubiquitin protein ligase

References

  • Abdull Razis AF, Noor NM (2013) Sulforaphane is superior to glucoraphanin in modulating carcinogen-metabolising enzymes in Hep G2 cells. Asian Pac J Cancer Prev 14(7):4235–4238

    Article  PubMed  Google Scholar 

  • Albrecht P, Bouchachia I, Goebels N et al (2012) Effects of dimethyl fumarate on neuroprotection and immunomodulation. J Neuroinflammation 9:163

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anderica-Romero AC, Hernandez-Damian J, Vazquez-Cervantes GI et al (2016) The MLN4924 inhibitor exerts a neuroprotective effect against oxidative stress injury via Nrf2 protein accumulation. Redox Biol 8:341–347

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arbeeny C, Ling H, Smith MM et al (2019) CXA-10, a nitrated fatty acid, is renoprotective in deoxycorticosterone acetate-salt nephropathy. J Pharmacol Exp Ther 369:503–510

    Article  CAS  PubMed  Google Scholar 

  • Arlt A, Sebens S, Krebs S et al (2013) Inhibition of the Nrf2 transcription factor by the alkaloid trigonelline renders pancreatic cancer cells more susceptible to apoptosis through decreased proteasomal gene expression and proteasome activity. Oncogene 32(40):4825–4835

    Article  CAS  PubMed  Google Scholar 

  • Attucks OC, Jasmer KJ, Hannink M et al (2014) Induction of heme oxygenase I (HMOX1) by HPP-4382: a novel modulator of Bach1 activity. PLoS One 9(7):e101044

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Axelsson AS, Tubbs E, Mecham B et al (2017) Sulforaphane reduces hepatic glucose production and improves glucose control in patients with type 2 diabetes. Sci Transl Med 9(394)

    Google Scholar 

  • Bahadoran Z, Mirmiran P, Hosseinpanah F et al (2012) Broccoli sprouts powder could improve serum triglyceride and oxidized LDL/LDL-cholesterol ratio in type 2 diabetic patients: a randomized double-blind placebo-controlled clinical trial. Diabetes Res Clin Pract 96(3):348–354

    Article  CAS  PubMed  Google Scholar 

  • Baird L, Lleres D, Swift S et al (2013) Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex. Proc Natl Acad Sci U S A 110(38):15259–15264

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Batthyany CI, Lopez GV (2015) Nitroalkene tocopherols and analogs thereof for use in the treatment and prevention of inflammation related conditions. Complexa Inc.

    Google Scholar 

  • Bertrand HC, Schaap M, Baird L et al (2015) Design, synthesis, and evaluation of Triazole derivatives that induce Nrf2 dependent gene products and inhibit the Keap1-Nrf2 protein-protein interaction. J Med Chem 58(18):7186–7194

    Article  CAS  PubMed  Google Scholar 

  • Biesalski HK, Grune T, Tinz J et al (2010) Reexamination of a meta-analysis of the effect of antioxidant supplementation on mortality and health in randomized trials. Nutrients 2(9):929–949

    Article  PubMed  PubMed Central  Google Scholar 

  • Biswas SK (2016) Does the interdependence between oxidative stress and inflammation explain the antioxidant paradox? Oxidative Med Cell Longev 2016:5698931

    Article  CAS  Google Scholar 

  • Bjelakovic G, Nikolova D, Gluud LL et al (2007) Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 297(8):842–857

    Article  CAS  PubMed  Google Scholar 

  • Boddupalli S, Mein JR, Lakkanna S et al (2012) Induction of phase 2 antioxidant enzymes by broccoli sulforaphane: perspectives in maintaining the antioxidant activity of vitamins A, C, and E. Front Genet 3:7

    Article  PubMed  PubMed Central  Google Scholar 

  • Boettler U, Sommerfeld K, Volz N et al (2011) Coffee constituents as modulators of Nrf2 nuclear translocation and ARE (EpRE)-dependent gene expression. J Nutr Biochem 22(5):426–440

    Article  CAS  PubMed  Google Scholar 

  • Bollong MJ, Yun H, Sherwood L et al (2015) A small molecule inhibits deregulated NRF2 transcriptional activity in cancer. ACS Chem Biol 10(10):2193–2198

    Article  CAS  PubMed  Google Scholar 

  • Booth L, Malkin M, Dent P (2016) Repurposing Tecfidera for cancer. Aging (Albany NY) 8(7):1289–1290

    Article  Google Scholar 

  • Bourhill T, Narendran A, Johnston RN (2017) Enzastaurin: a lesson in drug development. Crit Rev Oncol Hematol 112:72–79

    Article  CAS  PubMed  Google Scholar 

  • Bresciani A, Missineo A, Gallo M et al (2017) Nuclear factor (erythroid-derived 2)-like 2 (NRF2) drug discovery: biochemical toolbox to develop NRF2 activators by reversible binding of Kelch-like ECH-associated protein 1 (KEAP1). Arch Biochem Biophys 631:31–41

    Article  CAS  PubMed  Google Scholar 

  • Chao A, Lin CY, Wu RC et al (2018) The combination of everolimus and terameprocol exerts synergistic antiproliferative effects in endometrial cancer: molecular role of insulin-like growth factor binding protein 2. J Mol Med (Berl) 96(11):1251–1266

    Article  CAS  Google Scholar 

  • Chen Y, Inoyama D, Kong AN et al (2011) Kinetic analyses of Keap1-Nrf2 interaction and determination of the minimal Nrf2 peptide sequence required for Keap1 binding using surface plasmon resonance. Chem Biol Drug Des 78(6):1014–1021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen Y, Xue P, Hou Y et al (2013) Isoniazid suppresses antioxidant response element activities and impairs adipogenesis in mouse and human preadipocytes. Toxicol Appl Pharmacol 273(3):435–441

    Article  CAS  PubMed  Google Scholar 

  • Chen K, Li JJ, Li SN et al (2017) 15-Deoxy-Delta(12,14)-prostaglandin J2 alleviates hepatic ischemia-reperfusion injury in mice via inducing antioxidant response and inhibiting apoptosis and autophagy. Acta Pharmacol Sin 38(5):672–687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chian S, Li YY, Wang XJ et al (2014) Luteolin sensitizes two oxaliplatin-resistant colorectal cancer cell lines to chemotherapeutic drugs via inhibition of the Nrf2 pathway. Asian Pac J Cancer Prev 15(6):2911–2916

    Article  PubMed  Google Scholar 

  • Choi EJ, Jung BJ, Lee SH et al (2017) A clinical drug library screen identifies clobetasol propionate as an NRF2 inhibitor with potential therapeutic efficacy in KEAP1 mutant lung cancer. Oncogene 36(37):5285–5295

    Article  CAS  PubMed  Google Scholar 

  • Chowdhry S, Zhang Y, McMahon M et al (2013) Nrf2 is controlled by two distinct beta-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. Oncogene 32(32):3765–3781

    Article  CAS  PubMed  Google Scholar 

  • Cleasby A, Yon J, Day PJ et al (2014) Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO. PLoS One 9(6):e98896

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Cuadrado A (2015) Structural and functional characterization of Nrf2 degradation by glycogen synthase kinase 3/beta-TrCP. Free Radic Biol Med 88(Pt B):147–157

