Histone deacetylase inhibitors: apoptotic effects and clinical implications (Review).

Abstract

It has been shown that epigenetic modifications play an important role in tumorigenesis. Thus, affecting epigenetic tumorigenic alterations can represent a promising strategy for anticancer targeted therapy. Among the key chromatin modifying enzymes which influence gene expression, histone acetyltransferases (HATs) and histone deacetylases (HDACs) have recently attracted interest because of their impact on tumor development and progression. Increased expression of HDACs and disrupted activities of HATs have been found in several tumor types, with a consequent hypoacetylated state of chromatin that can be strictly correlated with low expression of either tumor suppressor or pro-apoptotic genes. Histone deacetylase inhibitors (HDACIs) represent a new and promising class of antitumor drugs that influence gene expression by enhancing acetylation of histones in specific chromatin domains. HDACIs have been shown to exert potent anticancer activities inducing cell cycle arrest and apoptosis. Notably, a high efficacy of these drugs has been selectively revealed in malignant cells rather than in normal cells. Moreover, the therapeutic potential of these agents is also supported by the evidence that HDACIs downregulate genes involved in tumor progression, invasion and angiogenesis. Several HDACIs are currently under clinical investigation, including vorinostat (SAHA), romidepsin (depsipeptide, FK-228), LAQ824/LBH589 and belinostat (PXD101), compounds that have shown therapeutic potential in many types of malignancies including solid tumors. Based on the ability of HDACIs to regulate many signaling pathways, co-treatment of these compounds with molecular targeted drugs is a promising strategy against many types of tumors.