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. 2017 May 26;22(6):883.
doi: 10.3390/molecules22060883.

Identification of Non-Electrophilic Nrf2 Activators from Approved Drugs

Qing-Ye Zhang  1 , Xin-Yi Chu  2 , Ling-Han Jiang  3 , Meng-Yuan Liu  4 , Zhi-Ling Mei  5 , Hong-Yu Zhang  1
Affiliations

Identification of Non-Electrophilic Nrf2 Activators from Approved Drugs

Qing-Ye Zhang et al. Molecules. .

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.

Keywords: Nrf2 activator; drug repositioning; oxidative stress; redox regulators.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The expressions of NQO1, HO-1, and GCLM genes after treatment with the positive control and the potential Nrf2-activating drugs at 6 h, 12 h, and 24 h time points. (A) The results of samples treated with the positive control d,l-sulforaphane (15 μM). (B), (C), and (D) The results of samples treated with astemizole (8 μM), trifluoperazine (10 μM), and tamoxifen (1 μM), respectively. The genes’ expression levels at 0 h are normalized to 1. Bars represent the average standard deviations, n = 3. The significance of the expression fold changes between samples treated with drugs and negative control at the same time points are tested using a paired t-test: * p < 0.05; ** p < 0.01; *** p < 0.001.
Figure 1
Figure 1
The expressions of NQO1, HO-1, and GCLM genes after treatment with the positive control and the potential Nrf2-activating drugs at 6 h, 12 h, and 24 h time points. (A) The results of samples treated with the positive control d,l-sulforaphane (15 μM). (B), (C), and (D) The results of samples treated with astemizole (8 μM), trifluoperazine (10 μM), and tamoxifen (1 μM), respectively. The genes’ expression levels at 0 h are normalized to 1. Bars represent the average standard deviations, n = 3. The significance of the expression fold changes between samples treated with drugs and negative control at the same time points are tested using a paired t-test: * p < 0.05; ** p < 0.01; *** p < 0.001.
Figure 2
Figure 2
The comparison of NQO1, HO-1, and GCLM expression changes after treatment with d,l-sulforaphane (15 μM) and astemizole (8 μM) at 6 h, 12 h, and 24 h time points. Bars represent the average standard deviations, n = 3. The significance of the expression fold changes between samples treated with d,l-sulforaphane and astemizole at the same time points are tested using a paired t-test: * p < 0.05; *** p < 0.001.
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