Mechanistic Insights into Vorinostat as a Repositioned Modulator of TACE-Mediated TNF-α Signaling via MAPK and NFκB Pathways

초록

Vorinostat, an FDA-approved histone deacetylase inhibitor, was evaluated for its potential anti-inflammatory activity through modulation of TACE (ADAM17)-mediated TNF-alpha signaling. The study was conducted using LPS-stimulated RAW264.7 macrophages. TACE enzymatic activity was assessed by a fluorogenic assay, TNF-alpha release was measured by ELISA, and phosphorylation of MAPKs and NF kappa B signaling proteins was examined by a western blot. Molecular docking was performed using GNINA to evaluate binding affinity to ERK. Vorinostat was found to modestly inhibit TACE enzymatic activity in vitro, while significantly suppressing TNF-alpha secretion in cells, comparable to the selective TACE inhibitor BMS-561392. A concentration-dependent reduction in phosphorylated I kappa B and NF kappa B was observed, along with selective inhibition of ERK phosphorylation. Docking studies indicated a stable, albeit weaker, binding of vorinostat to ERK compared to reference ERK inhibitors. These findings suggest that vorinostat suppresses TNF-alpha production primarily through indirect mechanisms involving ERK and NF-kappa B signaling pathways, rather than by direct TACE inhibition. The repositioning of vorinostat as a modulator of inflammatory signaling is supported, offering potential therapeutic value in inflammatory disorders.

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