Identification of Non-Electrophilic Nrf2 Activators from Approved Drugs

Abstract

Oxidative damage can lead to a wide range of diseases. Nrf2 is an important transcription factor that regulates many of the cytoprotective enzymes involved in the oxidative stress response. Therefore, targeting the regulation of Nrf2 activation is one logical and effective strategy to prevent or lower the risk of oxidative stress-related diseases. Until now, most research has focused on electrophilic indirect Nrf2 activators, but the risk of ‘off-target’ effects may be associated with these activators. To find novel small non-electrophilic modulators of Nrf2, we started from chemical agents derived from a connectivity map (cMap) and identified 22 non-electrophilic potential Nrf2-activating drugs through a drug repositioning tactic. By determining the expression changes of antioxidant genes in MCF7 cells that were treated with the potential Nrf2 activators using quantitative real-time polymerase chain reaction RT-PCR (real-time polymerase chain reaction) (qRT-PCR), astemizole was found to have a greater scale of upregulating antioxidant genes NQO1, HO-1, and GCLM than the positive control d,l-sulforaphane, although the testing concentration was lower than that of the control. Astemizole is a good potential redox regulator and deserves more pharmacodynamic experimentation to test and verify its feasibility for use as an Nrf2 activator.

Potential Applications of NRF2 Modulators in Cancer Therapy

“…Based on their structures, the chemicals were placed into one of seven groups consisting of: I-phenothiazine; II-tricyclics; III-trihexyphenidyl; IV-phenyl pyridine; V-quinolin-8-substituted; VI-tamoxifen substituted; and VII-hexetidine. The results indicated that each class was able to induce some level of NRF2-mediated increase in ARE-dependent protein expression [79]. These changes varied between class and protein, but the systematic approach used to identify biologically active non-electrophilic NRF2 activators opened many prospects for future development.…”

Measuring Sulforaphane and Its Metabolites in Human Plasma: A High Throughput Method

“…Sulforaphane is further metabolized into a number of other active metabolites (Figure 1). Sulforaphane and its metabolites are gene transcription activators that release bound nuclear factor erythroid factor 2 (NFE2L2) in the cell cytosol, allowing its nuclear translocation [13,[18][19][20][21]. In the nucleus, NFE2L2 induces transcription of a cassette of cellular "safeguarding" genes in the antioxidant response element (ARE) of cellular DNA [22].…”

“…Initial approaches to the measurement of sulforaphane and its metabolites in biological samples were limited in sensitivity and were unable to accurately quantify levels of metabolites in humans [24,25]. More recently, an approach offering increased sensitivity was described using liquid chromatography-mass spectrometry (LC-MS) [21]. This allowed quantification of sulforaphane and its metabolites at lower concentrations in both plasma and urine [26].…”

Identification of NUDT5 Inhibitors From Approved Drugs

“…Connectivity map (cMap), which is a database comprising gene expression profiles for five types of human cell lines treated with 1309 agents, have been widely used in drug repurposing studies (Lamb et al, 2006;Iorio et al, 2010). Previously, 49 drug-induced transcriptional modules reflecting the association of drugs and gene expression were identified through analyzing cMap data with a biclustering method , which is very helpful to clarify the pharmacological mechanisms and discover new activities of drugs Quan et al, 2015;Zhang et al, 2017). NUDT5 inhibitors have been proven capable of blocking estrogen signaling (Page et al, 2018), which is similar to the effect of antiestrogens.…”