Friend or Foe: Xenobiotic Activation of Nrf2 in Disease Control and Cardioprotection


Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that governs a highly conserved pathway central to the protection of cells against various oxidative stresses. However, the biological impact of xenobiotic intervention of Nrf2 in physiological and pathophysiological conditions remains debatable. Activation of Nrf2 in cancer cells has been shown to elevate drug resistance and increase cell survival and proliferation, while inhibition of Nrf2 sensitizes cancer cells to drug treatment. On the other hand, activation of Nrf2 in normal healthy cells has been explored as a rather successful strategy for cancer chemoprevention. Selective activation of Nrf2 in off-target cells has recently been investigated as an approach for protecting off-target tissues from untoward drug toxicity. Specifically, induction of antioxidant response element genes via Nrf2 activation in cardiac cells is being explored as a means to limit the well-documented cardiotoxicity accompanied by cancer treatment with commonly prescribed anthracycline drugs. In addition to cancers, Nrf2 has been implicated in many other diseases including Alzheimer’s and Parkinson’s Diseases, diabetes, and cardiovascular disease. In this review, we discuss the roles of Nrf2 and its downstream target genes in the treatment of various diseases, and its recently explored potential for increasing the benefit: risk ratio of commonly utilized cancer treatments.

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Fig. 1
Fig. 2



Alzheimer’s Disease


Aldo-keto reductase


Alpha linolenic acid


Acute myeloid leukemia


Antioxidant response element


Arsenic trioxide


Breast cancer resistance protein


Basic leucine zipper






Bardoxolone methyl


Chronic kidney disease


Dichloroacetyl chloride




Dimethyl fumarate




Extracellular signal regulated kinase pathway


Glutamate-cysteine ligase catalytic subunit


Glycogen synthase 3


Glutathione peroxidase




Heme oxygenase 1


Kelch like-ECH-associated protein 1


Lewy body variant of Alzheimer’s Disease


Leucine-rich repeat kinase 2




Multidrug resistance-associated protein


Nonalcoholic fatty liver disease


NAD(P)H quinone dehydrogenase


Nuclear factor (erythroid-derived 2)-like 2


Parkinson’s Disease


Protein kinase c


Reactive oxygen species


Scrambled RNA




Short hairpin RNA


Small interfering RNA


Superoxide dismutase


Sequestosome 1






Tauroursodeoxycholic acid


  1. 1.

    Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD, et al. Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev. 1999;13(1):76–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Kobayashi A, Kang MI, Okawa H, Ohtsuji M, Zenke Y, Chiba T, et al. Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol. 2004;24(16):7130–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun. 1997;236(2):313–22.

    CAS  PubMed  Google Scholar 

  4. 4.

    Yamamoto T, Suzuki T, Kobayashi A, Wakabayashi J, Maher J, Motohashi H, et al. Physiological significance of reactive cysteine residues of Keap1 in determining Nrf2 activity. Mol Cell Biol. 2008;28(8):2758–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Sekhar KR, Rachakonda G, Freeman ML. Cysteine-based regulation of the CUL3 adaptor protein Keap1. Toxicol Appl Pharmacol. 2010;244(1):21–6.

    CAS  PubMed  Google Scholar 

  6. 6.

    Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells: Devoted Mole Cell Mech. 2011;16(2):123–40.

    CAS  Google Scholar 

  7. 7.

    Zhang DD. Mechanistic studies of the Nrf2-Keap1 signaling pathway. Drug Metab Rev. 2006;38(4):769–89.

    CAS  PubMed  Google Scholar 

  8. 8.

    Taguchi K, Yamamoto M. The KEAP1-NRF2 system in Cancer. Front Oncol. 2017;7:85.

    PubMed  PubMed Central  Google Scholar 

  9. 9.

    Amer J, Ghoti H, Rachmilewitz E, Koren A, Levin C, Fibach E. Red blood cells, platelets and polymorphonuclear neutrophils of patients with sickle cell disease exhibit oxidative stress that can be ameliorated by antioxidants. Br J Haematol. 2006;132(1):108–13.

