Histone deacetylase inhibitors differentially mediate apoptosis in prostate cancer cells.
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.
Frønsdal
Katrine
K
Department of Molecular Biosciences, University of Oslo, Oslo, Norway.
Saatcioglu
Fahri
F
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002087:Butyrates / Q000494:pharmacology; D045744:Cell Line, Tumor; D047630:Depsipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry; D008297:Male; D008856:Microscopy, Fluorescence; D008858:Microscopy, Phase-Contrast; D011064:Poly Adenosine Diphosphate Ribose / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D014343:Trypan Blue / Q000737:chemistry
D002087:Butyrates; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D011064:Poly Adenosine Diphosphate Ribose; C012589:trichostatin A; C007293:DAPI; D006655:Histone Deacetylases; D014343:Trypan Blue