Triterpenoid inducers of Nrf2 signaling as potential therapeutic agents in sickle cell disease: a review

Frontiers of Medicine

Volumn 9, Issue 1, 2015, Pages 46-56

  Owusu Ansah, Amma ^a,b   Choi, Sung Hee ^a   Petrosiute, Agne ^a,b   Letterio, John J ^a,b   Huang, Alex Yee Chen ^a,b  

^a CASE WESTERN RESERVE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^b CASE WESTERN RESERVE UNIVERSITY   (United States)

Author keywords

CDDO Me; Nrf2; oxidative stress; sickle cell disease; triterpenoids; vaso occlusion

Indexed keywords

NFE2L2 PROTEIN, HUMAN; TRANSCRIPTION FACTOR NRF2; TRITERPENE;

ANEMIA, SICKLE CELL; DRUG EFFECTS; EXPERIMENTAL THERAPY; HUMAN; METABOLISM; MOLECULARLY TARGETED THERAPY; OXIDATIVE STRESS; PHYSIOLOGY; PROCEDURES; SIGNAL TRANSDUCTION; TRENDS;

ANEMIA, SICKLE CELL; HUMANS; MOLECULAR TARGETED THERAPY; NF-E2-RELATED FACTOR 2; OXIDATIVE STRESS; SIGNAL TRANSDUCTION; THERAPIES, INVESTIGATIONAL; TRITERPENES;

EID: 84939436744     PISSN: 20950217     EISSN: 20950225     Source Type: Journal    
DOI: 10.1007/s11684-015-0375-1     Document Type: Review

References (68)