    CAS  PubMed  Google Scholar 

  10. 10.

    Halliwell B. Oxidative stress and cancer: have we moved forward? Biochem J. 2007;401(1):1–11.

    CAS  PubMed  Google Scholar 

  11. 11.

    Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J. Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol. 2007;39(1):44–84.

    CAS  PubMed  Google Scholar 

  12. 12.

    Bonomini F, Tengattini S, Fabiano A, Bianchi R, Rezzani R. Atherosclerosis and oxidative stress. Histol Histopathol. 2008;23(3):381–90.

    CAS  PubMed  Google Scholar 

  13. 13.

    de Diego-Otero Y, Romero-Zerbo Y, el Bekay R, Decara J, Sanchez L, Rodriguez-de Fonseca F, et al. Alpha-tocopherol protects against oxidative stress in the fragile X knockout mouse: an experimental therapeutic approach for the Fmr1 deficiency. Neuropsychopharmacology. 2009;34(4):1011–26.

    PubMed  Google Scholar 

  14. 14.

    Dean OM, van den Buuse M, Berk M, Copolov DL, Mavros C, Bush AI. N-acetyl cysteine restores brain glutathione loss in combined 2-cyclohexene-1-one and d-amphetamine-treated rats: relevance to schizophrenia and bipolar disorder. Neurosci Lett. 2011;499(3):149–53.

    CAS  PubMed  Google Scholar 

  15. 15.

    Tsutsui H, Kinugawa S, Matsushima S. Oxidative stress and heart failure. Am J Physiol Heart Circ Physiol. 2011;301(6):H2181–90.

    CAS  PubMed  Google Scholar 

  16. 16.

    Parellada M, Moreno C, Mac-Dowell K, Leza JC, Giraldez M, Bailon C, et al. Plasma antioxidant capacity is reduced in Asperger syndrome. J Psychiatr Res. 2012;46(3):394–401.

    PubMed  Google Scholar 

  17. 17.

    Hwang O. Role of oxidative stress in Parkinson's disease. Exp Neurobiol. 2013;22(1):11–7.

    PubMed  PubMed Central  Google Scholar 

  18. 18.

    Ramond A, Godin-Ribuot D, Ribuot C, Totoson P, Koritchneva I, Cachot S, et al. Oxidative stress mediates cardiac infarction aggravation induced by intermittent hypoxia. Fundam Clin Pharmacol. 2013;27(3):252–61.

    CAS  PubMed  Google Scholar 

  19. 19.

    Jimenez-Fernandez S, Gurpegui M, Diaz-Atienza F, Perez-Costillas L, Gerstenberg M, Correll CU. Oxidative stress and antioxidant parameters in patients with major depressive disorder compared to healthy controls before and after antidepressant treatment: results from a meta-analysis. J Clin Psychiatry. 2015;76(12):1658–67.

    PubMed  Google Scholar 

  20. 20.

    Joseph N, Zhang-James Y, Perl A, Faraone SV. Oxidative stress and ADHD: a meta-analysis. J Atten Disord. 2015;19(11):915–24.

    PubMed  Google Scholar 

  21. 21.

    Segal AW. How neutrophils kill microbes. Annu Rev Immunol. 2005;23:197–223.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Gems D, Partridge L. Stress-response hormesis and aging: "that which does not kill us makes us stronger". Cell Metab. 2008;7(3):200–3.

    CAS  PubMed  Google Scholar 

  23. 23.

    Yun J, Finkel T. Mitohormesis. Cell Metab. 2014;19(5):757–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Arlt A, Sebens S, Krebs S, Geismann C, Grossmann M, Kruse ML, et al. 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. 2013;32(40):4825–35.

    CAS  PubMed  Google Scholar 

  25. 25.

    Gao AM, Ke ZP, Shi F, Sun GC, Chen H. Chrysin enhances sensitivity of BEL-7402/ADM cells to doxorubicin by suppressing PI3K/Akt/Nrf2 and ERK/Nrf2 pathway. Chem Biol Interact. 2013;206(1):100–8.

