Sensitization of tumor cells by targeting histone deacetylases

Epigenetic mechanisms may contribute to drug resistance by interfering with tumor growth regulatory pathways and pro-apoptotic programs. Since gene expression is regulated by acetylation status of histones, a large variety of histone deacetylase (HDAC) inhibitors have been studied as antitumor agents. On the basis of their pro-apoptotic activity, HDAC inhibitors have been combined with conventional antitumor agents or novel target-specific agents to increase susceptibility to apoptosis and drug sensitivity of cancer cells. Several combination strategies including HDAC inhibitors have been explored in preclinical studies. Promising therapeutic effects have been reported in combination with DNA damaging agents, taxanes, targeted agents, death receptor agonists and hormonal therapies. Some histone deacetylases, such as HDAC6, can also modulate the function of non-histone proteins involved in critical regulatory processes which may be relevant as therapeutic targets. Given the pleiotropic effects of most of the available inhibitors, the mechanisms of the sensitization are not completely elucidated. A better understanding of the involved mechanisms will provide a rational basis to improve the therapeutic outcome of the available antitumor agents. (C) 2011 Elsevier Inc. All rights reserved.