Dimethyl fumarate and monoethyl fumarate exhibit differential effects on KEAP1, NRF2 activation, and glutathione depletion in vitro

PLoS ONE

Volumn 10, Issue 3, 2015, Pages

  Brennan, Melanie S ^a   Matos, Maria F ^a   Li, Bing ^a   Hronowski, Xiaoping ^a   Gao, Benbo ^a   Juhasz, Peter ^a   Rhodes, Kenneth J ^a   Scannevin, Robert H ^a  

^a BIOGEN   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYSTEINE; FUMARIC ACID DIMETHYL ESTER; FUMARIC ACID ETHYL ESTER; GLUTATHIONE; KELCH LIKE ECH ASSOCIATED PROTEIN 1; TRANSCRIPTION FACTOR NRF2; ETHYL FUMARATE; FUMARIC ACID DERIVATIVE; KEAP1 PROTEIN, HUMAN; SIGNAL PEPTIDE;

ARTICLE; ASTROCYTE; CELL NUCLEUS; CONCENTRATION RESPONSE; CONJUGATION; CONTROLLED STUDY; CYTOPLASM; DRUG EFFECT; EMBRYO; GENE EXPRESSION; GENETIC TRANSCRIPTION; HUMAN; HUMAN CELL; IN VITRO STUDY; PROTEIN MODIFICATION; PROTEIN TRANSPORT; CHEMISTRY; DRUG EFFECTS; EXTRACELLULAR SPACE; GENE EXPRESSION REGULATION; GENETICS; HEK293 CELL LINE; METABOLISM;

ASTROCYTES; CELL NUCLEUS; CYSTEINE; DIMETHYL FUMARATE; EXTRACELLULAR SPACE; FUMARATES; GENE EXPRESSION REGULATION; GLUTATHIONE; HEK293 CELLS; HUMANS; INTRACELLULAR SIGNALING PEPTIDES AND PROTEINS; KELCH-LIKE ECH-ASSOCIATED PROTEIN 1; NF-E2-RELATED FACTOR 2; PROTEIN TRANSPORT;

EID: 84925745399     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0120254     Document Type: Article

References (44)