1. Wood KC, Granger DN. Sickle cell disease: role of reactive oxygen and nitrogen metabolites. Clin Exp Pharmacol Physiol 2007; 34(9): 926–932
2. Rees DC, Williams TN, Gladwin MT. Sickle-cell disease. Lancet 2010; 376(9757): 2018–2031
3. Steinberg MH. Pathophysiologically based drug treatment of sickle cell disease. Trends Pharmacol Sci 2006; 27(4): 204–210
4. Nur E, Biemond BJ, Otten HM, Brandjes DP, Schnog JJ; CURAMA Study Group. Oxidative stress in sickle cell disease; pathophysiology and potential implications for disease management. Am J Hematol 2011; 86(6): 484–489
5. Platt OS, Brambilla DJ, Rosse WF, Milner PF, Castro O, Steinberg MH, Klug PP. Mortality in sickle cell disease. Life expectancy and risk factors for early death. N Engl J Med 1994; 330(23): 1639–1644
6. Platt OS, Thorington BD, Brambilla DJ, Milner PF, Rosse WF, Vichinsky E, Kinney TR. Pain in sickle cell disease. Rates and risk factors. N Engl J Med 1991; 325(1): 11–16
7. Watson J, Starman AW, Bilello FP. The significance of the paucity of sickle cells in newborn Negro infants. Am J Med Sci 1948; 215(4): 419–423
8. Steinberg MH, Chui DH, Dover GJ, Sebastiani P, Alsultan A. Fetal hemoglobin in sickle cell anemia: a glass half full? Blood 2014; 123(4): 481–485
9. Sankaran VG, Orkin SH. The switch from fetal to adult hemoglobin. Cold Spring Harb Perspect Med 2013; 3(1): a011643
10. Chaves MA, Leonart MS, do Nascimento AJ. Oxidative process in erythrocytes of individuals with hemoglobin S. Hematology 2008; 13(3): 187–192
11. Silva DGH, Belini Junior E, de Almeida EA, Bonini-Domingos CR. Oxidative stress in sickle cell disease: an overview of erythrocyte redox metabolism and current antioxidant therapeutic strategies. Free Radic Biol Med 2013; 65(0): 1101–1109
12. Gizi A, Papassotiriou I, Apostolakou F, Lazaropoulou C, Papastamataki M, Kanavaki I, Kalotychou V, Goussetis E, Kattamis A, Rombos I, Kanavakis E. Assessment of oxidative stress in patients with sickle cell disease: the glutathione system and the oxidantantioxidant status. Blood Cells Mol Dis 2011; 46(3): 220–225
13. Liby K, Hock T, Yore MM, Suh N, Place AE, Risingsong R, Williams CR, Royce DB, Honda T, Honda Y, Gribble GW, Hill-Kapturczak N, Agarwal A, Sporn MB. The synthetic triterpenoids, CDDO and CDDO-imidazolide, are potent inducers of heme oxygenase-1 and Nrf2/ARE signaling. Cancer Res 2005; 65(11): 4789–4798
14. Surh YJ, Kundu JK, Na HK. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med 2008; 74(13): 1526–1539
15. Yates MS, Kensler TW. Chemopreventive promise of targeting the Nrf2 pathway. Drug News Perspect 2007; 20(2): 109–117
16. Lee JM, Li J, Johnson DA, Stein TD, Kraft AD, Calkins MJ, Jakel RJ, Johnson JA. Nrf 2, a multi-organ protector? FASEB J 2005; 19(9): 1061–1066
17. Sangokoya C, Telen MJ, Chi JT. microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease. Blood 2010; 116(20): 4338–4348
18. Itoh K, Wakabayashi N, Katoh Y, Ishii T, O’Connor T, Yamamoto M. Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes Cells 2003; 8(4): 379–391
19. Zhu H, Itoh K, Yamamoto M, Zweier JL, Li Y. Role of Nrf2 signaling in regulation of antioxidants and phase 2 enzymes in cardiac fibroblasts: protection against reactive oxygen and nitrogen species-induced cell injury. FEBS Lett 2005; 579(14): 3029–3036
20. Dröge W. Free radicals in the physiological control of cell function. Physiol Rev 2002; 82(1): 47–95
21. Junqueira VBC, Barros SB, Chan SS, Rodrigues L, Giavarotti L, Abud RL, Deucher GP. Aging and oxidative stress. Mol Aspects Med 2004; 25(1–2): 5–16
