Modulation of the TGF-ß-induced epithelial-to-mesenchymal transition by pan-selective PDE inhibitors in A549 cells

Epithelial-to mesenchymal transition (EMT) occurs both in physiological and pathological conditions in the body. This phenomenon is important for normal embryonic development and wound healing but occurs also during cancer progression. Additionally, it is one of the causes of excessive tissue fibrosis. Recent reports indicate that intracellular cAMP-elevating compounds, including phosphodiesterases (PDE) inhibitors, may represent a promising class of anti-fibrotic agents. Thus the aim of this study was to explore the effect of new, pan-selective PDE inhibitors on transforming growth factor type β (TGF-β)-induced EMT in A549 alveolar epithelial cells. We used a known and the clinically used PDE inhibitor - theophylline, the non-specific PDE inhibitor - IBMX, as well as several newly synthesized derivatives of 7,8-disubstituted purine-2,6-dione (1 and 2) with preferential activity as pan-selective PDE inhibitors. In this study, we confirmed that all tested PDE inhibitors may variably modulate TGF-β-induced EMT in alveolar epithelial cells through inhibition of cells proliferation and migration as well as reduction of Snail, N-cadherin and vimentin expression and increased of E-cadherin expression. The obtained results suggested that substances representing simultaneously strong inhibitory properties against PDE1, PDE3, PDE4 and PDE8 were particularly effective in reducing TGF-β-induced EMT. The findings shown an anti-fibrotic impact of pan-selective PDE inhibitors on A549 cells via repression of epithelial-to-mesenchymal transition. Acknowledgements: This study was supported by the National Science Centre, Poland, funded grants No. UMO-2017/27/B/NZ7/01633