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Apoptotic and autophagic cell death induced by histone deacetylase inhibitors

Yufang Shao1, Zhonghua Gao, Paul A Marks

  • 1Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.

Proceedings of the National Academy of Sciences of the United States of America
|December 15, 2004
PubMed

Insights

Histone deacetylase (HDAC) inhibitors trigger cancer cell death through apoptosis and a distinct form of programmed cell death called autophagy. This dual mechanism offers new therapeutic strategies for cancers with defects in apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Histone deacetylase (HDAC) inhibitors are known to induce cancer cell death.
  • The precise mechanisms by which HDAC inhibitors trigger cell death remain incompletely understood.
  • Understanding these pathways is crucial for optimizing cancer therapy.

Purpose of the Study:

  • To elucidate the mechanisms of cell death induced by HDAC inhibitors in human cancer cells.
  • To investigate the roles of apoptosis and autophagy in HDAC inhibitor-mediated cell death.
  • To explore the clinical implications of these findings for cancer treatment.

Main Methods:

  • Treatment of human cancer cell lines with HDAC inhibitors (butyrate and SAHA).
  • Assessment of caspase-3 activation and apoptotic pathway involvement (using Apaf-1 knockout and Bcl-XL overexpression).
  • Morphological analysis to identify autophagic cell death features.

Main Results:

  • HDAC inhibitors induced caspase-3 activation via the mitochondria/cytochrome c pathway.
  • Apaf-1 knockout and Bcl-XL overexpression partially inhibited apoptosis but not overall cell death.
  • Cells exhibited morphological characteristics of autophagic cell death, independent of caspase activation.

Conclusions:

  • HDAC inhibitors can induce both apoptosis and caspase-independent autophagic cell death.
  • Autophagic cell death induction by HDAC inhibitors presents a promising therapeutic avenue for cancers with apoptotic defects.
  • These findings highlight the complex interplay of cell death pathways in response to HDAC inhibition.

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