1. Noseworthy JH, Lucchinetti C, Rodriguez M, Weinshenker BG. Multiple sclerosis. N Engl J Med. 2000; 343: 938-952. PMID: 11006371
2. Fox RJ, Bethoux F, Goldman MD, Cohen JA. Multiple sclerosis: advances in understanding, diagnosing, and treating the underlying disease. Cleve Clin J Med. 2006; 73: 91-102. PMID: 16444920
3. Freedman MS. Disease-modifying drugs for multiple sclerosis: current and future aspects. Expert Opin Pharmacother. 2006;Suppl 1: : S1-9. PMID: 17020427
4. Gilgun-Sherki Y, Melamed E, Offen D. The role of oxidative stress in the pathogenesis of multiple sclerosis: the need for effective antioxidant therapy. J Neurol. 2004; 25: 261-268.
5. van Horssen J, Witte ME, Schreibelt G, de Vries HE. Radical changes in multiple sclerosis pathogenesis. Biochim Biophys Acta. 2011; 1812: 141-150. doi: 10.1016/j.bbadis.2010.06.011 PMID: 20600869
6. Witherick J, Wilkins A, Scolding N, Kemp K. Mechanisms of oxidative damage in multiple sclerosis and a cell therapy approach to treatment. Autoimmune Dis. 2010; 2011: 164608. doi: 10.4061/2011/164608 PMID: 21197107
7. Linker RA, Lee DH, Ryan S, van Dam AM, Conrad R, Bista P, et al. Fumaric acid esters exert neuroprotective effects in neuroinflammation via activation of the Nrf2 antioxidant pathway. Brain. 2011; 134: 678-692. doi: 10.1093/brain/awq386 PMID: 21354971
8. Scannevin RH, Chollate S, Jung MY, Shackett M, Patel H, Bista P, et al. Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway. J Pharmacol Exp Ther. 2012; 341: 274-284. doi: 10.1124/jpet.111.190132 PMID: 22267202
9. Itoh K, Wakabayashi N, Katoh Y, Ishii T, O'Connor T, Yamamoto M. Keap1 regulates both cytoplasmicnuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes Cells. 2003; 8: 379-391. PMID: 12653965
10. Kobayashi M, 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 proteosomal degradation of Nrf2. Mol and Cell Biol. 2004; 24: 7130-7139. PMID: 15282312
11. Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, et al. Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proc Natl Acad Sci USA. 2002; 99: 11908-11913. PMID: 12193649
12. Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K. An Nrf2/small Maf heterodimer mediated the induction of the phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun. 1997; 236: 313-322. PMID: 9240432
13. Nguyen T, Sherratt PJ, Pickett CB. Regulatory mechanisms controlling gene expression mediated by the antioxidant response element. Annu Rev Pharmacol Toxicol. 2003; 43: 233-260. PMID: 12359864
14. Matusheski NV, Juvik JA, Jeffrey EH. Heating decreases epithiospecifier protein activity and increases sulforaphane formation in broccoli. Phytochemistry. 2004; 65: 1273-1281. PMID: 15184012
15. Angeloni C, Leoncini E, Malaguti M, Angelini S, Hrelia P, Hrelia S. Modulation of phase II enzymes by sulforaphane: implications for its cardioprotective potential. J Agric Food Chem. 2009; 57: 5615-5622. doi: 10.1021/jf900549c PMID: 19456137
16. Balogun E, Hoque M, Gong P, Killeen E, Green CJ, Foresti R, et al. Curcumin activates the heme oxy-genase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochem J. 2003; 371: 887-895. PMID: 12570874
17. Garg R, Gupta S, Maru GB. Dietary curcumin modulated transcriptional regulators of phase I and II enzymes in benzoyl[a]pyrene-treated mice: mechanism of its anti-initiating action. Carcinogenesis. 2008; 29: 1022-1032. doi: 10.1093/carcin/bgn064 PMID: 18321868
18. Chen ZH, Saito Y, Yoshida Y, Sekine A, Noguchi N, Niki E. 4-Hydroxynonenal Induces Adaptive Response and Enhances PC12 Cell Tolerance Primarily through Induction of Thioredoxin Reductase 1 via Activation of Nrf2. J Biol Chem. 2005; 280: 41921-41927. PMID: 16219762
19. Chen H, Assmann JC, Krenz A, Rahman M, Grimm M, Karsten CM, et al. Hydroxycarboxylic acid receptor 2 mediates dimethyl fumarate's protective effect in EAE. J Clin Invest. 2014 pii: 72151.
20. Schmidt TJ, Ak M, Mrowietz U. Reactivity of dimethyl fumarate and methylhydrogen fumarate towards glutathione and N-acetyl-L-cysteine-preparation of S-substituted thiosuccinic acid esters. Bioorg Med Chem. 2007; 15: 333-342. PMID: 17049250
21. Loewe R, Holnthoner W, Groger M, Pillinger M, Gruber F, Mechtcheriakova D, et al. Dimethylfumarate inhibits TBF-induced nuclear entry of NF-kappa B/p65 in human endothelial cells. J Immunol; 2002; 168: 4781-4787. PMID: 11971029
22. Wiesner D, Merdian I, Lewerenz J, Ludolph AC, Dupuis L, Wiiting A. Fumaric acid esters stimulare astrocytic VEGF expression through HIF-1α and Nrf2. PLoS One. 2013; 8: e76670. doi: 10.1371/journal. pone.0076670 PMID: 24098549