    Article  CAS  PubMed  Google Scholar 

  • Cuadrado A, Martin-Moldes Z, Ye J et al (2014) Transcription factors NRF2 and NF-kappaB are coordinated effectors of the rho family, GTP-binding protein RAC1 during inflammation. J Biol Chem 289(22):15244–15258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cuadrado A, Manda G, Hassan A et al (2018) Transcription factor NRF2 as a therapeutic target for chronic diseases: a systems medicine approach. Pharmacol Rev 70(2):348–383

    Article  CAS  PubMed  Google Scholar 

  • Cuadrado A, Rojo AI, Wells G et al (2019) Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nat Rev Drug Discov 18:295–317

    Article  CAS  PubMed  Google Scholar 

  • Dayalan Naidu S, Muramatsu A, Saito R et al (2018) C151 in KEAP1 is the main cysteine sensor for the cyanoenone class of NRF2 activators, irrespective of molecular size or shape. Sci Rep 8(1):8037

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • de la Vega MR, Dodson M, Gross C et al (2016) Role of Nrf2 and autophagy in acute lung injury. Curr Pharmacol Rep 2(2):91–101

    Article  CAS  Google Scholar 

  • de Miranda Ramos V, Gasparotto J, Figueiro F et al (2019) Retinoic acid downregulates thiol antioxidant defences and homologous recombination while promotes A549 cells sensitization to cisplatin. Cell Signal 62:109356

    Article  PubMed  CAS  Google Scholar 

  • Decensi A, Puntoni M, Goodwin P et al (2010) Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila) 3(11):1451–1461

    Article  CAS  Google Scholar 

  • DeNicola GM, Karreth FA, Humpton TJ et al (2011) Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475(7354):106–109

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dhakshinamoorthy S, Jain AK, Bloom DA et al (2005) Bach1 competes with Nrf2 leading to negative regulation of the antioxidant response element (ARE)-mediated NAD(P)H:quinone oxidoreductase 1 gene expression and induction in response to antioxidants. J Biol Chem 280(17):16891–16900

    Article  CAS  PubMed  Google Scholar 

  • Dibbert S, Clement B, Skak-Nielsen T et al (2013) Detection of fumarate-glutathione adducts in the portal vein blood of rats: evidence for rapid dimethylfumarate metabolism. Arch Dermatol Res 305(5):447–451

    Article  CAS  PubMed  Google Scholar 

  • Ding S, Hu A, Hu Y et al (2014) Anti-hepatoma cells function of luteolin through inducing apoptosis and cell cycle arrest. Tumour Biol 35(4):3053–3060

    Article  CAS  PubMed  Google Scholar 

  • Dinkova-Kostova AT, Liby KT, Stephenson KK et al (2005) Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci U S A 102(12):4584–4589

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Do MT, Kim HG, Khanal T et al (2013) Metformin inhibits heme oxygenase-1 expression in cancer cells through inactivation of Raf-ERK-Nrf2 signaling and AMPK-independent pathways. Toxicol Appl Pharmacol 271(2):229–238

    Article  CAS  PubMed  Google Scholar 

  • Do MT, Kim HG, Choi JH et al (2014) Metformin induces microRNA-34a to downregulate the Sirt1/Pgc-1alpha/Nrf2 pathway, leading to increased susceptibility of wild-type p53 cancer cells to oxidative stress and therapeutic agents. Free Radic Biol Med 74:21–34

    Article  PubMed  CAS  Google Scholar 

  • Duda DM, Borg LA, Scott DC et al (2008) Structural insights into NEDD8 activation of cullin-RING ligases: conformational control of conjugation. Cell 134(6):995–1006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Egea J, Buendia I, Parada E et al (2015) Melatonin-sulforaphane hybrid ITH12674 induces neuroprotection in oxidative stress conditions by a 'drug-prodrug' mechanism of action. Br J Pharmacol 172(7):1807–1821

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Evans JP, Winiarski BK, Sutton PA et al (2018) The Nrf2 inhibitor brusatol is a potent antitumour agent in an orthotopic mouse model of colorectal cancer. Oncotarget 9(43):27104–27116

    Article  PubMed  PubMed Central  Google Scholar 

  • Fabrizio FP, Sparaneo A, Trombetta D et al (2018) Epigenetic versus genetic deregulation of the KEAP1/NRF2 Axis in solid tumors: focus on methylation and noncoding RNAs. Oxidative Med Cell Longev 2018:2492063

    Article  CAS  Google Scholar 

  • Faessel HM, Mould DR, Zhou X et al (2019) Population pharmacokinetics of pevonedistat alone or in combination with standard of care in patients with solid tumours or haematological malignancies. Br J Clin Pharmacol 85(11):2568–2579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feng X, Yu W, Li X et al (2017) Apigenin, a modulator of PPARgamma, attenuates HFD-induced NAFLD by regulating hepatocyte lipid metabolism and oxidative stress via Nrf2 activation. Biochem Pharmacol 136:136–149

    Article  CAS  PubMed  Google Scholar 

  • Fox RJ, Miller DH, Phillips JT et al (2012) Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 367(12):1087–1097

    Article  CAS  PubMed  Google Scholar 

  • Franceschi C, Garagnani P, Parini P et al (2018) Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 14(10):576–590

    Article  CAS  PubMed  Google Scholar 

  • Frankfurt O, Rosen ST (2004) Mechanisms of glucocorticoid-induced apoptosis in hematologic malignancies: updates. Curr Opin Oncol 16(6):553–563

    Article  CAS  PubMed  Google Scholar 

  • Gao AM, Ke ZP, Wang JN et al (2013) Apigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway. Carcinogenesis 34(8):1806–1814

    Article  CAS  PubMed  Google Scholar 

  • Gao AM, Zhang XY, Ke ZP (2017) Apigenin sensitizes BEL-7402/ADM cells to doxorubicin through inhibiting miR-101/Nrf2 pathway. Oncotarget 8(47):82085–82091

    Article  PubMed  PubMed Central  Google Scholar 

  • Ghadiri M, Rezk A, Li R et al (2017) Dimethyl fumarate-induced lymphopenia in MS due to differential T-cell subset apoptosis. Neurol Neuroimmunol Neuroinflamm 4(3):e340

    Article  PubMed  PubMed Central  Google Scholar 

  • Gold R, Kappos L, Arnold DL et al (2012) Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 367(12):1098–1107

    Article  CAS  PubMed  Google Scholar 

  • Gong TT, Liu XD, Zhan ZP et al (2020) Sulforaphane enhances the cisplatin sensitivity through regulating DNA repair and accumulation of intracellular cisplatin in ovarian cancer cells. Exp Cell Res:112061

    Google Scholar 

  • Gu Y, Kaufman JL, Bernal L et al (2014) MLN4924, an NAE inhibitor, suppresses AKT and mTOR signaling via upregulation of REDD1 in human myeloma cells. Blood 123(21):3269–3276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gupta S, Afaq F, Mukhtar H (2001) Selective growth-inhibitory, cell-cycle deregulatory and apoptotic response of apigenin in normal versus human prostate carcinoma cells. Biochem Biophys Res Commun 287(4):914–920

    Article  CAS  PubMed  Google Scholar 

  • Han JM, Lee YJ, Lee SY et al (2007) Protective effect of sulforaphane against dopaminergic cell death. J Pharmacol Exp Ther 321(1):249–256

    Article  CAS  PubMed  Google Scholar 

  • Hancock R, Bertrand HC, Tsujita T et al (2012) Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction. Free Radic Biol Med 52(2):444–451

