Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

Evaluation of antioxidant activation by potential nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Keap1 complex inhibitors

Inas Saleh Almazari¹ , Shada Youssef Elhayek²

¹Faculty of Pharmacy, Department of Clinical Pharmacy, Zarqa University, Zarqa 13132, Jordan; ²Faculty of Mathematical and Natural Sciences, Department of Pharmacy, Heinrich-Heine-University Düsseldorf, 40522 Düsseldorf, Germany.

For correspondence:- Inas Almazari Email: ialmazari@zu.edu.jo

Accepted: 16 August 2021 Published: 30 September 2021

Citation: Almazari IS, Elhayek SY. Evaluation of antioxidant activation by potential nuclear factor (erythroid-derived 2)-like 2 (Nrf2)/Keap1 complex inhibitors. Trop J Pharm Res 2021; 20(9):1861-1873 doi: 10.4314/tjpr.v20i9.12

© 2021 The authors.
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Abstract

Purpose: To investigate the binding affinities of forty-one (41) National Cancer Institute (NCI)-generated compounds, to the Nrf2 ligand, and possible activation of Nrf2 in the MCF-7 cell line.

Methods: To investigate the inhibition of the Nrf2/Keap1 complex, the MCF-7 cell line was treated with each of the 41 compounds, at a working concentration of 30 μM. The extent of Nrf2 activation and corresponding Nrf2/Keap1 complex inhibition was evaluated in terms of Nrf2 expression and its antioxidant-associated enzyme gamma-glutamylcysteine synthetase (GCS), using western blot analysis.

Results: Twenty-nine compounds out of the 41 targeted compounds activated GCS, and some showed comparable or greater activation capacity than the standard Nrf2 activator tBHQ. To confirm that the activation of GCS was mediated via Nrf2 activation, cell lysates were tested for their Nrf2 protein expression, and it was found that Nrf2 was activated by the examined compounds for more than 24 h, indicating that the effect of the chosen compounds were not transient.

Conclusion: These results might be useful for identifying better targets for cytoprotection, and for oxidative stress alleviation through Nrf2 pathway activation. Further studies are required on the effects of these targets on the prevention and treatment of various oxidative stress disorders, including cancer.

Keywords: NCI compounds, Nrf2/Keap1, Cancer, Antioxidants, Gamma-glutamylcysteine synthetase (GCS), MCF7, Pharmacophore, Docking, Co-crystallized structure