NCS 613, a Potent PDE4 Inhibitor, Displays Anti-Inflammatory and Anti-Proliferative Properties on A549 Lung Epithelial Cells and Human Lung Adenocarcinoma Explants.

Issaka Yougbare,Lazare Belemnaba,Eric Rousseau,Yannick F Senouvo,Abdurazzag Abusnina,Thérèse Keravis,Caroline Morin,Claire Lugnier

doi:10.3389/fphar.2020.01266

Abstract

Chronic inflammation is a deleterious process occurring in several pulmonary diseases; it is a driving force promoting tumorigenesis. By regulating local cyclic nucleotide concentration, cyclic nucleotide phosphodiesterases (PDE) govern important biological processes, including inflammation and proliferation. The aim of this study was to investigate the anti-inflammatory and anti-proliferative effects of NCS 613, a specific PDE4 inhibitor, on TNFα-treated human lung adenocarcinoma cell line (A549) and on human lung adenocarcinoma explants. PDE4 isoforms and inflammatory pathways mediated by p38 MAPK, ERK1/2, and IκBα were analyzed by Western blot and immunostainings. Proliferation were performed using [3H]-thymidine incorporation under different experimental conditions. TNFα-stimulation increased p38 MAPK phosphorylation and NF-κB translocation into the nucleus, which was abolished by NCS 613 treatment. Concomitantly, NCS 613 restores IκBα detection level in human adenocarcinoma. An IC50 value of 8.5 μM was determined for NCS 613 on anti-proliferative properties while ERK1/2 signaling was down-regulated in A549 cells and lung adenocarcinoma explants. These findings shed light on PDE4 signaling as a key regulator of chronic inflammation and cancer epithelial cell proliferation. It suggests that PDE4 inhibition by NCS 613 represent potential and interesting strategy for therapeutic intervention in tackling chronic inflammation and cell proliferation.

Highlights

Chronic inflammation, which is a deleterious process occurring in inflammatory respiratory diseases, is believed to be a tumor promoter in cancer induction (Lee et al, 2009; Balkwill and Mantovani, 2010; Phillips, 2020)
We did not detect PDE4D isoforms by Western blot in A549 cell line. These results suggest that cAMP accumulation subsequent to PDE4 inhibition induces a shift in isoform transcription and biosynthesis
The data revealed that TNFa stimulation significantly abolished PDE4B 96 kDa while it increased PDE4A 70 kDa and PDE4B 66 kDa detection in A549 cells, suggesting that these later isoforms could be involved in TNFa signaling (Figures 1A, C)

Summary

Introduction

Chronic inflammation, which is a deleterious process occurring in inflammatory respiratory diseases, is believed to be a tumor promoter in cancer induction (Lee et al, 2009; Balkwill and Mantovani, 2010; Phillips, 2020). Downstream of surface membrane receptor activation, cyclic nucleotide phosphodiesterases (PDE) which encompass 11 families play a pivotal role in cAMP and cGMP signaling (Lugnier, 2006; Conti and Beavo, 2007). These enzymes hydrolyze cyclic nucleotides as a feedback mechanism for rapidly returning local nucleotide concentration to basal levels (Keravis et al, 2012; Maurice et al, 2014; Baillie et al, 2019; Lugnier et al, 2020). This study aimed to investigate the anti-inflammatory and antiproliferative effects of NCS 613 on human lung adenocarcinoma cell line (A549) and cultured human lung adenocarcinoma explants

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