22. Akohoue SA, Shankar S, Milne GL, Morrow J, Chen KY, Ajayi WU, Buchowski MS. Energy expenditure, inflammation, and oxidative stress in steady-state adolescents with sickle cell anemia. Pediatr Res 2007; 61(2): 233–238
23. Manfredini V, Lazzaretti LL, Griebeler IH, Santin AP, Brandão VD, Wagner S, Castro SM, Peralba Mdo C, Benfato MS. Blood antioxidant parameters in sickle cell anemia patients in steady state. J Natl Med Assoc 2008; 100(8): 897–902
24. Klings ES, Christman BW, McClung J, Stucchi AF, McMahon L, Brauer M, Farber HW. Increased F2 isoprostanes in the acute chest syndrome of sickle cell disease as a marker of oxidative stress. Am J Respir Crit Care Med 2001; 164(7): 1248–1252
25. Nath KA, Grande JP, Haggard JJ, Croatt AJ, Katusic ZS, Solovey A, Hebbel RP. Oxidative stress and induction of heme oxygenase-1 in the kidney in sickle cell disease. Am J Pathol 2001; 158(3): 893–903
26. Reiter CD, Wang X, Tanus-Santos JE, Hogg N, Cannon RO 3rd, Schechter AN, Gladwin MT. Cell-free hemoglobin limits nitric oxide bioavailability in sickle-cell disease. Nat Med 2002; 8(12): 1383–1389
27. Morris CR. Mechanisms of vasculopathy in sickle cell disease and thalassemia. Hematology Am Soc Hematol Educ Program 2008;2008(1): 177–185
28. Schnog JB, Teerlink T, van der Dijs FP, Duits AJ, Muskiet FA; CURAMA Study Group. Plasma levels of asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, are elevated in sickle cell disease. Ann Hematol 2005; 84(5): 282–286
29. Wood KC, Hebbel RP, Lefer DJ, Granger DN. Critical role of endothelial cell-derived nitric oxide synthase in sickle cell diseaseinduced microvascular dysfunction. Free Radic Biol Med 2006; 40(8): 1443–1453
30. Kiefmann R, Rifkind JM, Nagababu E, Bhattacharya J. Red blood cells induce hypoxic lung inflammation. Blood 2008; 111(10): 5205–5214
31. Brugnara C. Erythrocyte dehydration in pathophysiology and treatment of sickle cell disease. Curr Opin Hematol 1995; 2(2): 132–138
32. Hofstra TC, Kalra VK, Meiselman HJ, Coates TD. Sickle erythrocytes adhere to polymorphonuclear neutrophils and activate the neutrophil respiratory burst. Blood 1996; 87(10): 4440–4447
33. Vichinsky E. Emerging ‘A’ therapies in hemoglobinopathies: agonists, antagonists, antioxidants, and arginine. Hematology Am Soc Hematol Educ Program 2012; 2012(1): 271–275
34. Nur E, Brandjes DP, Teerlink T, Otten HM, Oude Elferink RP, Muskiet F, Evers LM, ten Cate H, Biemond BJ, Duits AJ, Schnog JJ; CURAMA study group. N-acetylcysteine reduces oxidative stress in sickle cell patients. Ann Hematol 2012; 91(7): 1097–1105
35. Zimmerman SA, Schultz WH, Davis JS, Pickens CV, Mortier NA, Howard TA, Ware RE. Sustained long-term hematologic efficacy of hydroxyurea at maximum tolerated dose in children with sickle cell disease. Blood 2004; 103(6): 2039–2045
36. Silva DG, Belini Junior E, Torres LS, Ricci Júnior O, Lobo CC, Bonini-Domingos CR, de Almeida EA. Relationship between oxidative stress, glutathione S-transferase polymorphisms and hydroxyurea treatment in sickle cell anemia. Blood Cells Mol Dis 2011; 47(1): 23–28
37. Torres Lde S, da Silva DG, Belini Junior E, de Almeida EA, Lobo CL, Cançado RD, Ruiz MA, Bonini-Domingos CR. The influence of hydroxyurea on oxidative stress in sickle cell anemia. Rev Bras Hematol Hemoter 2012; 34(6): 421–425
38. Steinberg MH, Barton F, Castro O, Pegelow CH, Ballas SK, Kutlar A, Orringer E, Bellevue R, Olivieri N, Eckman J, Varma M, Ramirez G, Adler B, Smith W, Carlos T, Ataga K, DeCastro L, Bigelow C, Saunthararajah Y, Telfer M, Vichinsky E, Claster S, Shurin S, Bridges K, Waclawiw M, Bonds D, Terrin M. Effect of hydroxyurea on mortality and morbidity in adult sickle cell anemia: risks and benefits up to 9 years of treatment. JAMA 2003; 289(13): 1645–1651
39. Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 1995; 332(20): 1317–1322
40. Pace BS, Zein S. Understanding mechanisms of gamma-globin gene regulation to develop strategies for pharmacological fetal hemoglobin induction. Dev Dyn 2006; 235(7): 1727–1737
41. Fathallah H, Atweh GF. Induction of fetal hemoglobin in the treatment of sickle cell disease. Hematology Am Soc Hematol Educ Program 2006: 58–62
42. DeSimone J, Heller P, Hall L, Zwiers D. 5-Azacytidine stimulates fetal hemoglobin synthesis in anemic baboons. Proc Natl Acad Sci USA 1982; 79(14): 4428–4431
43. Saunthararajah Y, Hillery CA, Lavelle D, Molokie R, Dorn L, Bressler L, Gavazova S, Chen YH, Hoffman R, DeSimone J. Effects of 5-aza-2′-deoxycytidine on fetal hemoglobin levels, red cell adhesion, and hematopoietic differentiation in patients with sickle cell disease. Blood 2003; 102(12): 3865–3870
44. Fard AD, Hosseini SA, Shahjahani M, Salari F, Jaseb K. Evaluation of novel fetal hemoglobin inducer drugs in treatment of betahemoglobinopathy disorders. Int J Hematol Oncol Stem Cell Res 2013; 7(3): 47–54
45. List A, Dewald G, Bennett J, Giagounidis A, Raza A, Feldman E, Powell B, Greenberg P, Thomas D, Stone R, Reeder C, Wride K, Patin J, Schmidt M, Zeldis J, Knight R; Myelodysplastic Syndrome-003 Study Investigators. Lenalidomide in the myelodysplastic syndrome with chromosome 5q deletion. N Engl J Med 2006; 355(14): 1456–1465
46. + cells. J Clin Invest 2008; 118(1): 248–258
47. Rodgers GP, Dover GJ, Noguchi CT, Schechter AN, Nienhuis AW. Hematologic responses of patients with sickle cell disease to treatment with hydroxyurea. N Engl J Med 1990; 322(15): 1037–1045
48. King SB. Nitric oxide production from hydroxyurea. Free Radic Biol Med 2004; 37(6): 737–744
49. Gladwin MT, Shelhamer JH, Ognibene FP, Pease-Fye ME, Nichols JS, Link B, Patel DB, Jankowski MA, Pannell LK, Schechter AN, Rodgers GP. Nitric oxide donor properties of hydroxyurea in patients with sickle cell disease. Br J Haematol 2002; 116(2): 436–444
50. Gladwin MT, Kato GJ, Weiner D, Onyekwere OC, Dampier C, Hsu L, Hagar RW, Howard T, Nuss R, Okam MM, Tremonti CK, Berman B, Villella A, Krishnamurti L, Lanzkron S, Castro O, Gordeuk VR, Coles WA, Peters-Lawrence M, Nichols J, Hall MK, Hildesheim M, Blackwelder WC, Baldassarre J, Casella JF; DeNOVO Investigators. Nitric oxide for inhalation in the acute treatment of sickle cell pain crisis: a randomized controlled trial. JAMA 2011; 305(9): 893–902
51. Morris CR, Kuypers FA, Lavrisha L, Ansari M, Sweeters N, Stewart M, Gildengorin G, Neumayr L, Vichinsky EP. A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes. Haematologica 2013; 98(9): 1375–1382
52. Pace BS, Shartava A, Pack-Mabien A, Mulekar M, Ardia A, Goodman SR. Effects of N-acetylcysteine on dense cell formation in sickle cell disease. Am J Hematol 2003; 73(1): 26–32
53. Field JJ, Nathan DG, Linden J. Targeting iNKT cells for the treatment of sickle cell disease. Clin Immunol 2011; 140(2): 177–183
54. Morris CR, Suh JH, Hagar W, Larkin S, Bland DA, Steinberg MH, Vichinsky EP, Shigenaga M, Ames B, Kuypers FA, Klings ES. Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease. Blood 2008; 111(1): 402–410
55. Liby KT, Sporn MB. Synthetic oleanane triterpenoids: multifunctional drugs with a broad range of applications for prevention and treatment of chronic disease. Pharmacol Rev 2012; 64(4): 972–1003
