Histone deacetylation : an attractive target for cancer therapy?

Abstract

Recent research has elucidated another mechanism for gene expression and signalling protein regulation in malignant cells. Histone deacetylases (HDACs) have been associated with silencing of tumour suppressor genes, and with other functions that promote malignant cell phenotype, such as the function of the chaperone protein heat shock protein (HSP)-90. Malignant cells overexpress some HDACs, and aberrant gene products have been shown to recruit HDACs to DNA to accomplish silencing of differentiation in other genes. Several chemical classes of small molecule inhibitors of HDAC have been synthesized, including small chain fatty acids, benzamides, hydroxamic acids and hybrid molecules. All have shown preclinical activity in vitro and/or in vivo in nanomolar to micromolar concentrations. Some have shown activity in clinical trials. One (vorinostat; suberoylanalide hydroxamic acid [SAHA]) has been approved by the US FDA for therapy of T-cell lymphomas. HDAC inhibitors show the most promising activity as single agents in haematological malignancies rather than solid tumours. Clinical trials testing combinations of HDAC inhibitors with other antineoplastic agents and with demethylating agents have shown promising results. HDAC inhibitors also seem to enhance radiation effects on malignant tissue, while potentially sparing toxicity to normal tissues. In this article, we review the rationale for development of HDAC inhibitors as therapy for malignant diseases, as well as the preclinical and clinical trial data for some HDAC inhibitors under development.