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.
Highlights
Nrf2 (nuclear factor-like 2) is an important transcription factor that regulates many of the cytoprotective enzymes that are involved in the adaptive oxidative stress response [5]
These antioxidant and detoxifying enzymes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO1), and glutamate-cysteine ligase (GCL), which consists of a catalytic subunit (GCLC) and a modulatory subunit (GCLM), are upregulated by Nrf2 and have important roles in protecting cells against oxidative stress; they serve as common biomarkers for evaluating the Nrf2 dependent transcription [3,9,10]
We measured the expression changes of antioxidant genes NQO1, HO-1, and GCLM in cells treated with nine different candidate drugs using quantitative RT-PCR
Summary
Developing effective means to protect against metabolic oxidative stress and exposure to environmental toxicants is an essential requirement for the evolution of early eukaryotic life [1]. ARE-dependent genes, encoding a group of approximately 500 proteins that are expressed in various isoforms and distributed in various organelles and subcellular compartments These antioxidant and detoxifying enzymes such as NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase 1 (HO1), and glutamate-cysteine ligase (GCL), which consists of a catalytic subunit (GCLC) and a modulatory subunit (GCLM), are upregulated by Nrf and have important roles in protecting cells against oxidative stress; they serve as common biomarkers for evaluating the Nrf dependent transcription [3,9,10]. Several successful electrophilic indirect Nrf activators have been approved and used as first-line oral drugs, the risk of ‘off-target’ effects may be associated with them due to the complex molecular mechanisms of action of the traditional electrophilic Nrf activators, which covalently bind to the thiol of the cysteine in Keap. All the agents coupled with module 36 were analyzed and screened based on their chemical characteristics and approved information for further biological testing
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