23. Lehmann JC, Listopad JJ, Rentzsch CU, Igney FH, von Bonin A, Hennekes HH, et al. Dimethylfumarate induces immunosuppression via glutathione depletion and subsequent induction of heme oxygenase1. J Invest Dermatol. 2007; 127: 835-845. PMID: 17235328
24. Ghoreschi K, Brück J, Kellerer C, Deng C, Peng H, Rothfuss O, et al. Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells. J Exp Med. 2011; 208: 2291-2303. doi: 10.1084/ jem.20100977 PMID: 21987655
25. Nelson KC, Carlson JL, Newman ML, Sternberg P Jr, Jones DP, Kavanagh TJ, et al. Effect of dietary inducer dimethylfumarate on glutathione in cultured human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 1999; 40: 1927-1935. PMID: 10440245
26. Schmidt MM, Dringen R. Fumaric acid diesters deprive cultured primary astrocytes rapidly of glutathione. Neurochem Int. 2010; 57: 460-467. doi: 10.1016/j.neuint.2010.01.006 PMID: 20096739
27. Lin SX, Lisi L, Dello Russo C, Polak PE, Sharp A, Weinberg G, et al. The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1. ANS Neuro. 2011; 3: pii e00055. doi: 10.1128/mBio.00055-11 PMID: 21586647
28. Morris G, Anderson G, Dean O, Berk M, Galecki P, Martin-Subero M, et al. The glutathione system: a new drug target in neuroimmune disorders. Mol Neurobiol. 2014;Apr 22. [Epub ahead of print].
29. Fumaderm Summary of Product Characteristics, February 2009, Biogen Idec.
30. Itoh K, Wakabayashi N, Katoh Y, Ishii T, O'Connor T, Yamamoto M. Keap1 regulates both cytoplasmicnuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes Cells. 2003; 8: 379-391. PMID: 12653965
31. 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: 2758-2770. doi: 10.1128/MCB.01704-07 PMID: 18268004
32. Holland R, Fishbein JC. Chemistry of the cysteine sensors in Kelch-like ECH-associated protein 1. Antioxid Redox Sign. 2010; 13: 1749-1761. doi: 10.1089/ars.2010.3273 PMID: 20486763
33. Taguchi K, Motohashi H, Yamamoto M. Molecular mechanisms of Keap1-Nrf2 pathway in stress response and cancer evolution. Genes Cells. 2011; 16: 123-140. doi: 10.1111/j.1365-2443.2010.01473. x PMID: 21251164
34. Thimmulappa RK, Mai KH, Srisuma S, Kensler TW, Yamamoto M, Biswal S. Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res. 2002; 62: 5196-5203. PMID: 12234984
35. Schmidt TJ, Ak M, Mrowietz U. Reactivity of dimethyl fumarate and methylhydrogen fumarate towards glutathione and N-acetyl-L-cysteine-preparation of S-substituted thiosuccinic acid esters. Bioorg Med Chem. 2007; 15: 333-342. PMID: 17049250
36. Nguyen T, Sherratt PJ, Nioi P, Yang CS, Pickett CB. Nrf2 controls constitutive and inducible expression of ARE-driven genes through a dynamic pathway involving nucleocytoplasmic shuttling by Keap1. J Biol Chem. 2005; 280: 32485-32492. PMID: 16000310
37. Zhang DD, Hannink M. Distinct cysteine residues in Keap1 are required for Keap1-dependet ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventative agents and oxidative stress. Mol Cell Biol. 2003; 23: 8137-8151. PMID: 14585973
38. Eggler AL, Liu G, Pezzuto JM, van Breeman RB, Mesecar AD. Modifying specific cysteines of the elec-trophile-sensing human Keap1 protein is insufficient to disrupt binding to the Nrf2 domain of Neh2. Proc Nat Acad Sci USA. 2005; 102: 10070-10075. PMID: 16006525
39. Hong F, Freeman ML, Liebler DC. Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventative agent sulforaphane. Chem Res Toxicol. 2005; 18: 1917-1926. PMID: 16359182
40. Holland R, Fishbein JC. Chemistry of the cysteine sensors in Kelch-like ECH-associated protein 1. Antioxid Redox Signaling. 2010; 13:1749-1761. doi: 10.1089/ars.2010.3273 PMID: 20486763
41. Aschner M. Neuron-astrocyte interactions: implications for cellular energetics and antioxidant levels. Neurotoxicology. 2000; 21: 1101-1107. PMID: 11233756
42. Horikawa S, Yoneya R, Nagashima Y, Hagiwara K, Ozasa H. Prior induction of heme oxygenase-1 with glutathione depletory ameliorates the renal ischemia and reperfusion injury in the rat. FEBS Lett. 2002; 510: 221-224. PMID: 11801258
43. Ewing JF, Maines MD. Glutathione depletion induces heme oxygenase-1 (HSP32) mRNA and protein in rat brain. J Neurochem. 1993; 60: 1512-1519. PMID: 8455037
44. Nathens AB, Rotstein OD, Jones JJ, Dackiw AP, Gorczynski R. The glutathione depleting agent diethylmaleate prolongs renal allograft survival. J Surg Res. 1998; 77: 75-79. doi: 10.1006/jsre.1998. 5338 PMID: 9698537