    Article  CAS  PubMed  Google Scholar 

  • Hancock R, Schaap M, Pfister H et al (2013) Peptide inhibitors of the Keap1-Nrf2 protein-protein interaction with improved binding and cellular activity. Org Biomol Chem 11(21):3553–3557

    Article  CAS  PubMed  Google Scholar 

  • Harder B, Tian W, La Clair JJ et al (2017) Brusatol overcomes chemoresistance through inhibition of protein translation. Mol Carcinog 56(5):1493–1500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hast BE, Goldfarb D, Mulvaney KM et al (2013) Proteomic analysis of ubiquitin ligase KEAP1 reveals associated proteins that inhibit NRF2 ubiquitination. Cancer Res 73(7):2199–2210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Havrdova E, Hutchinson M, Kurukulasuriya NC et al (2013) Oral BG-12 (dimethyl fumarate) for relapsing-remitting multiple sclerosis: a review of DEFINE and CONFIRM. Evaluation of: Gold R, Kappos L, Arnold D, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med 2012;367:1098–107; and Fox RJ, Miller DH, Phillips JT, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med 2012;367:1087–97. Expert Opin Pharmacother 14(15):2145–2156

    Article  CAS  PubMed  Google Scholar 

  • Hayashi G, Jasoliya M, Sahdeo S et al (2017) Dimethyl fumarate mediates Nrf2-dependent mitochondrial biogenesis in mice and humans. Hum Mol Genet 26(15):2864–2873

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hayes JD, Dinkova-Kostova AT (2014) The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem Sci 39(4):199–218

    Article  CAS  PubMed  Google Scholar 

  • Heiss E, Herhaus C, Klimo K et al (2001) Nuclear factor kappa B is a molecular target for sulforaphane-mediated anti-inflammatory mechanisms. J Biol Chem 276(34):32008–32015

    Article  CAS  PubMed  Google Scholar 

  • Holland R, Hawkins AE, Eggler AL et al (2008) Prospective type 1 and type 2 disulfides of Keap1 protein. Chem Res Toxicol 21(10):2051–2060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hooper C, Killick R, Lovestone S (2008) The GSK3 hypothesis of Alzheimer’s disease. J Neurochem 104(6):1433–1439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Houghton CA, Fassett RG, Coombes JS (2016) Sulforaphane and other nutrigenomic Nrf2 activators: can the clinician's expectation be matched by the reality? Oxidative Med Cell Longev 2016:7857186

    Article  CAS  Google Scholar 

  • Hoxtermann S, Nuchel C, Altmeyer P (1998) Fumaric acid esters suppress peripheral CD4- and CD8-positive lymphocytes in psoriasis. Dermatology 196(2):223–230

    Article  CAS  PubMed  Google Scholar 

  • Hu R, Saw CL, Yu R et al (2010) Regulation of NF-E2-related factor 2 signaling for cancer chemoprevention: antioxidant coupled with antiinflammatory. Antioxid Redox Signal 13(11):1679–1698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hu L, Magesh S, Chen L et al (2013) Discovery of a small-molecule inhibitor and cellular probe of Keap1-Nrf2 protein-protein interaction. Bioorg Med Chem Lett 23(10):3039–3043

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Huang HC, Nguyen T, Pickett CB (2000) Regulation of the antioxidant response element by protein kinase C-mediated phosphorylation of NF-E2-related factor 2. Proc Natl Acad Sci U S A 97(23):12475–12480

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hybertson BM, Gao B, Bose S et al (2019) Phytochemical combination PB125 activates the Nrf2 pathway and induces cellular protection against oxidative injury. Antioxidants (Basel) 8(5)

    Google Scholar 

  • Inoyama D, Chen Y, Huang X et al (2012) Optimization of fluorescently labeled Nrf2 peptide probes and the development of a fluorescence polarization assay for the discovery of inhibitors of Keap1-Nrf2 interaction. J Biomol Screen 17(4):435–447

    Article  CAS  PubMed  Google Scholar 

  • Iso T, Suzuki T, Baird L et al (2016) Absolute amounts and status of the Nrf2-Keap1-Cul3 complex within cells. Mol Cell Biol 36(24):3100–3112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jain A, Lamark T, Sjottem E et al (2010) p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J Biol Chem 285(29):22576–22591

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jazwa A, Rojo AI, Innamorato NG et al (2011) Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism. Antioxid Redox Signal 14(12):2347–2360

    Article  CAS  PubMed  Google Scholar 

  • Jiang ZY, Lu MC, Xu LL et al (2014) Discovery of potent Keap1-Nrf2 protein-protein interaction inhibitor based on molecular binding determinants analysis. J Med Chem 57(6):2736–2745

    Article  CAS  PubMed  Google Scholar 

  • Jiang G, Liu J, Ren B et al (2017) Anti-tumor and chemosensitization effects of Cryptotanshinone extracted from Salvia miltiorrhiza Bge. On ovarian cancer cells in vitro. J Ethnopharmacol 205:33–40

    Article  CAS  PubMed  Google Scholar 

  • Jnoff E, Albrecht C, Barker JJ et al (2014) Binding mode and structure-activity relationships around direct inhibitors of the Nrf2-Keap1 complex. ChemMedChem 9(4):699–705

    Article  CAS  PubMed  Google Scholar 

  • Ju W, Wang X, Shi H et al (2007) A critical role of luteolin-induced reactive oxygen species in blockage of tumor necrosis factor-activated nuclear factor-kappaB pathway and sensitization of apoptosis in lung cancer cells. Mol Pharmacol 71(5):1381–1388

    Article  CAS  PubMed  Google Scholar 

  • Jung BJ, Yoo HS, Shin S et al (2018) Dysregulation of NRF2 in Cancer: from molecular mechanisms to therapeutic opportunities. Biomol Ther (Seoul) 26(1):57–68

    Article  CAS  Google Scholar 

  • Kanarek N, Ben-Neriah Y (2012) Regulation of NF-kappaB by ubiquitination and degradation of the IkappaBs. Immunol Rev 246(1):77–94

    Article  PubMed  CAS  Google Scholar 

  • Kansanen E, Bonacci G, Schopfer FJ et al (2011) Electrophilic nitro-fatty acids activate NRF2 by a KEAP1 cysteine 151-independent mechanism. J Biol Chem 286(16):14019–14027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Keller TL, Zocco D, Sundrud MS et al (2012) Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. Nat Chem Biol 8(3):311–317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ki SH, Cho IJ, Choi DW et al (2005) Glucocorticoid receptor (GR)-associated SMRT binding to C/EBPbeta TAD and Nrf2 Neh4/5: role of SMRT recruited to GR in GSTA2 gene repression. Mol Cell Biol 25(10):4150–4165

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim HV, Kim HY, Ehrlich HY et al (2013) Amelioration of Alzheimer's disease by neuroprotective effect of sulforaphane in animal model. Amyloid 20(1):7–12

    Article  CAS  PubMed  Google Scholar 

  • Kimura K, Huang RC (2016) Tetra-O-methyl nordihydroguaiaretic acid broadly suppresses cancer metabolism and synergistically induces strong anticancer activity in combination with etoposide, Rapamycin and UCN-01. PLoS One 11(2):e0148685

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kitamura H, Motohashi H (2018) NRF2 addiction in cancer cells. Cancer Sci 109(4):900–911

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Knorr KL, Schneider PA, Meng XW et al (2015) MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors. Cell Death Differ 22(12):2133–2142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kobayashi A, Kang MI, Okawa H et al (2004) Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 24(16):7130–7139

