trichostatin-a and Carcinoma--Ovarian-Epithelial

Histone deacetylase inhibitor-induced apoptosis in cancer cells may be mediated by the Ras/Raf/MEK/ERK and protein kinase B/Akt signaling pathways. However, inhibition of ERK and Akt activity has different effects on proliferation and apoptosis in cancer cells. We assessed and compared the inhibitory effects of Akt and ERK pathways on the apoptotic effect of trichostatin A using the human epithelial carcinoma cell lines OVCAR-3 and SK-OV-3. Trichostatin A induced nuclear damage, decrease in Bid and Bcl-2 protein levels, increase in Bax levels, cytochrome c release, activation of caspases (8, 9, and 3) and increase in tumor suppressor p53 levels. Akt inhibitor potentiated trichostatin A-induced apoptosis-related protein activation and cell death, whereas ERK inhibitor exhibited an additive toxic effect. These results suggest that the Akt and ERK inhibitors may have a differential effect on trichostatin A-induced apoptosis in human epithelial ovarian carcinoma cell lines. Akt inhibitor may potentiate the apoptotic effect of trichostatin A on ovarian carcinoma cell lines by increasing the activation of the caspase-8-dependent pathway and the mitochondria-mediated cell death pathway, leading to caspase activation. In contrast, ERK inhibitor may exhibit an additive toxic effect on trichostatin A toxicity by increasing apoptosis-related protein activation.

Topics: Apoptosis; bcl-2-Associated X Protein; BH3 Interacting Domain Death Agonist Protein; Blotting, Western; Carcinoma, Ovarian Epithelial; Caspase 8; Cell Line, Tumor; Cell Survival; Cytochromes c; Dose-Response Relationship, Drug; Drug Synergism; Enzyme Activation; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Inositol Phosphates; Microscopy, Fluorescence; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Tumor Suppressor Protein p53