    CAS  PubMed  Google Scholar 

  26. 26.

    Gao AM, Ke ZP, Wang JN, Yang JY, Chen SY, Chen H. Apigenin sensitizes doxorubicin-resistant hepatocellular carcinoma BEL-7402/ADM cells to doxorubicin via inhibiting PI3K/Akt/Nrf2 pathway. Carcinogenesis. 2013;34(8):1806–14.

    CAS  PubMed  Google Scholar 

  27. 27.

    Tang X, Wang H, Fan L, Wu X, Xin A, Ren H, et al. 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. 2011;50(11):1599–609.

    CAS  PubMed  Google Scholar 

  28. 28.

    Tarumoto T, Nagai T, Ohmine K, Miyoshi T, Nakamura M, Kondo T, et al. Ascorbic acid restores sensitivity to imatinib via suppression of Nrf2-dependent gene expression in the imatinib-resistant cell line. Exp Hematol. 2004;32(4):375–81.

    CAS  PubMed  Google Scholar 

  29. 29.

    Ren D, Villeneuve NF, Jiang T, Wu T, Lau A, Toppin HA, et al. Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci U S A. 2011;108(4):1433–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Wang XJ, Sun Z, Villeneuve NF, Zhang S, Zhao F, Li Y, et al. Nrf2 enhances resistance of cancer cells to chemotherapeutic drugs, the dark side of Nrf2. Carcinogenesis. 2008;29(6):1235–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Shim GS, Manandhar S, Shin DH, Kim TH, Kwak MK. Acquisition of doxorubicin resistance in ovarian carcinoma cells accompanies activation of the NRF2 pathway. Free Radic Biol Med. 2009;47(11):1619–31.

    CAS  PubMed  Google Scholar 

  32. 32.

    Manandhar S, Lee S, Kwak MK. Effect of stable inhibition of NRF2 on doxorubicin sensitivity in human ovarian carcinoma OV90 cells. Arch Pharm Res. 2010;33(5):717–26.

    CAS  PubMed  Google Scholar 

  33. 33.

    Hong YB, Kang HJ, Kwon SY, Kim HJ, Kwon KY, Cho CH, et al. Nuclear factor (erythroid-derived 2)-like 2 regulates drug resistance in pancreatic cancer cells. Pancreas. 2010;39(4):463–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Ji L, Li H, Gao P, Shang G, Zhang DD, Zhang N, et al. Nrf2 pathway regulates multidrug-resistance-associated protein 1 in small cell lung cancer. PLoS One. 2013;8(5):e63404.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Karathedath S, Rajamani BM, Musheer Aalam SM, Abraham A, Varatharajan S, Krishnamurthy P, et al. Role of NF-E2 related factor 2 (Nrf2) on chemotherapy resistance in acute myeloid leukemia (AML) and the effect of pharmacological inhibition of Nrf2. PLoS One. 2017;12(5):e0177227.

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Gu S, Lai Y, Chen H, Liu Y, Zhang Z. miR-155 mediates arsenic trioxide resistance by activating Nrf2 and suppressing apoptosis in lung cancer cells. Sci Rep. 2017;7(1):12155.

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Bialk P, Wang Y, Banas K, Kmiec EB. Functional gene knockout of NRF2 increases Chemosensitivity of human lung Cancer A549 cells in vitro and in a Xenograft mouse model. Mol Ther Oncolytics. 2018;11:75–89.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Banas K, Rivera-Torres N, Bialk P, Yoo B-C, Kmiec EB. Temporal analyses of CRISPR-directed gene editing on NRF2, a clinically relevant human gene involved in chemoresistance. bioRxiv. 2019:799676.

  39. 39.

    Li R, Jia Z, Zhu H. Regulation of Nrf2 signaling. React Oxyg Species (Apex). 2019;8(24):312–22.

    CAS  Google Scholar 

  40. 40.

    Al-Sawaf O, Clarner T, Fragoulis A, Kan YW, Pufe T, Streetz K, et al. Nrf2 in health and disease: current and future clinical implications. Clin Sci (Lond). 2015;129(12):989–99.