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kobayashi EH, Suzuki T, Funayama R et al (2016) Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat Commun 7:11624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kolm RH, Danielson UH, Zhang Y et al (1995) Isothiocyanates as substrates for human glutathione transferases: structure-activity studies. Biochem J 311(Pt 2):453–459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Komatsu M, Kurokawa H, Waguri S et al (2010) The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1. Nat Cell Biol 12(3):213–223

    Article  CAS  PubMed  Google Scholar 

  • Kratschmar DV, Calabrese D, Walsh J et al (2012) Suppression of the Nrf2-dependent antioxidant response by glucocorticoids and 11beta-HSD1-mediated glucocorticoid activation in hepatic cells. PLoS One 7(5):e36774

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kumar A, Corey C, Scott I et al (2016) Minnelide/triptolide impairs mitochondrial function by regulating SIRT3 in P53-dependent manner in non-small cell lung cancer. PLoS One 11(8):e0160783

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Kwak MK, Itoh K, Yamamoto M et al (2002) Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter. Mol Cell Biol 22(9):2883–2892

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lal H, Ahmad F, Woodgett J et al (2015) The GSK-3 family as therapeutic target for myocardial diseases. Circ Res 116(1):138–149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lau A, Wang XJ, Zhao F et al (2010) A noncanonical mechanism of Nrf2 activation by autophagy deficiency: direct interaction between Keap1 and p62. Mol Cell Biol 30(13):3275–3285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lee C (2018) Therapeutic modulation of virus-induced oxidative stress via the Nrf2-dependent Antioxidative pathway. Oxidative Med Cell Longev 2018:6208067

    Google Scholar 

  • Levonen AL, Landar A, Ramachandran A et al (2004) Cellular mechanisms of redox cell signalling: role of cysteine modification in controlling antioxidant defences in response to electrophilic lipid oxidation products. Biochem J 378(Pt 2):373–382

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li J, Calkins MJ, Johnson DA et al (2007) Role of Nrf2-dependent ARE-driven antioxidant pathway in neuroprotection. Methods Mol Biol 399:67–78

    Article  CAS  PubMed  Google Scholar 

  • Li W, Saud SM, Young MR et al (2015a) Cryptotanshinone, a Stat3 inhibitor, suppresses colorectal cancer proliferation and growth in vitro. Mol Cell Biochem 406(1–2):63–73

    Article  CAS  PubMed  Google Scholar 

  • Li S, Wang H, Hong L et al (2015b) Cryptotanshinone inhibits breast cancer cell growth by suppressing estrogen receptor signaling. Cancer Biol Ther 16(1):176–184

    Article  CAS  PubMed  Google Scholar 

  • Li R, Rezk A, Ghadiri M et al (2017) Dimethyl Fumarate treatment mediates an anti-inflammatory shift in B cell subsets of patients with multiple sclerosis. J Immunol 198(2):691–698

    Article  CAS  PubMed  Google Scholar 

  • Liang J, Hansch GM, Hubner K et al (2019) Sulforaphane as anticancer agent: a double-edged sword? Tricky balance between effects on tumor cells and immune cells. Adv Biol Regul 71:79–87

    Article  CAS  PubMed  Google Scholar 

  • Liao JC, Lee KT, You BJ et al (2015) Raf/ERK/Nrf2 signaling pathway and MMP-7 expression involvement in the trigonelline-mediated inhibition of hepatocarcinoma cell migration. Food Nutr Res 59:29884

    Article  PubMed  CAS  Google Scholar 

  • Liby KT, Sporn MB (2012) Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol Rev 64(4):972–1003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin JJ, Milhollen MA, Smith PG et al (2010) NEDD8-targeting drug MLN4924 elicits DNA rereplication by stabilizing Cdt1 in S phase, triggering checkpoint activation, apoptosis, and senescence in cancer cells. Cancer Res 70(24):10310–10320

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin SX, Lisi L, Dello Russo C et al (2011) The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1. ASN Neuro 3(2):AN20100033

    Article  CAS  Google Scholar 

  • Linker RA, Lee DH, Ryan S et al (2011) Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain 134(Pt 3):678–692

    Article  PubMed  Google Scholar 

  • Lipton SA, Rezaie T, Nutter A et al (2016) Therapeutic advantage of pro-electrophilic drugs to activate the Nrf2/ARE pathway in Alzheimer’s disease models. Cell Death Dis 7(12):e2499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu GH, Qu J, Shen X (2008) NF-kappaB/p65 antagonizes Nrf2-ARE pathway by depriving CBP from Nrf2 and facilitating recruitment of HDAC3 to MafK. Biochim Biophys Acta 1783(5):713–727

    Article  CAS  PubMed  Google Scholar 

  • Liu Y, Chen F, Wang S et al (2013) Low-dose triptolide in combination with idarubicin induces apoptosis in AML leukemic stem-like KG1a cell line by modulation of the intrinsic and extrinsic factors. Cell Death Dis 4:e948

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu J, Su H, Qu QM (2016) Carnosic acid prevents beta-amyloid-induced injury in human neuroblastoma SH-SY5Y cells via the induction of autophagy. Neurochem Res 41(9):2311–2323

    Article  CAS  PubMed  Google Scholar 

  • Lo SC, Li X, Henzl MT et al (2006) Structure of the Keap1:Nrf2 interface provides mechanistic insight into Nrf2 signaling. EMBO J 25(15):3605–3617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lombardi G, Pambuku A, Bellu L et al (2017) Effectiveness of antiangiogenic drugs in glioblastoma patients: a systematic review and meta-analysis of randomized clinical trials. Crit Rev Oncol Hematol 111:94–102

    Article  PubMed  Google Scholar 

  • Lovestone S, Boada M, Dubois B et al (2015) A phase II trial of Tideglusib in Alzheimer’s disease. J Alzheimers Dis 45(1):75–88

    Article  CAS  PubMed  Google Scholar 

  • Lu MC, Ji JA, Jiang YL et al (2016) An inhibitor of the Keap1-Nrf2 protein-protein interaction protects NCM460 colonic cells and alleviates experimental colitis. Sci Rep 6:26585

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu J, Guo S, Xue X et al (2017) Identification of a novel series of anti-inflammatory and anti-oxidative phospholipid oxidation products containing the cyclopentenone moiety in vitro and in vivo: implication in atherosclerosis. J Biol Chem 292(13):5378–5391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lu MC, Jiao Q, Liu T et al (2018) Discovery of a head-to-tail cyclic peptide as the Keap1-Nrf2 protein-protein interaction inhibitor with high cell potency. Eur J Med Chem 143:1578–1589

    Article  CAS  PubMed  Google Scholar 

  • Lu MC, Zhao J, Liu YT et al (2019) CPUY192018, a potent inhibitor of the Keap1-Nrf2 protein-protein interaction, alleviates renal inflammation in mice by restricting oxidative stress and NF-kappaB activation. Redox Biol 26:101266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Luo J (2009) Glycogen synthase kinase 3beta (GSK3beta) in tumorigenesis and cancer chemotherapy. Cancer Lett 273(2):194–200

    Article  CAS  PubMed  Google Scholar 

  • Lynch DR, Farmer J, Hauser L et al (2019) Safety, pharmacodynamics, and potential benefit of omaveloxolone in Friedreich ataxia. Ann Clin Transl Neurol 6(1):15–26

