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  2. Zinc supplementation augments the suppressive effects of repurposed NF-κB inhibitors on ACE2 expression in human lung cell lines

Zinc supplementation augments the suppressive effects of repurposed NF-κB inhibitors on ACE2 expression in human lung cell lines

  • Life Sci. 2021 Sep 1;280:119752. doi: 10.1016/j.lfs.2021.119752.
Ming-Cheng Lee 1 Yin-Kai Chen 2 Jyy-Jih Tsai-Wu 3 Yih-Jen Hsu 4 Bor-Ru Lin 5
Affiliations

Affiliations

  • 1 Department of Internal Medicine, Hospital and College of Medicine, National Taiwan University, Taipei 10051, Taiwan, ROC.
  • 2 Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan, ROC; Department of Hematology, National Taiwan University Cancer Center, Taipei 10672, Taiwan, ROC.
  • 3 Department of Medical Research, National Taiwan University Hospital, Taipei 10051, Taiwan, ROC.
  • 4 Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei 10051, Taiwan, ROC.
  • 5 Department of Internal Medicine, Hospital and College of Medicine, National Taiwan University, Taipei 10051, Taiwan, ROC; Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei 10051, Taiwan, ROC. Electronic address: brucelin@ntuh.gov.tw.
Abstract

Aims: Angiotensin-converting Enzyme 2 (ACE2) is a key negative regulator of the renin-angiotensin system and also a major receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Infection. Here, we reveal a role for NF-κB in human lung cell expression of ACE2, and we further explore the potential utility of repurposing NF-κB inhibitors to downregulate ACE2.

Main methods: Expression of ACE2 was assessed by Western blotting and RT-qPCR in multiple human lung cell lines with or without NF-κB Inhibitor treatment. Surface ACE2 expression and intracellular Reactive Oxygen Species (ROS) levels were measured with flow cytometry. p50 was knocked down with siRNA. Cytotoxicity was monitored by PARP cleavage and MTS assay.

Key findings: Pyrrolidine dithiocarbamate (PDTC), an NF-κB Inhibitor, suppressed endogenous ACE2 mRNA and protein expression in H322M and Calu-3 cells. The ROS level in H322M cells was increased after PDTC treatment, and pretreatment with N-acetyl-cysteine (NAC) reversed PDTC-induced ACE2 suppression. Meanwhile, treatment with hydrogen peroxide augmented ACE2 suppression in H322M cells with p50 knockdown. Two repurposed NF-κB inhibitors, the anthelmintic drug triclabendazole and the antiprotozoal drug emetine, also reduced ACE2 mRNA and protein levels. Moreover, zinc supplementation augmented the suppressive effects of triclabendazole and emetine on ACE2 expression in H322M and Calu-3 cells.

Significance: These results suggest that ACE2 expression is modulated by ROS and NF-κB signaling in human lung cells, and the combination of zinc with triclabendazole or emetine shows promise for clinical treatment of ACE2-related disease.

Keywords

ACE2; Emetine; NF-kappa B; ROS; Triclabendazole; Zinc.

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