A review of Nrf2 roles in cancer and cytoprotection: modulation by dimethyl fumarate

Introduction: Fumaric acid esters (FAEs) such as dimethyl fumarate (DMF) have a cytoprotection role in target organ toxicity. DMF is approved to treat moderate-to-severe psoriasis in adults. It also may be used as an immunosuppressive agent in the treatment of multiple sclerosis. Here, we would like to investigate the molecular mechanisms of DMF, as an activator of Nrf2, and its active metabolite, monomethyl fumarate (MMF), which exert anti-inflammatory and immune modulatory effects, in normal and cancer cells.Methods: To find related articles, the two keywords Nrf2 activators and Dimethyl fumarate in the Google Scholar engine as well as the phrase Review article in the Pubmed database were created and searched.Result: Currently, there are five main mechanisms for DMF/MMF that have been described so far, these mechanisms are summarized as follow:1. Modulates intracellular GSH levels in responses to oxidative stress;2. Stimulates cytoprotective and anti-inflammatory factors such as HO-1 by Nrf2 activation pathway;3. Inhibits Th1/Th17 responses and promotes Th2 responses by NF-κB inhibition;4. Modulates oxidative stress-sensitive transcription factors HIF-1α and STATs through inhibition of genes regulated by HIF-1α and STAT3/STAT1;5. Inhibition of neutrophil recruitment by agonism of HCA2 (hydroxy-carboxylic acid receptor 2).Discussion & Conclusion: The major molecules that are affected by DMF and which exert its effects on the cell are the classical signalling molecules Nrf2 and NF-κB, as well as intracellular GSH levels and cytoprotective proteins such as HO-1. Many studies showed that Nrf2 is a double-edged sword in cancer; capable of acting both as a tumor suppressor in one way and as a proto-oncogene in another. Inhibition of Nrf2 increases ROS and leads to cancer treatment. So that, combination therapy of Nrf2 inhibitors with anticancer agents, such as cisplatin and doxorubicin, resulted in improved antitumor activity of these chemotherapeutic agents in cancer cell line studies and animal models. On the other hand, it has been shown that activation of the Nrf2/Keap1/ARE signaling pathway in cancer cells can metabolically deactivate antitumor agents and reduce their intracellular concentration which may contribute to tumor formation. Overall, the role of Nrf2 activation such as DMF in cancer is paradoxical and requires further research.

Keywords:

Dimethyl fumarate , Nrf2 activators , Nrf2/Keap1/ARE signaling pathway , Nrf2 inhibitors