    Article  CAS  PubMed  Google Scholar 

  • Magesh S, Chen Y, Hu L (2012) Small molecule modulators of Keap1-Nrf2-ARE pathway as potential preventive and therapeutic agents. Med Res Rev 32(4):687–726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manna A, Saha P, Sarkar A et al (2012) Malabaricone-A induces a redox imbalance that mediates apoptosis in U937 cell line. PLoS One 7(5):e36938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manna A, Bauri AK, Chattopadhyay S et al (2015) Generation of redox imbalance mediates the cytotoxic effect of Malabaricone-a in a multidrug resistant cell line. Anti Cancer Agents Med Chem 15(9):1156–1163

    Article  CAS  Google Scholar 

  • Marcotte D, Zeng W, Hus JC et al (2013) Small molecules inhibit the interaction of Nrf2 and the Keap1 Kelch domain through a non-covalent mechanism. Bioorg Med Chem 21(14):4011–4019

    Article  CAS  PubMed  Google Scholar 

  • McCord JM, Hybertson BM, Cota-Gomez A, et al (2020) Nrf2 activator PB125(R) as a potential therapeutic agent against COVID-19. bioRxiv

    Google Scholar 

  • Miao W, Hu L, Scrivens PJ et al (2005) Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes. J Biol Chem 280(21):20340–20348

    Article  CAS  PubMed  Google Scholar 

  • Milhollen MA, Traore T, Adams-Duffy J et al (2010) MLN4924, a NEDD8-activating enzyme inhibitor, is active in diffuse large B-cell lymphoma models: rationale for treatment of NF-{kappa}B-dependent lymphoma. Blood 116(9):1515–1523

    Article  CAS  PubMed  Google Scholar 

  • Milkovic L, Zarkovic N, Saso L (2017) Controversy about pharmacological modulation of Nrf2 for cancer therapy. Redox Biol 12:727–732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mills EA, Ogrodnik MA, Plave A et al (2018a) Emerging understanding of the mechanism of action for dimethyl Fumarate in the treatment of multiple sclerosis. Front Neurol 9:5

    Article  PubMed  PubMed Central  Google Scholar 

  • Mills EL, Ryan DG, Prag HA et al (2018b) Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556(7699):113–117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mizunoe Y, Kobayashi M, Sudo Y et al (2018) Trehalose protects against oxidative stress by regulating the Keap1-Nrf2 and autophagy pathways. Redox Biol 15:115–124

    Article  CAS  PubMed  Google Scholar 

  • Morales DR, Morris AD (2015) Metformin in cancer treatment and prevention. Annu Rev Med 66:17–29

    Article  CAS  PubMed  Google Scholar 

  • Myung SK, Ju W, Cho B et al (2013) Efficacy of vitamin and antioxidant supplements in prevention of cardiovascular disease: systematic review and meta-analysis of randomised controlled trials. BMJ 346:f10

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Myzak MC, Dashwood RH (2006) Chemoprotection by sulforaphane: keep one eye beyond Keap1. Cancer Lett 233(2):208–218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nasiri HR, Linge S, Ullmann D (2016) Thermodynamic profiling of inhibitors of Nrf2:Keap1 interactions. Bioorg Med Chem Lett 26(2):526–529

    Article  CAS  PubMed  Google Scholar 

  • Nilsson L, Palm F, Norregaard R (2017) 15-Deoxy-Delta(12,14)-prostaglandin J2 exerts antioxidant effects while exacerbating inflammation in mice subjected to ureteral obstruction. Mediat Inflamm 2017:3924912

    Article  CAS  Google Scholar 

  • Noel P, von Hoff DD, Saluja AK et al (2019) Triptolide and its derivatives as cancer therapies. Trends Pharmacol Sci 40(5):327–341

    Article  CAS  PubMed  Google Scholar 

  • Ohta T, Iijima K, Miyamoto M et al (2008) Loss of Keap1 function activates Nrf2 and provides advantages for lung cancer cell growth. Cancer Res 68(5):1303–1309

    Article  CAS  PubMed  Google Scholar 

  • Olayanju A, Copple IM, Bryan HK et al (2015) Brusatol provokes a rapid and transient inhibition of Nrf2 signaling and sensitizes mammalian cells to chemical toxicity-implications for therapeutic targeting of Nrf2. Free Radic Biol Med 78:202–212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Padmanabhan B, Tong KI, Ohta T et al (2006) Structural basis for defects of Keap1 activity provoked by its point mutations in lung cancer. Mol Cell 21(5):689–700

    Article  CAS  PubMed  Google Scholar 

  • Pajares M, Jimenez-Moreno N, Dias IH et al (2015) Redox control of protein degradation. Redox Biol 6:409–420

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pajares M, Jimenez-Moreno N, Garcia-Yague AJ et al (2016) Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes. Autophagy 12(10):1902–1916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pajares M, Cuadrado A, Rojo AI (2017) Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases. Redox Biol 11:543–553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Palomo V, Martinez A (2017) Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2014-2015). Expert Opin Ther Pat 27(6):657–666

    Article  CAS  PubMed  Google Scholar 

  • Pan J, Shen F, Tian K et al (2019) Triptolide induces oxidative damage in NRK-52E cells through facilitating Nrf2 degradation by ubiquitination via the GSK-3beta/Fyn pathway. Toxicol In Vitro 58:187–194

    Article  CAS  PubMed  Google Scholar 

  • Paredes-Gonzalez X, Fuentes F, Jeffery S et al (2015) Induction of NRF2-mediated gene expression by dietary phytochemical flavones apigenin and luteolin. Biopharm Drug Dispos 36(7):440–451

    Article  CAS  PubMed  Google Scholar 

  • Park HM, Kim JA, Kwak MK (2009) Protection against amyloid beta cytotoxicity by sulforaphane: role of the proteasome. Arch Pharm Res 32(1):109–115

    Article  CAS  PubMed  Google Scholar 

  • Patel D, Shukla S, Gupta S (2007) Apigenin and cancer chemoprevention: progress, potential and promise (review). Int J Oncol 30(1):233–245

    CAS  PubMed  Google Scholar 

  • Peng H, Wang H, Xue P et al (2016) Suppression of NRF2-ARE activity sensitizes chemotherapeutic agent-induced cytotoxicity in human acute monocytic leukemia cells. Toxicol Appl Pharmacol 292:1–7

    Article  CAS  PubMed  Google Scholar 

  • Pergola PE, Raskin P, Toto RD et al (2011) Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med 365(4):327–336

    Article  CAS  PubMed  Google Scholar 

  • Ping Z, Liu W, Kang Z et al (2010) Sulforaphane protects brains against hypoxic-ischemic injury through induction of Nrf2-dependent phase 2 enzyme. Brain Res 1343:178–185

    Article  CAS  PubMed  Google Scholar 

  • Rabbani PS, Ellison T, Waqas B et al (2018) Targeted Nrf2 activation therapy with RTA 408 enhances regenerative capacity of diabetic wounds. Diabetes Res Clin Pract 139:11–23

    Article  CAS  PubMed  Google Scholar 

  • Rada P, Rojo AI, Evrard-Todeschi N et al (2012) Structural and functional characterization of Nrf2 degradation by the glycogen synthase kinase 3/beta-TrCP axis. Mol Cell Biol 32(17):3486–3499

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Raghunath A, Sundarraj K, Nagarajan R et al (2018) Antioxidant response elements: discovery, classes, regulation and potential applications. Redox Biol 17:297–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramos-Gomez M, Dolan PM, Itoh K et al (2003) Interactive effects of nrf2 genotype and oltipraz on benzo[a]pyrene-DNA adducts and tumor yield in mice. Carcinogenesis 24(3):461–467

