Histone deacetylase inhibitors require caspase activity to induce apoptosis in lung and prostate carcinoma cells.
Histone deacetylase inhibitors (HDIs) are a promising new class of antineoplastic agents with the capacity to induce growth arrest and/or apoptosis of cancer cells. However, their precise mechanism of action is uncertain; particularly, the role of caspases in the apoptotic response to HDIs is controversial. Here, we show that the HDIs explored, suberoylanilide hydroxamic acid, sodium butyrate and trichostatin A, activated caspase-3 in A549 and PC-3 carcinoma cells. Additionally, the poly-caspase inhibitor z-VAD-fmk prevented HDI-induced apoptosis, as judged by determining mitochondrial membrane potential and by quantifying internucleosomal DNA fragmentation. Importantly, z-VAD-fmk also significantly inhibited HDI-elicited cell death, as assessed by measuring propidium iodide uptake. As an accessory finding, with the inhibition of caspases, a HDI-induced G2-M arrest became evident. Taken together, these results provide evidence that HDIs require activated caspases to induce apoptosis of carcinoma cells.
Sonnemann
Jürgen
J
Peter Holtz Research Center of Pharmacology and Experimental Therapeutics, Ernst Moritz Arndt University, Greifswald, Germany.
Hartwig
Maite
M
Plath
Andrea
A
Saravana Kumar
K
K
Müller
Cornelia
C
Beck
James F
JF
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000502:physiology*; D045744:Cell Line, Tumor; D053938:DNA Fragmentation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology
D000590:Amino Acid Chloromethyl Ketones; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D020169:Caspases