Histone-deacetylase inhibitors produce positive results in the GADD45a-GFP GreenScreen HC assay

Histone-deacetylase inhibitors (HDACi) are able to induce cell-cycle arrest, apoptosis and differentiation in a variety of tumour cell lines. The mechanisms leading to these cellular outcomes are not fully understood, however, it is has been proposed that induction of cell-cycle arrest might be a result of genotoxic stress. Despite the potential for genotoxic activity of this class of compounds, there are very few data available to provide evidence for this, either in vitro or in vivo. In this study, four HDACi, viz. trichostatin A, sodium butyrate, APHA compound 8 and apicidin, were tested in the human lymphoblastoid TK6 cell line-hosted GADD45a-GFP assay, which has high sensitivity and specificity in the detection of genotoxic carcinogens and in vivo genotoxicants. All four compounds produced positive genotoxicity results within the acceptable toxic dose range of the assay, with APHA compound 8 producing the weakest response. Taken alongside recent evidence demonstrating that GADD45a is not induced by non-genotoxic apoptogens, this study suggests that genotoxicity contributes to the anti-tumour activity of HDACi drugs.