    Article  CAS  PubMed  Google Scholar 

  • Ranjan N, Fulcrand G, King A et al (2014) Selective inhibition of bacterial topoisomerase I by alkynyl-bisbenzimidazoles. MedChemComm 5(6):816–825

    Article  CAS  PubMed  Google Scholar 

  • Reddy SP (2008) The antioxidant response element and oxidative stress modifiers in airway diseases. Curr Mol Med 8(5):376–383

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ren D, Villeneuve NF, Jiang T et al (2011) Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci U S A 108(4):1433–1438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Richardson BG, Jain AD, Speltz TE et al (2015) Non-electrophilic modulators of the canonical Keap1/Nrf2 pathway. Bioorg Med Chem Lett 25(11):2261–2268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robledinos-Anton N, Fernandez-Gines R, Manda G et al (2019) Activators and inhibitors of NRF2: a review of their potential for clinical development. Oxidative Med Cell Longev 2019:9372182

    Article  CAS  Google Scholar 

  • Roh JL, Kim EH, Jang H et al (2017a) Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis. Redox Biol 11:254–262

    Article  CAS  PubMed  Google Scholar 

  • Roh JL, Jang H, Kim EH et al (2017b) Targeting of the glutathione, thioredoxin, and Nrf2 antioxidant systems in head and neck cancer. Antioxid Redox Signal 27(2):106–114

    Article  CAS  PubMed  Google Scholar 

  • Rojo AI, Medina-Campos ON, Rada P et al (2012) Signaling pathways activated by the phytochemical nordihydroguaiaretic acid contribute to a Keap1-independent regulation of Nrf2 stability: role of glycogen synthase kinase-3. Free Radic Biol Med 52(2):473–487

    Article  CAS  PubMed  Google Scholar 

  • Rushworth SA, Zaitseva L, Murray MY et al (2012) The high Nrf2 expression in human acute myeloid leukemia is driven by NF-kappaB and underlies its chemo-resistance. Blood 120(26):5188–5198

    Article  CAS  PubMed  Google Scholar 

  • Saito R, Suzuki T, Hiramoto K et al (2015) Characterizations of three major cysteine sensors of Keap1 in stress response. Mol Cell Biol 36(2):271–284

    Article  PubMed  CAS  Google Scholar 

  • Saito T, Ichimura Y, Taguchi K et al (2016) p62/Sqstm1 promotes malignancy of HCV-positive hepatocellular carcinoma through Nrf2-dependent metabolic reprogramming. Nat Commun 7:12030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sangokoya C, Telen MJ, Chi JT (2010) microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease. Blood 116(20):4338–4348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Saraswati AP, Ali Hussaini SM, Krishna NH et al (2018) Glycogen synthase kinase-3 and its inhibitors: potential target for various therapeutic conditions. Eur J Med Chem 144:843–858

    Article  CAS  PubMed  Google Scholar 

  • Sarkar S, Rubinsztein DC (2008) Small molecule enhancers of autophagy for neurodegenerative diseases. Mol BioSyst 4(9):895–901

    Article  CAS  PubMed  Google Scholar 

  • Sato M, Aoki T, Inoue H et al (2013) Keap1 protein binding compound, Cristal of complex between the same and Keap1 protein, and method for producing the same. Toray Industries

    Google Scholar 

  • Satoh T, McKercher SR, Lipton SA (2013) Nrf2/ARE-mediated antioxidant actions of pro-electrophilic drugs. Free Radic Biol Med 65:645–657

    Article  CAS  PubMed  Google Scholar 

  • Schenk T, Stengel S, Zelent A (2014) Unlocking the potential of retinoic acid in anticancer therapy. Br J Cancer 111(11):2039–2045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schimrigk S, Brune N, Hellwig K et al (2006) Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol 13(6):604–610

    Article  CAS  PubMed  Google Scholar 

  • Schmidlin CJ, Dodson MB, Madhavan L et al (2019) Redox regulation by NRF2 in aging and disease. Free Radic Biol Med 134:702–707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schulze-Topphoff U, Varrin-Doyer M, Pekarek K et al (2016) Dimethyl fumarate treatment induces adaptive and innate immune modulation independent of Nrf2. Proc Natl Acad Sci U S A 113(17):4777–4782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shah JJ, Jakubowiak AJ, O’Connor OA et al (2016) Phase I study of the novel investigational NEDD8-activating enzyme inhibitor Pevonedistat (MLN4924) in patients with relapsed/refractory multiple myeloma or lymphoma. Clin Cancer Res 22(1):34–43

    Article  CAS  PubMed  Google Scholar 

  • Sharma S, Ray A, Sadasivam B (2020) Metformin in COVID-19: a possible role beyond diabetes. Diabetes Res Clin Pract 164:108183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shibata T, Ohta T, Tong KI et al (2008) Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci U S A 105(36):13568–13573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sihvola V, Levonen AL (2017) Keap1 as the redox sensor of the antioxidant response. Arch Biochem Biophys 617:94–100

    Article  CAS  PubMed  Google Scholar 

  • Silva T, Reis J, Teixeira J et al (2014) Alzheimer's disease, enzyme targets and drug discovery struggles: from natural products to drug prototypes. Ageing Res Rev 15:116–145

    Article  CAS  PubMed  Google Scholar 

  • Singh SV, Warin R, Xiao D et al (2009) Sulforaphane inhibits prostate carcinogenesis and pulmonary metastasis in TRAMP mice in association with increased cytotoxicity of natural killer cells. Cancer Res 69(5):2117–2125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Singh A, Venkannagari S, Oh KH et al (2016) Small molecule inhibitor of NRF2 selectively intervenes therapeutic resistance in KEAP1-deficient NSCLC tumors. ACS Chem Biol 11(11):3214–3225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smale ST (2011) Hierarchies of NF-kappaB target-gene regulation. Nat Immunol 12(8):689–694

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Smith MD, Martin KA, Calabresi PA et al (2017) Dimethyl fumarate alters B-cell memory and cytokine production in MS patients. Ann Clin Transl Neurol 4(5):351–355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Solis LM, Behrens C, Dong W et al (2010) Nrf2 and Keap1 abnormalities in non-small cell lung carcinoma and association with clinicopathologic features. Clin Cancer Res 16(14):3743–3753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Son YO, Pratheeshkumar P, Wang Y et al (2017) Protection from Cr(VI)-induced malignant cell transformation and tumorigenesis of Cr(VI)-transformed cells by luteolin through Nrf2 signaling. Toxicol Appl Pharmacol 331:24–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Soucy TA, Smith PG, Milhollen MA et al (2009) An inhibitor of NEDD8-activating enzyme as a new approach to treat cancer. Nature 458(7239):732–736

    Article  CAS  PubMed  Google Scholar 

  • Steel R, Cowan J, Payerne E et al (2012) Anti-inflammatory effect of a cell-penetrating peptide targeting the Nrf2/Keap1 interaction. ACS Med Chem Lett 3(5):407–410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun H, Zhu J, Lin H et al (2017) Recent progress in the development of small molecule Nrf2 modulators: a patent review (2012-2016). Expert Opin Ther Pat 27(7):763–785

    Article  CAS  PubMed  Google Scholar 

  • Sun X, Li X, Ma S et al (2018) MicroRNA-98-5p ameliorates oxygen-glucose deprivation/reoxygenation (OGD/R)-induced neuronal injury by inhibiting Bach1 and promoting Nrf2/ARE signaling. Biochem Biophys Res Commun 507(1–4):114–121

