Histone deacetylase inhibitors: Understanding a new wave of anticancer agents

Abstract

Cancer is as much an epigenetic disease as it is a genetic and cytogenetic disease. The discovery that drastic changes in DNA methylation and histone modifications are commonly found in human tumors has inspired various laboratories and pharmaceutical companies to develop and study epigenetic drugs. One of the most promising groups of agents is the inhibitors of histone deacetylases (HDACs), which have different biochemical and biologic properties but have a single common activity: induction of acetylation in histones, the key proteins in nucleosome and chromatin structure. One of the main mechanisms of action of HDAC inhibitors is the transcriptional reactivation of dormant tumor-suppressor genes, such as p21 WAF1 . However, their pleiotropic nature leaves open the possibility that their wellknown differentiation, cell-cycle arrest and apoptotic properties are also involved in other functions associated with HDAC inhibition. Many phase I clinical trials indicate that HDAC inhibitors appear to be well-tolerated drugs. Thus, the field is ready for rigorous biologic and clinical scrutiny to validate the therapeutic potential of these drugs. Our current data indicate that the use of HDAC inhibitors, probably in association with classical chemotherapy drugs or in combination with DNA-demethylating agents, could be promising for cancer patients.

MUC2 expression is regulated by histone H3 modification and DNA methylation in pancreatic cancer

“…However, further analyses of all the histone termini (H2 to H4) are needed to confirm this hypothesis. 18,42 TSA has been reported to act synergistically with 5-aza to reactivate DNA methylation-silenced genes, [43][44][45][46] and Xiong et al have reported that histone deacetylase (HDAC) inhibitors decrease DNA methyltransferase-3B (DNMT3B) mRNA stability and down regulate de novo DNA methyltransferase. 47 To examine the relationship between histone modification and DNA methylation, we treated PANC1 cells with 5-aza and/or TSA.…”

Epigenetics provides a new generation of oncogenes and tumour-suppressor genes

“…Epigenetics can offer many new targets for this approach. However, only two types of epigenetic drugs, neither of which is very specific, have nowadays a real impact: DNA-demethylating agents and histone deacetylase inhibitors (HADCis) (Villar-Garea and Esteller, 2004;Esteller, 2005b). We have to be patient with other potential epigenetic drugs, such as histone acetyltransferase inhibitors, including anacardic acid, curcumin, and peptide CoA conjugates; in addition to undisclosed histone methyltransferase inhibitors or those HDACis that are specific for SIRT1 (class III HDAC), such as nicotinamide and splitomycin.…”

“…Overall, HDACis manifest a wide range of activities against all HDACs. These compounds can be classified into the following groups according to their chemical nature: hydroxamic acids, such as trichostatin A, SAHA, PXD101 and NVP-LAQ-824; carboxylic acids, such as sodium valproate and butyrate; benzamides, such as MS-272 and others, including trapoxins and FK228 (Villar-Garea and Esteller, 2004). It is believed that the anticancer effects of HDACis are mediated by the reactivation of the expression of tumour-suppressor genes.…”

Identification of (1H)-pyrroles as histone deacetylase inhibitors with antitumoral activity

“…These active sites consist of a zinc (II) cation surrounded by three coordinating residuestwo aspartates and one histidine. Finally, there are other channels in AA-HDAC, the function of which is thought to be associated with the exit of the hydrolysis by product, namely, the acetate anion (Wang et al, 2004) (Figure 1a).The currently reported HDAC inhibitors, such as SAHA or TSA, share the following common features (Villar-Garea and Esteller, 2004) (Figure 1b): (i) a zinc-chelating group, for example, hydroxamic acid; (ii) a linear hydrophobic chain that mimics the 1,4-butylene alkyl chain of the lysine residue present in the natural substrates of HDACs and (iii) a filling cap, usually an aromatic or heteroaromatic ring that fills the entrance to the hydrophobic channel. On the basis of our structural analysis of class-I human HDACs, we concluded that there are at least three possible interaction modes that could improve the binding of the inhibitors (Figure 1c): (i) An acidic residue at the edge of the hydrophobic channel, consisting of an aspartate residue; (ii) several shallow cavities surrounding the entrance to the channel, made up of hydrophobic and aromatic residues and (iii) basic groups close to this entrance, consisting of lysine, arginine or histidine residues, depending on the class-I HDAC under consideration.…”

“…Quantification of histone acetylation by high-performance capillary electrophoresis (HPCE) upon 6h and 6l treatment also confirmed the induction of histone hyperacetylation (Supplementary Figure 1). From a gene-base standpoint, both 6h and 6l were able to induce the expression of p21 WAF1/CIP1 and gelsolin (Figure 3c), two of the best-characterized target genes upregulated by HDAC inhibitors in cancer cell lines (Villar-Garea and Esteller, 2004;Marks, 2007).…”