Histone deacetylase inhibitors differentially mediate apoptosis in prostate cancer cells

Prostate. 2005 Feb 15;62(3):299-306. doi: 10.1002/pros.20140.

Abstract

Background: Histone deacetylase (HDAC) inhibitors have shown significant anti-proliferative and apoptotic properties on various cancer cells, including prostate cancer, and are therefore being evaluated as treatment modalities. However, the specific effect of HDAC inhibitors on androgen-sensitive and androgen-independent cell lines have not been thoroughly studied which we hypothesized could be different. We therefore assessed whether three structurally unrelated HDAC inhibitors, trichostatin A (TSA), depsipeptide (FR901228), and sodium butyrate, affect cell death in the prostate cancer cell lines LNCaP, DU-145, and PC-3.

Methods: To investigate the extent and the nature of cell death, we used Trypan blue exclusion assay, phase-contrast light microscopy, fluorescence microscopy, and Western blot analyses.

Results: At concentrations where they potentiate transcriptional activation, all three HDAC inhibitors induced cell death in LNCaP and DU-145 cells, but not in PC-3 cells, within the timeline of the experiments. HDAC inhibitor-induced cell death in LNCaP and DU-145 cells showed several characteristic apoptotic features, such as cell shrinkage, nuclear condensation, and poly(ADP) ribose polymerase cleavage. However, there were differences in the way LNCaP and DU-145 cells responded to treatment with various HDAC inhibitors. For example, whereas TSA and FR901228 were more effective in inducing apoptosis in LNCaP cells compared with DU-145 cells, the reverse was true for sodium butyrate. Moreover, within the same cell line, TSA, FR901228, and sodium butyrate exhibited different potencies for induction of apoptosis.

Conclusions: Collectively, these results suggest that the response of prostate cancer cells to HDAC inhibitors is not uniform, but cell line and inhibitor specific. Given that prostate cancer is generally a multiclonal disease representing different cell lineages, it is important to develop HDAC inhibitors that will be effective against all of these cell types.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Blotting, Western
  • Butyrates / pharmacology
  • Cell Line, Tumor
  • Depsipeptides / pharmacology
  • Enzyme Inhibitors / pharmacology*
  • Histone Deacetylase Inhibitors*
  • Histone Deacetylases / metabolism
  • Humans
  • Hydroxamic Acids / pharmacology
  • Indoles / chemistry
  • Male
  • Microscopy, Fluorescence
  • Microscopy, Phase-Contrast
  • Poly Adenosine Diphosphate Ribose / metabolism
  • Prostatic Neoplasms / drug therapy*
  • Prostatic Neoplasms / enzymology
  • Prostatic Neoplasms / pathology
  • Trypan Blue / chemistry

Substances

  • Butyrates
  • Depsipeptides
  • Enzyme Inhibitors
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Indoles
  • Poly Adenosine Diphosphate Ribose
  • trichostatin A
  • DAPI
  • Histone Deacetylases
  • Trypan Blue