    Article  CAS  PubMed  Google Scholar 

  • Suzuki T, Motohashi H, Yamamoto M (2013) Toward clinical application of the Keap1-Nrf2 pathway. Trends Pharmacol Sci 34(6):340–346

    Article  CAS  PubMed  Google Scholar 

  • Swords RT, Watts J, Erba HP et al (2017) Expanded safety analysis of pevonedistat, a first-in-class NEDD8-activating enzyme inhibitor, in patients with acute myeloid leukemia and myelodysplastic syndromes. Blood Cancer J 7(2):e520

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Taguchi K, Yamamoto M (2017) The KEAP1-NRF2 system in cancer. Front Oncol 7:85

    Article  PubMed  PubMed Central  Google Scholar 

  • Taguchi K, Motohashi H, Yamamoto M (2011) Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells 16(2):123–140

    Article  CAS  PubMed  Google Scholar 

  • Tang X, Wang H, Fan L et al (2011) Luteolin inhibits Nrf2 leading to negative regulation of the Nrf2/ARE pathway and sensitization of human lung carcinoma A549 cells to therapeutic drugs. Free Radic Biol Med 50(11):1599–1609

    Article  CAS  PubMed  Google Scholar 

  • Tao S, Wang S, Moghaddam SJ et al (2014) Oncogenic KRAS confers chemoresistance by upregulating NRF2. Cancer Res 74(24):7430–7441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tarozzi A, Angeloni C, Malaguti M et al (2013) Sulforaphane as a potential protective phytochemical against neurodegenerative diseases. Oxidative Med Cell Longev 2013:415078

    Article  CAS  Google Scholar 

  • Tarumoto T, Nagai T, Ohmine K et al (2004) Ascorbic acid restores sensitivity to imatinib via suppression of Nrf2-dependent gene expression in the imatinib-resistant cell line. Exp Hematol 32(4):375–381

    Article  CAS  PubMed  Google Scholar 

  • Tong KI, Katoh Y, Kusunoki H et al (2006) Keap1 recruits Neh2 through binding to ETGE and DLG motifs: characterization of the two-site molecular recognition model. Mol Cell Biol 26(8):2887–2900

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tong KI, Padmanabhan B, Kobayashi A et al (2007) Different electrostatic potentials define ETGE and DLG motifs as hinge and latch in oxidative stress response. Mol Cell Biol 27(21):7511–7521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tsuchida K, Tsujita T, Hayashi M et al (2017) Halofuginone enhances the chemo-sensitivity of cancer cells by suppressing NRF2 accumulation. Free Radic Biol Med 103:236–247

    Article  CAS  PubMed  Google Scholar 

  • Tu J, Zhang X, Zhu Y et al (2015) Cell-permeable peptide targeting the Nrf2-Keap1 interaction: a potential novel therapy for global cerebral ischemia. J Neurosci 35(44):14727–14739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Valenzuela M, Glorieux C, Stockis J et al (2014) Retinoic acid synergizes ATO-mediated cytotoxicity by precluding Nrf2 activity in AML cells. Br J Cancer 111(5):874–882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vanderdys V, Allak A, Guessous F et al (2018) The Neddylation inhibitor Pevonedistat (MLN4924) suppresses and Radiosensitizes head and neck squamous carcinoma cells and tumors. Mol Cancer Ther 17(2):368–380

    Article  CAS  PubMed  Google Scholar 

  • Verma AK, Yadav A, Dewangan J et al (2015) Isoniazid prevents Nrf2 translocation by inhibiting ERK1 phosphorylation and induces oxidative stress and apoptosis. Redox Biol 6:80–92

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Vilcheze C, Jacobs WR Jr (2014) Resistance to isoniazid and ethionamide in Mycobacterium tuberculosis: genes, mutations, and causalities. Microbiol Spectr 2(4):MGM2-0014-2013

    Article  PubMed  CAS  Google Scholar 

  • von Glehn F, Dias-Carneiro RPC, Moraes AS et al (2018) Dimethyl fumarate downregulates the immune response through the HCA2/GPR109A pathway: implications for the treatment of multiple sclerosis. Mult Scler Relat Disord 23:46–50

    Article  Google Scholar 

  • Wagner AE, Boesch-Saadatmandi C, Breckwoldt D et al (2011) Ascorbic acid partly antagonizes resveratrol mediated heme oxygenase-1 but not paraoxonase-1 induction in cultured hepatocytes - role of the redox-regulated transcription factor Nrf2. BMC Complement Altern Med 11:1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wakabayashi N, Dinkova-Kostova AT, Holtzclaw WD et al (2004) Protection against electrophile and oxidant stress by induction of the phase 2 response: fate of cysteines of the Keap1 sensor modified by inducers. Proc Natl Acad Sci U S A 101(7):2040–2045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang XJ, Hayes JD, Henderson CJ et al (2007) Identification of retinoic acid as an inhibitor of transcription factor Nrf2 through activation of retinoic acid receptor alpha. Proc Natl Acad Sci U S A 104(49):19589–19594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang H, Liu K, Geng M et al (2013) RXRalpha inhibits the NRF2-ARE signaling pathway through a direct interaction with the Neh7 domain of NRF2. Cancer Res 73(10):3097–3108

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Li F, Wang S (2016) MicroRNA93 is overexpressed and induces apoptosis in glaucoma trabecular meshwork cells. Mol Med Rep 14(6):5746–5750

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Lu HL, Liu YD et al (2017) Cryptotanshinone sensitizes antitumor effect of paclitaxel on tongue squamous cell carcinoma growth by inhibiting the JAK/STAT3 signaling pathway. Biomed Pharmacother 95:1388–1396

    Article  CAS  PubMed  Google Scholar 

  • Wang W, Wang X, Zhang XS et al (2018) Cryptotanshinone attenuates oxidative stress and inflammation through the regulation of Nrf-2 and NF-kappaB in mice with unilateral ureteral obstruction. Basic Clin Pharmacol Toxicol 123(6):714–720

    Article  CAS  PubMed  Google Scholar 

  • Wardyn JD, Ponsford AH, Sanderson CM (2015) Dissecting molecular cross-talk between Nrf2 and NF-kappaB response pathways. Biochem Soc Trans 43(4):621–626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Watanabe G, Pena P, Albanese C et al (1997) Adrenocorticotropin induction of stress-activated protein kinase in the adrenal cortex in vivo. J Biol Chem 272(32):20063–20069

    Article  CAS  PubMed  Google Scholar 

  • Wen X, Thorne G, Hu L et al (2015) Activation of NRF2 signaling in HEK293 cells by a first-in-class direct KEAP1-NRF2 inhibitor. J Biochem Mol Toxicol 29(6):261–266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson MK, Baguley BC, Wall C et al (2014) Review of high-dose intravenous vitamin C as an anticancer agent. Asia Pac J Clin Oncol 10(1):22–37

    Article  PubMed  Google Scholar 

  • Wolenski FS, Fisher CD, Sano T et al (2015) The NAE inhibitor pevonedistat (MLN4924) synergizes with TNF-alpha to activate apoptosis. Cell Death Discov 1:15034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wong DPW, Ng MY, Leung JY et al (2018) Regulation of the NRF2 transcription factor by andrographolide and organic extracts from plant endophytes. PLoS One 13(10):e0204853