    CAS  Google Scholar 

  41. 41.

    Ramsey CP, Glass CA, Montgomery MB, Lindl KA, Ritson GP, Chia LA, et al. Expression of Nrf2 in neurodegenerative diseases. J Neuropathol Exp Neurol. 2007;66(1):75–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Barone MC, Sykiotis GP, Bohmann D. Genetic activation of Nrf2 signaling is sufficient to ameliorate neurodegenerative phenotypes in a Drosophila model of Parkinson's disease. Dis Model Mech. 2011;4(5):701–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Skibinski G, Hwang V, Ando DM, Daub A, Lee AK, Ravisankar A, et al. Nrf2 mitigates LRRK2- and alpha-synuclein-induced neurodegeneration by modulating proteostasis. Proc Natl Acad Sci U S A. 2017;114(5):1165–70.

    CAS  PubMed  Google Scholar 

  44. 44.

    Moreira S, Fonseca I, Nunes MJ, Rosa A, Lemos L, Rodrigues E, et al. Nrf2 activation by tauroursodeoxycholic acid in experimental models of Parkinson's disease. Exp Neurol. 2017;295:77–87.

    CAS  PubMed  Google Scholar 

  45. 45.

    Tian Y, Wang W, Xu L, Li H, Wei Y, Wu Q, et al. Activation of Nrf2/ARE pathway alleviates the cognitive deficits in PS1V97L-Tg mouse model of Alzheimer's disease through modulation of oxidative stress. J Neurosci Res. 2019;97(4):492–505.

    CAS  PubMed  Google Scholar 

  46. 46.

    Stenvinkel P. Chronic kidney disease: a public health priority and harbinger of premature cardiovascular disease. J Intern Med. 2010;268(5):456–67.

    CAS  PubMed  Google Scholar 

  47. 47.

    Mann JF, Schmieder RE, McQueen M, Dyal L, Schumacher H, Pogue J, et al. Investigators O. renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372(9638):547–53.

    CAS  PubMed  Google Scholar 

  48. 48.

    Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF. Aldosterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2009;4(3):542–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    de Haan JB. Nrf2 activators as attractive therapeutics for diabetic nephropathy. Diabetes. 2011;60(11):2683–4.

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Xue M, Qian Q, Adaikalakoteswari A, Rabbani N, Babaei-Jadidi R, Thornalley PJ. Activation of NF-E2-related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease. Diabetes. 2008;57(10):2809–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Zheng H, Whitman SA, Wu W, Wondrak GT, Wong PK, Fang D, et al. Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. Diabetes. 2011;60(11):3055–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med. 2011;365(4):327–36.

    CAS  PubMed  Google Scholar 

  53. 53.

    Piao CS, Gao S, Lee GH, Kim DS, Park BH, Chae SW, et al. Sulforaphane protects ischemic injury of hearts through antioxidant pathway and mitochondrial K(ATP) channels. Pharmacol Res. 2010;61(4):342–8.

    CAS  PubMed  Google Scholar 

  54. 54.

    Gorbunov N, Petrovski G, Gurusamy N, Ray D, Kim DH, Das DK. Regeneration of infarcted myocardium with resveratrol-modified cardiac stem cells. J Cell Mol Med. 2012;16(1):174–84.

    CAS  PubMed  Google Scholar 

  55. 55.

    Gurusamy N, Ray D, Lekli I, Das DK. Red wine antioxidant resveratrol-modified cardiac stem cells regenerate infarcted myocardium. J Cell Mol Med. 2010;14(9):2235–9.

    PubMed  PubMed Central  Google Scholar 

  56. 56.

    Sahni SK, Rydkina E, Sahni A. The proteasome inhibitor MG132 induces nuclear translocation of erythroid transcription factor Nrf2 and cyclooxygenase-2 expression in human vascular endothelial cells. Thromb Res. 2008;122(6):820–5.

    CAS  PubMed  Google Scholar 

  57. 57.

    Dreger H, Westphal K, Weller A, Baumann G, Stangl V, Meiners S, et al. Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for proteasome inhibitor-mediated cardioprotection. Cardiovasc Res. 2009;83(2):354–61.

