Histone deacetylase inhibitors in cancer therapy. A review

Abstract

a Background. Despite recent success toward discovery of more effective anticancer drugs, chemoresistance remains a major cause of treatment failure. There is emerging evidence that epigenetics plays a key role in the development of the resistance. Epigenetic regulators such as histone acetyltransferases (HATs) and histone deacetylases (HDACs) play an important role in gene expression. The latter are found to be commonly linked with many types of cancers and influence cancer development. Overall, histone acetylation is being investigated as a therapeutic target because of its importance in regulating gene expression. This review summarizes mechanisms of the anticancer effects of histone deacetylase (HDAC) inhibitors and the results of clinical studies. Results. Different HDAC inhibitors induce cancer cell death by different mechanisms that include changes in gene expression and alteration of both histone and non-histone proteins. Enhanced histone acetylation in tumors results in modification of expression of genes involved in cell signaling. Inhibition of HDACs causes changed expression in 2-10 % of genes involved in important biological processes. The results of experiments and clinical studies demonstrate that combination of HDAC inhibitors with some anticancer drugs have synergistic or additive effects. Conclusions. Even though many biological effects of HDAC inhibitors have been found, most of the mechanisms of their action remain unclear. In addition, their use in combination with other drugs and the combination regime need to be investigated. The discovery of predictive factors is also necessary. Finally, a key question is whether the pan-HDAC inhibitors or the selective inhibitors will be more efficient for different types of cancers.

Histone deacetylase inhibition enhances the lymphomacidal activity of the anti-CD22 monoclonal antibody HB22.7

“…A substantial amount of research now indicates a role for http://dx.doi.org/10.1016/j.leukres.2014.08.014 0145-2126/Published by Elsevier Ltd. deregulated epigenetic mechanisms in cancer, both in the development of tumors and their acquisition of chemoresistance [14][15][16][17]. As a result, chromatin-modifying enzymes such as histone methyltransferases and demethylases [14], histone acetyltransferases (HAT), and histone deacetylases (HDAC) [15][16][17] are promising therapeutic targets. Histone deacetylases catalyze the removal of negatively charged acetyl groups from lysine residues in the core histones, which results in a more compact and transcriptionally repressed chromatin structure.…”

Methamphetamine promotes α-tubulin deacetylation in endothelial cells: The protective role of acetyl-l-carnitine

“…In addition to hyperacetylation of the respective substrates, HDACs inhibition is also known to lead to increased histone acetylation and consequent chromatin remodeling (Li et al, 2013;Xu et al, 2007). Under TSA treatment, chromatin relaxation is known to increase the expression of CDKN1A (cyclin-dependent kinases inhibitor, or p21) gene (Blagosklonny et al, 2002;Hrabeta et al, 2014;Ocker and Schneider-Stock, 2007;Xu et al, 2007). As such, CDKN1A (p21) expression is frequently used as a marker of HDAC inhibition (Harrison and Dexter, 2013;Huang et al, 2012;Xu et al, 2007).…”

“…Of note, it was recently shown that interfering with HDAC6 is sufficient to prevent microtubule deacetylation (Gold et al, 2015). There is growing evidence that HDACs inhibition is strongly associated with decreased cell mobility, which is of particular interest in the oncology field (Hrabeta et al, 2014;Ocker and Schneider-Stock, 2007). Although there are several studies showing that METH and other psychostimulants affect the expression of HDACs (Cassel et al, 2006;Host et al, 2011;Martin et al, 2012;Omonijo et al, 2014), and in particular the expression of HDAC6 (Omonijo et al, 2014), the effect of METH in microtubules acetylation was not yet explored.…”

Histone deacetylases: structural determinants of inhibitor selectivity

“…In cell-based studies, HDACIs have been shown to induce cell cycle arrest, cell differentiation, and apoptosis. Furthermore, HDACIs were reported to intensify the host immune response and decrease angiogenesis [20][21][22][23][24]. For these reasons, several HDACIs are currently at various stages of clinical trials, individually or in combination with radiotherapy and/or chemotherapy for cancer treatment in patients with hematological and solid malignancies [25].…”