Sodium butyrate enhances the antiproliferative action of low actinomycin D concentrations

Resumo

Histone deacetylase inhibitors (HDIs) cause an irreversible cell cycle arrest in G₁ phase and senescence of E1A + Ras transformed fibroblasts. The modulation of the antiproliferative action of the RNA synthesis inhibitor actinomycin D (AMD) with sodium butyrate (NaBut) has been studied. It is shown that NaBut enhances the cytotoxic effect of low AMD concentrations (<8 nM). However, at high concentrations of AMD, NaBut increases E1A + Ras cell viability insignificantly. At low concentrations of AMD, NaBut dramatically reduces the clonogenic ability of transformed cells and increases their death. The study of the mechanisms of cell death induced by combined action of low AMD concentrations and NaBut showed that combined exposure led to activation of the p53 proapoptotic transcription factor and suppression of the NF-κΒ antiapoptotic factor activity. Thus, NaBut enhances the cytotoxic effect of low AMD concentrations on oncogene-transformed cells, enhancing their apoptotic death. These results can be used in the selection of the optimal combination of AMD and HDIs in combination therapy of tumors.