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

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 TNFa-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 IkBa were analyzed by Western blot and immunostainings. Proliferation were performed using [ 3 H]-thymidine incorporation under different experimental conditions. TNFa-stimulation increased p38 MAPK phosphorylation and NF-kB translocation into the nucleus, which was abolished by NCS 613 treatment. Concomitantly, NCS 613 restores IkBa detection level in human adenocarcinoma. An IC 50 value of 8.5 mM was determined for NCS 613 on antiproliferative 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.

Ibudilast Attenuates Folic Acid–Induced Acute Kidney Injury by Blocking Pyroptosis Through TLR4-Mediated NF-κB and MAPK Signaling Pathways

“…In addition, an overdose FA injection induced the activation of the MAPK pathway, which is the main target involved in the protective effect on FA-induced AKI (Jiang et al, 2016). A recent study reported that NCS613, another potent PDE4 inhibitor, was a negative modulator of p38 phosphorylation that exerts anti-inflammatory effects on TNF-α-treated lung epithelial cells by inhibiting the activation of the MAPK signaling pathway (Yougbare et al, 2020). Moreover, some studies have suggested that the MAPK signaling pathway mainly contributes to cell pyroptosis, which further drives massive inflammation (Yao and Sun 2019).…”

Cyclic adenosine monophosphate/phosphodiesterase 4 pathway associated with immune infiltration and PD-L1 expression in lung adenocarcinoma cells

“…PDE4 inhibitors have cytotoxic effects on A549 lung cancer cells ( 27 ), and PDE4 is a key regulator of normal and cancer epithelial cell proliferation. PDE4 may thus be effective for the treatment of chronic inflammation and cancer cell proliferation ( 28 ). The role of PDE4B as a prognostic and therapeutic target, however, differs between specific tumors.…”

Alterations of cAMP/cGMP Signaling Pathways in Lupus Nephritis

“…In other study, it has been shown that PDE4 inhibitors improve kidney damage by increasing cAMP levels after renal ischemia-reperfusion injury in rats 32 . Our recent study has shown that PDE4 inhibition by NCS 613 exerts antiproliferative effects on A549 lung epithelial cells and human lung adenocarcinoma explants, as well as anti-proliferative effects on mesangial cells 29,33 . From animal studies to patient bed site, our translational observations strongly support the idea that inhibition of PDE4 activities in peripheral mononuclear cells (PBMCs) can control proinflammatory signaling.…”

“…NCS 613 is a new potent PDE4 inhibitor which exerts anti-inflammatory properties (Figure 1). Oral administration of NCS 613 reduces neutrophil recruitment in lipopolysaccharide (LPS)-treated mouse bronchi as and abolishes hyperresponsiveness of cultured human bronchi [27][28][29] . Recently, we reported that NCS 613 suppresses systemic inflammation and immunes complexes deposition in kidney of lupus prone mice 30 .…”