Dimethyl fumarate, a two‐edged drug: Current status and future directions

Abstract

Dimethyl fumarate (DMF) is a fumaric acid ester registered for the treatment of relapsing‐remitting multiple sclerosis (RRMS). It induces protein succination leading to inactivation of cysteine‐rich proteins. It was first shown to possess cytoprotective and antioxidant effects in noncancer models, which appeared related to the induction of the nuclear factor erythroid 2 (NF‐E2)–related factor 2 (NRF2) pathway. DMF also displays antitumor activity in several cellular and mice models. Recently, we showed that the anticancer mechanism of DMF is dose‐dependent and is paradoxically related to the decrease in the nuclear translocation of NRF2. Some other studies performed indicate also the potential role of DMF in cancers, which are dependent on the NRF2 antioxidant and cellular detoxification program, such as KRAS‐mutated lung adenocarcinoma. It, however, seems that DMF has multiple biological effects as it has been shown to also inhibit the transcription factor nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB), thus blocking downstream targets that may be involved in the development and progression of inflammatory cascades leading to various disease processes, including tumors, lymphomas, diabetic retinopathy, arthritis, and psoriasis. Herein, we present the current status and future directions of the use of DMF in various diseases models with particular emphases on its targeting of specific intracellular signal transduction cascades in cancer; to shed some light on its possible mode of action.

Electrophiles against (Skin) Diseases: More Than Nrf2

“…Dimethyl fumarate (DMF) is the main component of Fumaderm ® (Biogen Idec), a drug which was approved in 1994 in Germany for the treatment of patients suffering from severe psoriasis, and then in 2008 for moderate psoriasis. In 2017, a similar DMF product termed Skilarence ® (Almirall) was approved by the European Medicines Agency for moderate and severe psoriasis [20,51,52]. Psoriasis is a chronic T cell-and DC(dendritic cell)-mediated inflammatory skin disease affecting 2%-4% of the population and plaque psoriasis is the most common type, affecting about 90% of all patients [53].…”

“…DMF treatment causes a shift to a Th2 anti-inflammatory type response and DMF-treated patients have fewer circulating immune cells [51,52,[56][57][58]. As a Th1/Th17 cytokine profile is also a characteristic of several other diseases, DMF may be also efficient in patients suffering from diseases such as colitis, Crohn's disease, rheumatoid arthritis or systemic sclerosis [51,57,59]. Indeed, several clinical trials suggest the efficacy of DMF in patients suffering from other inflammatory diseases and cancer ( Table 1).…”

“…DMF is a hydrophobic electrophile that easily enters cells across the plasma membrane and reacts with the sulfhydryl group of cysteine residues via the Michael addition ( Figure 4a) in an irreversible manner [51]. DMF treatment has multiple effects in vitro ( Figure 4b) [51]. However, the molecular mechanisms underlying the therapeutic activity of DMF in psoriasis and MS patients are poorly understood.…”

“…All these pathways antagonize inflammation, favoring a shift from a proinflammatory Th1/Th17 to a regulatory Th2 phenotype [57,58]. In addition, after entering the cells, DMF is trapped after reaction with GSH, free cysteine and thioredoxin (see 2) [51,60]. This causes a shift in the cellular redox potential, subsequent activation of NRF2 and inhibition of NF-κB and inflammasomes [39,58].…”

Enhanced activity of glycolytic enzymes in Drosophila and human cell models of Parkinson’s disease based on DJ-1 deficiency

“…It has been shown that this compound appears to increase the glycolytic rate [42]. However, high DMF concentrations can downregulate glycolysis by inactivation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a rate-limiting enzyme in the glycolytic pathway [47,48].…”