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

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

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Acknowledgements

The authors gratefully acknowledge the following support for this work: Rainbow Fellow Research Award Program (AOA & AP), the Reuter Foundation (AOA and JJL); the St. Baldrick’s Foundation (AP & AYH); the Theresia G. and Stuart F. Kline Family Foundation Chair in Pediatric Oncology (AYH); the Jane and Lee Seidman Chair in Pediatric Cancer Innovation (JJL).

Amma Owusu-Ansah, Sung Hee Choi, Agne Petrosiute, John J. Letterio, and Alex Yee-Chen Huang declare that they have no conflict of interest. This manuscript is a review article and does not require research protocol approval by the Case Western Reserve University or University Hospitals of Cleveland’s Institutional Review Boards.

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