NFE2L2 inducers (e.g. sulforaphane, fumarates, and their derivatives) block ubiquitination of NFE2L2 by binding more or less irreversibly to L-cysteine 315 and other cysteine residues of KEAP1. This strongly enhances induction of expression of all genes with antioxidant response elements (ARE), the most prominent being HMOX1 and NQO1 (Hong et al, 2005).
Sulforaphane has proved to be an effective chemoprotective agent in cell culture, carcinogen-induced and genetic animal cancer models, as well as in xenograft models of cancer (Clarke et al, 2008). These preclinical studies demonstrate chemopreventive mode of actions of isothiocyanates, mainly related to a.) detoxification (induction of phase II enzymes), b.) anti-inflammatory properties by down-regulation of NFkappaB activity, c.) cyclin-mediated cell cycle arrest and d.) epigenetic modulation by inhibition of histone deacetylase activity. First prospective clinical trials were promising in patients with risk of prostate cancer recurrence (Gründemann and Huber, 2018; Kamal et al, 2020)
In cancer treatment, sulforaphane exhibited promising inhibitory effects on breast cancer, lung cancer, liver cancer, and other malignant tumors (Wu et al, 2020)
Five clinical trials showed a significant positive correlation between sulforaphane use and autism spectrum disorder (ASD) behavior and cognitive function. The current evidence shows with minimal side effects observed, sulforaphane appears to be a safe and effective treatment option for treating ASD (McGuinness and Kim, 2020).
Dimethyl fumarate (DMF) was effective in reducing the proportion of patients with MS relapse at 2 years (primary endpoint of DEFINE) and the annualized relapse rate (primary endpoint of CONFIRM) compared with placebo, with reduced disability progression also observed with the drug versus placebo in DEFINE. Dimethyl fumarate also reduced disease activity measures relative to placebo in these trials (Buress and Deeks, 2014; Xu et al, 2015). DMF is completely metabolized to monomethyl fumarate (MMF), and by giving it directly the usually mild side effects are alleviated further (Wynn et al, 2020).