    CAS  PubMed  Google Scholar 

  58. 58.

    Yu X, Cui L, Zhang Z, Zhao Q, Li S. alpha-Linolenic acid attenuates doxorubicin-induced cardiotoxicity in rats through suppression of oxidative stress and apoptosis. Acta Biochim Biophys Sin (Shanghai). 2013;45(10):817–26.

    CAS  Google Scholar 

  59. 59.

    Calvert JW, Jha S, Gundewar S, Elrod JW, Ramachandran A, Pattillo CB, et al. Hydrogen sulfide mediates cardioprotection through Nrf2 signaling. Circ Res. 2009;105(4):365–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Zhang Y, Sano M, Shinmura K, Tamaki K, Katsumata Y, Matsuhashi T, et al. 4-hydroxy-2-nonenal protects against cardiac ischemia-reperfusion injury via the Nrf2-dependent pathway. J Mol Cell Cardiol. 2010;49(4):576–86.

    CAS  PubMed  Google Scholar 

  61. 61.

    Li XH, Li CY, Xiang ZG, Hu JJ, Lu JM, Tian RB, et al. Allicin ameliorates cardiac hypertrophy and fibrosis through enhancing of Nrf2 antioxidant signaling pathways. Cardiovasc Drugs Ther. 2012;26(6):457–65.

    CAS  PubMed  Google Scholar 

  62. 62.

    Deng C, Sun Z, Tong G, Yi W, Ma L, Zhao B, et al. alpha-Lipoic acid reduces infarct size and preserves cardiac function in rat myocardial ischemia/reperfusion injury through activation of PI3K/Akt/Nrf2 pathway. PLoS One. 2013;8(3):e58371.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Kavian N, Mehlal S, Jeljeli M, Saidu NEB, Nicco C, Cerles O, et al. The Nrf2-antioxidant response element signaling pathway controls fibrosis and autoimmunity in scleroderma. Front Immunol. 2018;9:1896.

    PubMed  PubMed Central  Google Scholar 

  64. 64.

    Banerjee N, Wang H, Wang G, Khan MF. Enhancing the Nrf2 antioxidant signaling provides protection against Trichloroethene-mediated inflammation and autoimmune response. Toxicol Sci. 2020;175(1):64–74.

    CAS  PubMed  Google Scholar 

  65. 65.

    Schimrigk S, Brune N, Hellwig K, Lukas C, Bellenberg B, Rieks M, et al. Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study. Eur J Neurol. 2006;13(6):604–10.

    CAS  PubMed  Google Scholar 

  66. 66.

    Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, et al. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012;367(12):1098–107.

    CAS  PubMed  Google Scholar 

  67. 67.

    Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, et al. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012;367(12):1087–97.

    CAS  PubMed  Google Scholar 

  68. 68.

    Hoxtermann S, Nuchel C, Altmeyer P. Fumaric acid esters suppress peripheral CD4- and CD8-positive lymphocytes in psoriasis. Dermatology. 1998;196(2):223–30.

    CAS  PubMed  Google Scholar 

  69. 69.

    Sun H, Zhu J, Lin H, Gu K, Feng F. Recent progress in the development of small molecule Nrf2 modulators: a patent review (2012-2016). Expert Opin Ther Pat. 2017;27(7):763–85.

    CAS  PubMed  Google Scholar 

  70. 70.

    Zhang DD. Bardoxolone brings Nrf2-based therapies to light. Antioxid Redox Signal. 2013;19(5):517–8.

    PubMed  PubMed Central  Google Scholar 

  71. 71.

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

    CAS  PubMed  Google Scholar 

  72. 72.

    Kensler TW, Qian GS, Chen JG, Groopman JD. Translational strategies for cancer prevention in liver. Nat Rev Cancer. 2003;3(5):321–9.

    CAS  PubMed  Google Scholar 

  73. 73.

