The PDE4 inhibitor CHF6001 affects keratinocyte proliferation via cellular redox pathways.

Abstract

Psoriasis is a skin disease characterized by abnormal keratinocyte proliferation and inflammation. Currently, there are no cures for this disease, so the goal of treatment is to decrease inflammation and slow down the associated rapid cell growth and shedding. Recent advances have led to the usage of phosphodiesterase 4 (PDE4) inhibitors for treatment of this condition. For example, apremilast is an oral, selective PDE4 inhibitor that is able to reduce skin inflammation and is Food and Drug Administration (FDA)-approved to treat adults with moderate to severe psoriasis and/or psoriatic arthritis. However, common target-related adverse events, including diarrhea, nausea, headache, and insomnia limit the usage of this drug. To circumvent these effects, the usage of PDE4 inhibitors specifically designed for topical treatment, such as CHF6001, may combine local anti-inflammatory activity with limited systemic exposure, improving tolerability. In this study, we showed that CHF6001, currently undergoing clinical development for COPD, suppresses human keratinocyte proliferation as assessed via BrdU incorporation. We also observed decreased re-epithelialization in a scratch-wound model after CHF6001 treatment. At the molecular level, CHF6001 inhibited translocation of phosphorylated NF-κB subunit p65, promoting loss of nuclear cyclin D1 accumulation and an increase of cell cycle inhibitor p21. Furthermore, CHF6001 decreased oxidative stress, measured by assessing lipid peroxidation (4-HNE adduct formation), through the inactivation of the NADPH oxidase. These results suggest that CHF6001 has the potential to treat skin disorders associated with hyperproliferative keratinocytes, such as psoriasis by targeting oxidative stress, abnormal re-epithelization, and inflammation.

• Authors: Brittany Woodby, Claudia Sticozzi, Erika Pambianchi, Gino Villetti, Maurizio Civelli, Giuseppe Valacchi, Fabrizio Facchinetti
• Journal: Archives of biochemistry and biophysics (Arch Biochem Biophys) Vol. 685 Pg. 108355 (05 30 2020) ISSN: 1096-0384 [Electronic] United States
• PMID: 32268137 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• tanimilast
• Aldehydes
• CCND1 protein, human
• Phosphodiesterase 4 Inhibitors
• Sulfonamides
• Transcription Factor RelA
• para-Aminobenzoates
• Cyclin D1
• NADPH Oxidases
• 4-hydroxy-2-nonenal

Topics

• Aldehydes (metabolism)
• Cell Line
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyclin D1 (metabolism)
• Humans
• Keratinocytes (drug effects)
• Lipid Peroxidation (drug effects)
• NADPH Oxidases (metabolism)
• Oxidative Stress (drug effects)
• Phosphodiesterase 4 Inhibitors (pharmacology, toxicity)
• Psoriasis (drug therapy)
• Sulfonamides (pharmacology, toxicity)
• Transcription Factor RelA (metabolism)
• para-Aminobenzoates (pharmacology, toxicity)