56. Sporn MB, Liby KT, Yore MM, Fu L, Lopchuk JM, Gribble GW. New synthetic triterpenoids: potent agents for prevention and treatment of tissue injury caused by inflammatory and oxidative stress. J Nat Prod 2011; 74(3): 537–545
57. Suh N, Wang Y, Honda T, Gribble GW, Dmitrovsky E, Hickey WF, Maue RA, Place AE, Porter DM, Spinella MJ, Williams CR, Wu G, Dannenberg AJ, Flanders KC, Letterio JJ, Mangelsdorf DJ, Nathan CF, Nguyen L, Porter WW, Ren RF, Roberts AB, Roche NS, Subbaramaiah K, Sporn MB. A novel synthetic oleanane triterpenoid, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid, with potent differentiating, antiproliferative, and anti-inflammatory activity. Cancer Res 1999; 59(2): 336–341
58. Dinkova-Kostova AT, Liby KT, Stephenson KK, Holtzclaw WD, Gao X, Suh N, Williams C, Risingsong R, Honda T, Gribble GW, Sporn MB, Talalay P. Extremely potent triterpenoid inducers of the phase 2 response: correlations of protection against oxidant and inflammatory stress. Proc Natl Acad Sci USA 2005; 102(12): 4584–4589
59. Cleasby A, Yon J, Day PJ, Richardson C, Tickle IJ, Williams PA, Callahan JF, Carr R, Concha N, Kerns JK, Qi H, Sweitzer T, Ward P, Davies TG. Structure of the BTB domain of Keap1 and its interaction with the triterpenoid antagonist CDDO. PLoS ONE 2014; 9(6): e98896
60. Yates MS, Tran QT, Dolan PM, Osburn WO, Shin S, McCulloch CC, Silkworth JB, Taguchi K, Yamamoto M, Williams CR, Liby KT, Sporn MB, Sutter TR, Kensler TW. Genetic versus chemoprotective activation of Nrf2 signaling: overlapping yet distinct gene expression profiles between Keap1 knockout and triterpenoidtreated mice. Carcinogenesis 2009; 30(6): 1024–1031
61. Thimmulappa RK, Scollick C, Traore K, Yates M, Trush MA, Liby KT, Sporn MB, Yamamoto M, Kensler TW, Biswal S. Nrf2-dependent protection from LPS induced inflammatory response and mortality by CDDO-Imidazolide. Biochem Biophys Res Commun 2006; 351(4): 883–889
62. Thimmulappa RK, Fuchs RJ, Malhotra D, Scollick C, Traore K, Bream JH, Trush MA, Liby KT, Sporn MB, Kensler TW, Biswal S. Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. Antioxid Redox Signal 2007; 9(11): 1963–1970
63. Heiss EH, Schachner D, Werner ER, Dirsch VM. Active NF-E2-related factor (Nrf2) contributes to keep endothelial NO synthase (eNOS) in the coupled state: role of reactive oxygen species (ROS), eNOS, and heme oxygenase (HO-1) levels. J Biol Chem 2009; 284(46): 31579–31586
64. Cho HY, Reddy SP, Yamamoto M, Kleeberger SR. The transcription factor NRF2 protects against pulmonary fibrosis. FASEB J 2004; 18(11): 1258–1260
65. de Zeeuw D, Akizawa T, Agarwal R, Audhya P, Bakris GL, Chin M, Krauth M, Lambers Heerspink HJ, Meyer CJ, McMurray JJ, Parving HH, Pergola PE, Remuzzi G, Toto RD, Vaziri ND, Wanner C, Warnock DG, Wittes J, Chertow GM. Rationale and trial design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON). Am J Nephrol 2013; 37(3): 212–222
66. Chertow GM, de Zeeuw D; BEACON Steering Committee. Bardoxolone methyl in type 2 diabetes and advanced chronic kidney disease. N Engl J Med 2014; 370(18): 1768
67. Pergola PE, Raskin P, Toto RD, Meyer CJ, Huff JW, Grossman EB, Krauth M, Ruiz S, Audhya P, Christ-Schmidt H, Wittes J, Warnock DG; BEAM Study Investigators. Bardoxolone methyl and kidney function in CKD with type 2 diabetes. N Engl J Med 2011; 365(4): 327–336
68. Boyd JH, Macklin EA, Strunk RC, DeBaun MR. Asthma is associated with increased mortality in individuals with sickle cell anemia. Haematologica 2007; 92(8): 1115–1118