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Wu T, Zhao F, Gao B et al (2014a) Hrd1 suppresses Nrf2-mediated cellular protection during liver cirrhosis. Genes Dev 28(7):708–722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu J, Wang H, Tang X (2014b) Rexinoid inhibits Nrf2-mediated transcription through retinoid X receptor alpha. Biochem Biophys Res Commun 452(3):554–559

    Article  CAS  PubMed  Google Scholar 

  • Wu CF, Klauck SM, Efferth T (2016) Anticancer activity of cryptotanshinone on acute lymphoblastic leukemia cells. Arch Toxicol 90(9):2275–2286

    Article  CAS  PubMed  Google Scholar 

  • Wu G, Yan Y, Zhou Y et al (2020) Sulforaphane: expected to become a novel anti-tumor compound. Oncol Res Featur Preclin Clin Cancer Therap

    Google Scholar 

  • Xia C, Bai X, Hou X et al (2015) Cryptotanshinone reverses Cisplatin resistance of human lung carcinoma A549 cells through down-regulating Nrf2 pathway. Cell Physiol Biochem 37(2):816–824

    Article  CAS  PubMed  Google Scholar 

  • Xiang Y, Ye W, Huang C et al (2018) Brusatol enhances the chemotherapy efficacy of gemcitabine in pancreatic cancer via the Nrf2 Signalling pathway. Oxidative Med Cell Longev 2018:2360427

    Article  CAS  Google Scholar 

  • Xiao C, Xia ML, Wang J et al (2019) Luteolin attenuates cardiac ischemia/reperfusion injury in diabetic rats by modulating Nrf2 Antioxidative function. Oxidative Med Cell Longev 2019:2719252

    Google Scholar 

  • Xu C, Huang MT, Shen G et al (2006) Inhibition of 7,12-dimethylbenz(a)anthracene-induced skin tumorigenesis in C57BL/6 mice by sulforaphane is mediated by nuclear factor E2-related factor 2. Cancer Res 66(16):8293–8296

    Article  CAS  PubMed  Google Scholar 

  • Xu Z, Zhang F, Sun F et al (2015) Dimethyl fumarate for multiple sclerosis. Cochrane Database Syst Rev 4:CD011076

    Google Scholar 

  • Yamamoto T, Suzuki T, Kobayashi A et al (2008) Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Mol Cell Biol 28(8):2758–2770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang M, Yao Y, Eades G et al (2011) MiR-28 regulates Nrf2 expression through a Keap1-independent mechanism. Breast Cancer Res Treat 129(3):983–991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu R, Chen C, Mo YY et al (2000) Activation of mitogen-activated protein kinase pathways induces antioxidant response element-mediated gene expression via a Nrf2-dependent mechanism. J Biol Chem 275(51):39907–39913

    Article  CAS  PubMed  Google Scholar 

  • Yu H, Shi L, Zhao S et al (2016) Triptolide attenuates myocardial ischemia/reperfusion injuries in rats by inducing the activation of Nrf2/HO-1 defense pathway. Cardiovasc Toxicol 16(4):325–335

    Article  CAS  PubMed  Google Scholar 

  • Yu C, Jiao Y, Xue J et al (2017) Metformin sensitizes non-small cell lung Cancer cells to an Epigallocatechin-3-Gallate (EGCG) treatment by suppressing the Nrf2/HO-1 signaling pathway. Int J Biol Sci 13(12):1560–1569

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zeidan TA, Duncan S, Hencken CP et al (2014) Prodrugs of fumarates and their use in treating various diseases. Alkermes Pharma Ireland Limited

    Google Scholar 

  • Zhang DD (2013) Bardoxolone brings Nrf2-based therapies to light. Antioxid Redox Signal 19(5):517–518

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhao J, Kobori N, Aronowski J et al (2006) Sulforaphane reduces infarct volume following focal cerebral ischemia in rodents. Neurosci Lett 393(2–3):108–112

    Article  CAS  PubMed  Google Scholar 

  • Zhao Y, Morgan MA, Sun Y (2014) Targeting Neddylation pathways to inactivate cullin-RING ligases for anticancer therapy. Antioxid Redox Signal 21(17):2383–2400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou H, Lu J, Liu L et al (2017) A potent small-molecule inhibitor of the DCN1-UBC12 interaction that selectively blocks cullin 3 neddylation. Nat Commun 8(1):1150

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhou Y, Wang X, Ying W et al (2019) Cryptotanshinone attenuates inflammatory response of microglial cells via the Nrf2/HO-1 pathway. Front Neurosci 13:852

    Article  PubMed  PubMed Central  Google Scholar 

  • Zhu J, Wang H, Chen F et al (2016) An overview of chemical inhibitors of the Nrf2-ARE signaling pathway and their potential applications in cancer therapy. Free Radic Biol Med 99:544–556

    Article  CAS  PubMed  Google Scholar 

  • Zhu J, Wang H, Chen F et al (2018) Triptolide enhances chemotherapeutic efficacy of antitumor drugs in non-small-cell lung cancer cells by inhibiting Nrf2-ARE activity. Toxicol Appl Pharmacol 358:1–9

    Article  CAS  PubMed  Google Scholar 

  • Zuo Q, Wu R, Xiao X et al (2018) The dietary flavone luteolin epigenetically activates the Nrf2 pathway and blocks cell transformation in human colorectal cancer HCT116 cells. J Cell Biochem 119(11):9573–9582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by grants SAF2016-76520-R of the Spanish Ministry of Economy and Competitiveness, B2017/BMD-3827 of the Autonomous Community of Madrid, and P_37_732/2016 REDBRAIN of the European Regional Development Fund, Competitiveness Operational Program 2014–2020. RFG and DL are recipient of FPI and FPU contracts, respectively, of the Spanish Ministry of Economy and Competitiveness.

Conflict of Interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

Author information

Author notes

  1. Gina Manda and Antonio Cuadrado contributed equally to this work.

Authors and Affiliations

  1. Instituto de Investigaciones Biomédicas “Alberto Sols” UAM-CSIC, Instituto de Investigación Sanitaria La Paz (IdiPaz), Madrid, Spain

    Diego Lastra, Raquel Fernández-Ginés & Antonio Cuadrado

  2. Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain

    Diego Lastra, Raquel Fernández-Ginés & Antonio Cuadrado

  3. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), ISCIII, Madrid, Spain

    Diego Lastra, Raquel Fernández-Ginés & Antonio Cuadrado

  4. Victor Babes National Institute of Pathology, Bucharest, Romania

    Gina Manda & Antonio Cuadrado

Authors
  1. Diego Lastra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raquel Fernández-Ginés
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gina Manda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Antonio Cuadrado
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Antonio Cuadrado .

Editor information

Editors and Affiliations

  1. Department of Pharmacology and Personalised Medicine, Maastricht University, Maastricht, The Netherlands

    Harald H. H. W. Schmidt

  2. Brighton and Sussex Medical School, Brighton, UK

    Pietro Ghezzi

  3. Department of Biochemistry, Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain

    Antonio Cuadrado

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Lastra, D., Fernández-Ginés, R., Manda, G., Cuadrado, A. (2020). Perspectives on the Clinical Development of NRF2-Targeting Drugs. In: Schmidt, H.H.H.W., Ghezzi, P., Cuadrado, A. (eds) Reactive Oxygen Species . Handbook of Experimental Pharmacology, vol 264. Springer, Cham. https://doi.org/10.1007/164_2020_381

Download citation

Publish with us

Policies and ethics

Search

Navigation