Sodium phenylbutyrate induces apoptosis in human retinoblastoma Y79 cells:The effect of combined treatment with the topoisomerase I-inhibitor topotecan

Our results demonstrate that sodium phenylbutyrate, a compound with a low d egree of toxicity, exerted a cytotoxic effect on human retinoblastoma Y79 c ells in a time- and dose-dependent manner. Treatment of Y79 cells for 72 h with phenylbutyrate reduced cell viability by 63% at 2 mM and 90% at 4 mM. Cell death caused by phenylbutyrate exhibited the typical features of apopt osis, as shown by light and fluorescent microscopy. Western blot analysis d emonstrated that exposure of Y79 cells to phenylbutyrate decreased the leve l of the antiapoptotic factor Bcl-2 and induced the activation of caspase-3 , a key enzyme in the execution phase of apoptosis. Moreover, treatment wit h phenylbutyrate markedly increased the level of acetylated histone-H3. Com bined treatment with phenylbutyrate and topotecan, a topoisomerase I-inhibi tor, resulted in a clear synergistic effect. We suggest that the effects ex erted by phenylbutyrate on Y79 cells essentially depend on modifications of gene expression consequent to histone, hyperacetylation.