Focus on deacetylation for therapeutic benefit

Preclinical studies have demonstrated that several genes silenced in cancer cells can be re-expressed in their fully functional state by epigenetic modifiers such as DNA methyltransferase inhibitors and histone deacetylase inhibitors (HDACIs). While gene reexpression may be a reason for the success of HDACIs in preclinical and clinical studies, it is not the only factor. HDACIs display pleiotropic effects, including inhibition of cell cycle progression, differentiation, apoptosis and anti-proliferative effects. In addition, many studies have indicated that combining HDACIs with other agents results in an enhanced anti-proliferative effect. Structure-activity relationship studies of HDACIs with their substrates, histone deacetylases, have enabled design and synthesis of improved HDACIs. Due to their activity and perceived low toxicity, HDACIs have gained popularity as agents for clinical investigation. This review focuses on the cellular and biological effects of HDACIs, either alone or in combination with other agents. A brief summary on completed and ongoing cancer clinical trials is provided.