    Okada K, Shoda J, Taguchi K, Maher JM, Ishizaki K, Inoue Y, et al. Ursodeoxycholic acid stimulates Nrf2-mediated hepatocellular transport, detoxification, and antioxidative stress systems in mice. Am J Physiol Gastrointest Liver Physiol. 2008;295(4):G735–47.

    CAS  PubMed  Google Scholar 

  74. 74.

    Kawata K, Kobayashi Y, Souda K, Kawamura K, Sumiyoshi S, Takahashi Y, et al. Enhanced hepatic Nrf2 activation after ursodeoxycholic acid treatment in patients with primary biliary cirrhosis. Antioxid Redox Signal. 2010;13(3):259–68.

    CAS  PubMed  Google Scholar 

  75. 75.

    Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer's disease. J Neurochem. 2008;104(6):1433–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Silva T, Reis J, Teixeira J, Borges F. Alzheimer's disease, enzyme targets and drug discovery struggles: from natural products to drug prototypes. Ageing Res Rev. 2014;15:116–45.

    CAS  PubMed  Google Scholar 

  77. 77.

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

    CAS  PubMed  Google Scholar 

  78. 78.

    Lal H, Ahmad F, Woodgett J, Force T. The GSK-3 family as therapeutic target for myocardial diseases. Circ Res. 2015;116(1):138–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Saraswati AP, Ali Hussaini SM, Krishna NH, Babu BN, Kamal A. Glycogen synthase kinase-3 and its inhibitors: potential target for various therapeutic conditions. Eur J Med Chem. 2018;144:843–58.

    CAS  PubMed  Google Scholar 

  80. 80.

    Lovestone S, Boada M, Dubois B, Hull M, Rinne JO, Huppertz HJ, et al. Investigators a. a phase II trial of tideglusib in Alzheimer's disease. J Alzheimers Dis. 2015;45(1):75–88.

    CAS  PubMed  Google Scholar 

  81. 81.

    Bourhill T, Narendran A, Johnston RN. Enzastaurin: a lesson in drug development. Crit Rev Oncol Hematol. 2017;112:72–9.

    CAS  PubMed  Google Scholar 

  82. 82.

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

    PubMed  Google Scholar 

  83. 83.

    Rojo AI, Medina-Campos ON, Rada P, Zuniga-Toala A, Lopez-Gazcon A, Espada S, et al. 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. 2012;52(2):473–87.

    CAS  PubMed  Google Scholar 

  84. 84.

    Palomo V, Martinez A. Glycogen synthase kinase 3 (GSK-3) inhibitors: a patent update (2014-2015). Expert Opin Ther Pat. 2017;27(6):657–66.

    CAS  PubMed  Google Scholar 

  85. 85.

    Di Marco A, Cassinelli G, Arcamone F. The discovery of daunorubicin. Cancer Treat Rep. 1981;65(Suppl 4):3–8.

    PubMed  Google Scholar 

  86. 86.

    Tan C, Tasaka H, Yu KP, Murphy ML, Karnofsky DA. Daunomycin, an antitumor antibiotic, in the treatment of neoplastic disease. Clinical evaluation with special reference to childhood leukemia. Cancer. 1967;20(3):333–53.

    CAS  PubMed  Google Scholar 

  87. 87.

    Arcamone F, Cassinelli G, Fantini G, Grein A, Orezzi P, Pol C, et al. Adriamycin, 14-hydroxydaunomycin, a new antitumor antibiotic from S. peucetius var. caesius. Biotechnol Bioeng. 1969;11(6):1101–10.

    CAS  PubMed  Google Scholar 

  88. 88.

    Di Marco A, Gaetani M, Scarpinato B. Adriamycin (NSC-123,127): a new antibiotic with antitumor activity. Cancer Chemother Rep. 1969;53(1):33–7.

    PubMed  Google Scholar 

  89. 89.

    Volkova M, Russell R 3rd. Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Curr Cardiol Rev. 2011;7(4):214–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    World Health Organization. WHO Model List of Essential Medicines. Geneva: World Health Organization; 2017.

    Google Scholar 

  91. 91.

