Histone deacetylation as a target for radiosensitization

Due to an increase in the understanding of molecular radiobiology, strategies for enhancing tumor radiosensitivity have begun to focus on targeting the molecules and processes that regulate cellular radioresponse. Toward this end, histone acetylation has begun to receive considerable attention as a potential target for radiosensitization. Histone acetylation, which is determined by the competing actions of histone acetylases (HATs) and histone deacetylases (HDACs), plays a role in regulating chromatin structure and gene expression--two parameters that have long been considered determinants of radioresponse. As a means of modifying histone acetylation status, considerable effort has been put into the development of inhibitors of HDAC activity, which is often aberrant in tumor cells. This has led to the generation of a relatively large number of structurally diverse compounds that inhibit HDAC activity and result in histone hyperacetylation, and importantly, are applicable to patient treatment. Whereas a number of these HDAC inhibitors have antitumor activity in preclinical cancer models when delivered as single agents, recent studies have indicated that these compounds also significantly enhance tumor cell radiosensitivity. A structurally diverse set of HDAC inhibitors have been shown to enhance the in vitro radiosensitivity of human tumor cell lines generated from a spectrum of solid tumors. Moreover, HDAC inhibitors increased the radiosensitivity of human tumor xenografts. Although the mechanism responsible for this radiosensitization has not been definitely elucidated, data suggest that inhibiting the repair of radiation-induced DNA damage may be involved. Whereas HDAC inhibitors are currently in clinical trials as single modalities and in combination with chemotherapeutic agents, recent results suggest that these compounds may also enhance the antitumor effectiveness of radiotherapy.