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Histone deacetylase inhibitors require caspase activity to induce apoptosis in lung and prostate carcinoma cells

Jürgen Sonnemann1, Maite Hartwig, Andrea Plath

  • 1Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Ernst Moritz Arndt University, Greifswald, Germany.

Cancer Letters
|February 7, 2006
PubMed

Insights

Histone deacetylase inhibitors (HDIs) activate caspases to induce cancer cell death. Blocking caspases with z-VAD-fmk prevents HDI-driven apoptosis and reveals cell cycle arrest, clarifying HDI mechanisms.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Histone deacetylase inhibitors (HDIs) are investigated as antineoplastic agents.
  • The precise mechanism of action for HDIs, especially the role of caspases in apoptosis, remains controversial.

Purpose of the Study:

  • To investigate the role of caspases in HDI-induced apoptosis in carcinoma cells.
  • To elucidate the mechanism by which HDIs trigger cancer cell death.

Main Methods:

  • Treatment of A549 and PC-3 carcinoma cells with HDIs (suberoylanilide hydroxamic acid, sodium butyrate, trichostatin A).
  • Assessment of apoptosis via mitochondrial membrane potential and DNA fragmentation.
  • Inhibition of caspases using the poly-caspase inhibitor z-VAD-fmk.
  • Quantification of cell death using propidium iodide uptake.
  • Cell cycle analysis to evaluate cell cycle arrest.

Main Results:

  • HDIs activated caspase-3 in A549 and PC-3 cells.
  • z-VAD-fmk inhibited HDI-induced apoptosis, mitochondrial membrane potential loss, DNA fragmentation, and cell death.
  • Caspase inhibition unmasked a G2-M cell cycle arrest in response to HDIs.

Conclusions:

  • Activated caspases are required for HDIs to induce apoptosis in carcinoma cells.
  • HDIs trigger cancer cell death through a caspase-dependent pathway.
  • Caspase inhibition reveals an alternative HDI-induced cell cycle arrest mechanism.

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