    Ripamonti M, Pezzoni G, Pesenti E, Pastori A, Farao M, Bargiotti A, et al. In vivo anti-tumour activity of FCE 23762, a methoxymorpholinyl derivative of doxorubicin active on doxorubicin-resistant tumour cells. Br J Cancer. 1992;65(5):703–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Volpetti S, Zaja F, Fanin R. Pixantrone for the treatment of adult patients with relapsed or refractory aggressive non-Hodgkin B-cell lymphomas. Onco Targets Ther. 2014;7:865–72.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Bigioni M, Benzo A, Irrissuto C, Lopez G, Curatella B, Maggi CA, et al. Antitumour effect of combination treatment with Sabarubicin (MEN 10755) and cis-platin (DDP) in human lung tumour xenograft. Cancer Chemother Pharmacol. 2008;62(4):621–9.

    CAS  PubMed  Google Scholar 

  94. 94.

    Cookson MS, Chang SS, Lihou C, Li T, Harper SQ, Lang Z, et al. Use of intravesical valrubicin in clinical practice for treatment of nonmuscle-invasive bladder cancer, including carcinoma in situ of the bladder. Ther Adv Urol. 2014;6(5):181–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Sinha BK, Trush MA, Kennedy KA, Mimnaugh EG. Enzymatic activation and binding of adriamycin to nuclear DNA. Cancer Res. 1984;44(7):2892–6.

    CAS  PubMed  Google Scholar 

  96. 96.

    Binaschi M, Bigioni M, Cipollone A, Rossi C, Goso C, Maggi CA, et al. Anthracyclines: selected new developments. Curr Med Chem Anticancer Agents. 2001;1(2):113–30.

    CAS  PubMed  Google Scholar 

  97. 97.

    Ruiz-Ruiz C, Robledo G, Cano E, Redondo JM, Lopez-Rivas A. Characterization of p53-mediated up-regulation of CD95 gene expression upon genotoxic treatment in human breast tumor cells. J Biol Chem. 2003;278(34):31667–75.

    CAS  PubMed  Google Scholar 

  98. 98.

    Muindi JR, Sinha BK, Gianni L, Myers CE. Hydroxyl radical production and DNA damage induced by anthracycline-iron complex. FEBS Lett. 1984;172(2):226–30.

    CAS  PubMed  Google Scholar 

  99. 99.

    Myers CE, McGuire WP, Liss RH, Ifrim I, Grotzinger K, Young RC. Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response. Science. 1977;197(4299):165–7.

    CAS  PubMed  Google Scholar 

  100. 100.

    Gewirtz DA. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochem Pharmacol. 1999;57(7):727–41.

    CAS  PubMed  Google Scholar 

  101. 101.

    Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004;56(2):185–229.

    CAS  PubMed  Google Scholar 

  102. 102.

    Wu X, Hasinoff BB. The antitumor anthracyclines doxorubicin and daunorubicin do not inhibit cell growth through the formation of iron-mediated reactive oxygen species. Anti-Cancer Drugs. 2005;16(1):93–9.

    CAS  PubMed  Google Scholar 

  103. 103.

    Zhang S, Liu X, Bawa-Khalfe T, Lu LS, Lyu YL, Liu LF, et al. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med. 2012;18(11):1639–42.

    PubMed  Google Scholar 

  104. 104.

    Cardinale D, Bacchiani G, Beggiato M, Colombo A, Cipolla CM. Strategies to prevent and treat cardiovascular risk in cancer patients. Semin Oncol. 2013;40(2):186–98.

    CAS  PubMed  Google Scholar 

  105. 105.

    Kremer LC, van Dalen EC, Offringa M, Ottenkamp J, Voute PA. Anthracycline-induced clinical heart failure in a cohort of 607 children: long-term follow-up study. J Clin Oncol. 2001;19(1):191–6.

    CAS  PubMed  Google Scholar 

  106. 106.

    Forssen EA, Tokes ZA. In vitro and in vivo studies with adriamycin liposomes. Biochem Biophys Res Commun. 1979;91(4):1295–301.

    CAS  PubMed  Google Scholar 

  107. 107.

