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Entinostat Induces Dual Apoptotic and Autophagic Cell Death in Small-Cell Lung Cancer via Epigenetic Modulation of

Zhongkai Tong1, Xiaoxiao Zhu1, Cenli Wang2

  • 1Department of Respiratory and Critical Care Medicine, Ningbo No.2 Hospital, Ningbo, China.

Journal of Biochemical and Molecular Toxicology
|March 12, 2026
PubMed

Insights

Entinostat, an HDAC1/3 inhibitor, shows anti-tumor effects in small cell lung cancer (SCLC) by inducing apoptosis and autophagy. It works by downregulating HDAC1, affecting p53, and modulating the AMPK/mTOR pathway.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Small cell lung cancer (SCLC) remains a challenging malignancy with limited treatment options.
  • The precise molecular mechanisms of HDAC inhibitors like Entinostat in SCLC are not fully understood.
  • Entinostat targets histone deacetylase 1 and 3 (HDAC1/3), showing prior anti-tumor activity.

Purpose of the Study:

  • To elucidate the functional role and mechanism of Entinostat in SCLC.
  • To investigate Entinostat's effects on cell death pathways, focusing on HDAC1 inhibition.
  • To explore the downstream molecular targets and signaling pathways affected by Entinostat.

Main Methods:

  • Evaluation of Entinostat's anti-tumor effects in SCLC cell lines and a xenograft mouse model.
  • Utilized MTT assays, flow cytometry, immunofluorescence, and western blotting.
  • Employed rescue experiments with HDAC1 overexpression and pathway-specific inhibitors.

Main Results:

  • Entinostat significantly inhibited SCLC cell viability and induced apoptosis and autophagy.
  • Mechanistically, Entinostat downregulated HDAC1, increased p53 acetylation/phosphorylation, activated AMPK, and suppressed mTOR signaling.
  • HDAC1 overexpression reversed Entinostat's effects, while in vivo studies confirmed tumor growth suppression and pathway modulation.

Conclusions:

  • Entinostat demonstrates potent anti-tumor activity in SCLC by inducing apoptosis and autophagy.
  • The drug exerts its effects through epigenetic modulation of p53 via HDAC1 inhibition.
  • Entinostat regulates the AMPK/mTOR axis, contributing to its overall anti-cancer efficacy in SCLC.
Keywords:
Entinostatacetylationapoptosisautophagicp53small cell lung cancer

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