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1From the William H. Havener Eye Center and the 3Department of Internal Medicine, Division of Hematology and Oncology, and the 4Department of Molecular and Cellular Biochemistry, The Ohio State University, Columbus, Ohio; and the 2Wexner Institute for Pediatric Research, Children’s Hospital, Columbus, Ohio.
PURPOSE. Uveal melanoma (UM) is the most common primary malignant ocular tumor in adults. No effective chemotherapy regimens are available for either intraocular or metastatic uveal melanoma. Therefore, the ability of the histone deacetylase inhibitors (HDACIs), depsipeptide, sodium butyrate (NaB) and trichostatin A (TSA), to induce apoptosis and inhibit cell growth of UM cell lines in vitro was examined.
METHODS. Three primary and two metastatic UM cell lines were treated in vitro with different concentrations of histone deacetylase inhibitors (HDACIs). Cell proliferation was studied in 24-well plates. Induction of apoptosis was studied by flow cytometry. Changes in gene expression of Fas/FasL, p21Waf/Cip1, and p27Kip1 were studied by RT-PCR. Western blot analysis was used to study histone acetylation, Fas/FasL, p21Waf/Cip1, p27Kip1 and caspase-3 protein levels. Real-time PCR was used to study changes in bcl-2/bax gene expression.
RESULTS. A dose-dependent increase in histone acetylation was observed in all cell lines. This corresponded to significant inhibition of cell growth and induction of apoptosis in all melanoma cell lines in a concentration-dependent manner. Western blot analysis revealed dose-dependent increases in the amount of caspase-3, Fas/FasL, p21Waf/Cip1, and p27Kip1 proteins. However, no changes in bcl-2/bax gene expression were detected by real-time PCR.
CONCLUSIONS. HDACIs are potent inhibitors of primary and metastatic UM cell growth in vitro. The apoptosis is probably mediated through the Fas/FasL signaling pathway, whereas bcl-2 appears not to be involved. These data support further clinical evaluation of depsipeptide and other HDACIs in patients with primary and metastatic UM.
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