Histone-deacetylase inhibitors: novel drugs for the treatment of cancer

Abstract

Alteration of chromatin architecture by means of post-translational modifications of histone tails is an important process for the regulation of gene expression. The coordinated actions of histone-tail acetylation, methylation and phosphorylation, and ATP-dependent chromatin remodelling, allow fine control of gene activation or repression. Histone acetylation and deacetylation is regulated by the opposing activities of histone acetyltransferases (HATs) and histone deacetylatransferases (HDACs). In cancer, the molecular processes that lead to inappropriate expression of genes due to altered chromatin structure are now being identified, and aberrant acetylation of histone tails is strongly linked to carcinogenesis. So, targeting the transcriptional lesions that lead to neoplasia provides an opportunity for therapeutic intervention at the very apex of the transformation process. Such therapies could affect several molecular programmes, and would therefore be more powerful than targeting the end stages of a single disrupted molecular pathway. HDAC inhibitors are an exciting new class of chemotherapeutic drugs. These agents interact with the catalytic site of HDACs, block substrate access and allow hyperacetylation of histone tails. The anticancer potential of HDAC inhibitors stems from their ability to affect several cellular processes that are dysregulated in neoplastic cells. Principally, activation of differentiation programmes, inhibition of the cell cycle and induction of apoptosis are the key antitumour activities of HDAC inhibitors. In addition, activation of the host immune response and inhibition of angiogenesis might also have important roles in HDAC-inhibitor-mediated tumour regression in vivo. Much interest and excitement has been generated following the success of HDAC inhibitors in potently inhibiting tumour progression in rodent models. HDAC inhibitors can mediate histone acetylation in vivo, induce tumour-cell differentiation or apoptosis depending on the cell type, and are associated with minimal toxicity as assessed by weight loss and post-mortem analyses. Given the success of HDAC inhibitors in preclinical studies, Phase I and II clinical trials using several different inhibitors have now been initiated. These drugs seem to be well tolerated at the doses required to hyperacetylate histones and achieve clinical outcomes, and their use in combination therapies is an area that can be further exploited in the clinic.