    Lefrak EA, Pitha J, Rosenheim S, Gottlieb JA. A clinicopathologic analysis of adriamycin cardiotoxicity. Cancer. 1973;32(2):302–14.

    CAS  PubMed  Google Scholar 

  108. 108.

    Von Hoff DD, Layard MW, Basa P, Davis HL Jr, Von Hoff AL, Rozencweig M, et al. Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med. 1979;91(5):710–7.

    Google Scholar 

  109. 109.

    Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97(11):2869–79.

    CAS  PubMed  Google Scholar 

  110. 110.

    Billingham ME, Mason JW, Bristow MR, Daniels JR. Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treat Rep. 1978;62(6):865–72.

    CAS  PubMed  Google Scholar 

  111. 111.

    Bristow MR, Mason JW, Billingham ME, Daniels JR. Doxorubicin cardiomyopathy: evaluation by phonocardiography, endomyocardial biopsy, and cardiac catheterization. Ann Intern Med. 1978;88(2):168–75.

    CAS  PubMed  Google Scholar 

  112. 112.

    Li S, Wang W, Niu T, Wang H, Li B, Shao L, et al. Nrf2 deficiency exaggerates doxorubicin-induced cardiotoxicity and cardiac dysfunction. Oxidative Med Cell Longev. 2014;2014:748524.

    Google Scholar 

  113. 113.

    Balogun E, Hoque M, Gong P, Killeen E, Green CJ, Foresti R, et al. Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J. 2003;371(Pt 3):887–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114.

    Venkatesan N. Curcumin attenuation of acute adriamycin myocardial toxicity in rats. Br J Pharmacol. 1998;124(3):425–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. 115.

    Li B, Kim DS, Yadav RK, Kim HR, Chae HJ. Sulforaphane prevents doxorubicin-induced oxidative stress and cell death in rat H9c2 cells. Int J Mol Med. 2015;36(1):53–64.

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Singh P, Sharma R, McElhanon K, Allen CD, Megyesi JK, Benes H, et al. Sulforaphane protects the heart from doxorubicin-induced toxicity. Free Radic Biol Med. 2015;86:90–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117.

    Wang LF, Su SW, Wang L, Zhang GQ, Zhang R, Niu YJ, et al. Tert-butylhydroquinone ameliorates doxorubicin-induced cardiotoxicity by activating Nrf2 and inducing the expression of its target genes. Am J Transl Res. 2015;7(10):1724–35.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. 118.

    Hajra S, Basu A, Singha Roy S, Patra AR, Bhattacharya S. Attenuation of doxorubicin-induced cardiotoxicity and genotoxicity by an indole-based natural compound 3,3′-diindolylmethane (DIM) through activation of Nrf2/ARE signaling pathways and inhibiting apoptosis. Free Radic Res. 2017;51(9–10):812–27.

    CAS  PubMed  Google Scholar 

  119. 119.

    Zagorski JW, Maser TP, Liby KT, Rockwell CE. Nrf2-dependent and -independent effects of tert-Butylhydroquinone, CDDO-Im, and H2O2 in human Jurkat T cells as determined by CRISPR/Cas9 gene editing. J Pharmacol Exp Ther. 2017;361(2):259–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Zheng A, Chevalier N, Calderoni M, Dubuis G, Dormond O, Ziros PG, et al. CRISPR/Cas9 genome-wide screening identifies KEAP1 as a sorafenib, lenvatinib, and regorafenib sensitivity gene in hepatocellular carcinoma. Oncotarget. 2019;10(66):7058–70.

    PubMed  PubMed Central  Google Scholar 

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The study was partly supported by the Food and Drug Administration (FDA) Maryland’s Center of Excellence in Regulatory Science and Innovation (M-CERSI) initiative (1U01FD005946). The authors disclose that there is no potential conflict of interest. The contents do not represent the views of the FDA.

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Hedrich, W.D., Wang, H. Friend or Foe: Xenobiotic Activation of Nrf2 in Disease Control and Cardioprotection. Pharm Res 38, 213–241 (2021).

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  • cardiotoxicity
  • doxorubicin
  • Nrf2