Histone Deacetylase Inhibitor Entinostat Exerts Anti-NSCLC Effects Through the EGFR Signaling Pathway and MDM2-p53 Axis

INTRODUCTION: Non-small cell lung cancer (NSCLC) is among the most aggressive malignancies threatening human health. Histone deacetylase inhibitors (HDACi) have been shown to suppress epidermal growth factor receptor (EGFR) signaling, making them promising candidates for NSCLC therapy. This study aimed to evaluate the effects of Entinostat on NSCLC. METHODS: The anti-proliferative effect of Entinostat was assessed using MTT assays, with four other HDAC inhibitors (the pan-HDAC inhibitor SAHA and selective HDAC inhibitors BRD73954, BG45, and NKL22) as controls. EGFR expression and phosphorylation of STAT3, AKT, and p38 were measured in vitro and in vivo via Western blot. Apoptosis was analyzed by flow cytometry, and expression of apoptosis regulators p53 and p21 was assessed by Western blot. The in vivo anti-tumor activity of Entinostat was evaluated using NSCLC xenograft models. RESULTS: Entinostat exhibited more potent anti-NSCLC activity than the other HDAC inhibitors in H460 and H1975 cell lines, with IC50 values of 0.69±0.03 μM and 0.20±0.01 μM, respectively. Western blot analysis demonstrated that Entinostat reduced EGFR expression and decreased phosphorylation of STAT3, AKT, and p38, indicating suppression of EGFR signaling both in vitro and in vivo. In xenograft models, treatment with 40 mg/kg Entinostat significantly inhibited tumor growth, though it also affected mouse body weight. CONCLUSION: Entinostat demonstrates strong anti-NSCLC activity by suppressing EGFR expression and downstream signaling, highlighting its potential as a therapeutic agent.