Investigation of the molecular mechanisms of action of L-sulforaphane, a potent dietary chromatin modifying compound

Histone deacetylase inhibitors are emerging as a new class of cancer chemotherapeutics. The anti-cancer effects of conventional HDAC inhibitors such as Trichostatin A, Vorinostat and valproic acid, which include inducing differentiation, cell cycle arrest, apoptosis, growth inhibition and cell death, are more pronounced in transformed cell-lines than in normal cells. These inhibitors have been relatively well investigated. However, they are thought to have low isoform-selectivities, which limit their therapeutic options. Therefore, highly specific, potent HDAC inhibitors with reduced toxicity as anti-cancer drugs are in growing need. Recently, numerous HDAC inhibitors found in the human diet have been identified. For example, L-sulforaphane (LSF), a natural compound derived from cruciferous vegetables, with anti-inflammatory effect and antioxidant property, has also exhibited HDAC inhibitory property in recent studies. In the present study, it has been hypothesised that dietary and conventional HDAC inhibitors will have analogous effects in model systems of diseases like cancers. In silico approaches were used as a complementary method to in vitro experiments to examine the specific inhibition of a range of HDAC isoforms by LSF. In particular we sought to identify the potential ability of LSF to selectively inhibit HDAC8. The mechanisms of inhibition, as well as the impact of LSF binding via both non-covalent and covalent interactions on HDAC8 structure were also investigated using in silico approaches.