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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front. Med.    2015, Vol. 9 Issue (1) : 46-56     DOI: 10.1007/s11684-015-0375-1
REVIEW |
Triterpenoid inducers of Nrf2 signaling as potential therapeutic agents in sickle cell disease: a review
Amma Owusu-Ansah1,2,Sung Hee Choi1,1_FMD-14249-OAA _FMD-14249-OAA,Agne Petrosiute1,2,John J. Letterio1,2,Alex Yee-Chen Huang1,2,*()
1. Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
2. The Angie Fowler Adolescent & Young Adult Cancer Institute at University Hospitals, Rainbow Babies & Children’s Hospital, Cleveland, OH 44106, USA
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Abstract  

Sickle cell disease (SCD) is an inherited disorder of hemoglobin in which the abnormal hemoglobin S polymerizes when deoxygenated. This polymerization of hemoglobin S not only results in hemolysis and vaso-occlusion but also precipitates inflammation, oxidative stress and chronic organ dysfunction. Oxidative stress is increasingly recognized as an important intermediate in these pathophysiological processes and is therefore an important target for therapeutic intervention. The transcription factor nuclear erythroid derived- 2 related factor 2 (Nrf2) controls the expression of anti-oxidant enzymes and is emerging as a protein whose function can be exploited with therapeutic intent. This review article is focused on triterpenoids that activate Nrf2, and their potential for reducing oxidative stress in SCD as an approach to prevent organ dysfunction associated with this disease. A brief overview of oxidative stress in the clinical context of SCD is accompanied by a discussion of several pathophysiological mechanisms contributing to oxidative stress. Finally, these mechanisms are then related to current management strategies in SCD that are either utilized currently or under evaluation. The article concludes with a perspective on the potential of the various therapeutic interventions to reduce oxidative stress and morbidity associated with SCD.

Keywords oxidative stress      Nrf2      triterpenoids      sickle cell disease      vaso-occlusion      CDDO-Me     
Corresponding Authors: Alex Yee-Chen Huang   
Just Accepted Date: 06 November 2014   Online First Date: 12 December 2014    Issue Date: 02 March 2015
URL:  
http://academic.hep.com.cn/fmd/EN/10.1007/s11684-015-0375-1     OR     http://academic.hep.com.cn/fmd/EN/Y2015/V9/I1/46
Fig.1  The Keap1-Nrf2 antioxidant pathway. CDDO-Me is a triterpenoid inhibitor of Keap1, the cytosolic repressor that targets Nrf2 for ubiquitination. Triterpenoid binds to reactive thiol groups on cysteine 151 within the redox sensitive BTB domain of Keap1. Under basal conditions, Nrf2 is bound to Keap1 in the cytoplasm and is ubiquitinated. Under conditions of electrophilic or oxidative stress, Nrf2 dissociates from Keap1 and is protected from degradation. Nrf2 then accumulates in the nucleus where it will heterodimerize with MAF proteins and then bind to the antioxidant response element (ARE), located on the promoter of several genes involved in the phase 2 response such as HO-1, GST, GCLC and NQO1.
Fig.2  Pathophysiological processes in SCD contribute to oxidative stress. A schematic diagram of how hemolysis, vasoconstriction, inflammation and ischemia reperfusion injury interact to create a state of oxidative stress is depicted. As byproducts of hemolysis, both arginase-depleting L arginine and free heme are released from red cells and subsequently diffuse into neighboring cells, leading to iron deposits which catalyze ROS formation. Free heme also recruits neutrophils to the endothelium. Endothelial NOS becomes uncoupled under conditions of NO depletion, generating ROS and reactive nitrogen species (RNS) instead of NO. Vasoconstriction occurs when endothelin-1 (ET1), a vasoconstrictor that opposes the vasodilatory effects of NO, predominates in NO depletion. The inhibitory effect of NO on inflammation and endothelial activation is lost leading to expression of adhesion molecules like VCAM, ICAM, P-selectins and L-selectins that recruit PMN and thrombospondin (TSP) to which reticulocytes adhere via CD36. Sickle red cells expressing externalized phosphatidylserine (PS) on their membranes cause platelet (plt) activation and are phagocytosed by macrophages (M) contributing further to hemolysis. Xanthine oxidase (XO) levels are increased during reperfusion injury, increasing ROS production.
Fig.3  Chemical structures of select SOTs. The structures of SOTs are depicted, including 2-cyano-3,12-dioxooleana-1,9(11)-diene-28-oic acid (CDDO) and its analogs methyl 2-cyano-3,12-dioxooleana-1,9(11)-diene-28-oate(CDDO-Me), 2-cyano-3,12-dioxooleana-1,9-diene-28-oic acid-methylamide (CDDO-MA), 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]-imidazole (CDDO-Im), and CDDO trifluoroethylamide (CDDO-TFEA).
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