Epigenetic drugs against cancer: an evolving landscape

Abstract

Alteration of the chromatin orchestra seems to play a critical role in cancer. In recent years, in-depth studies of epigenetic machinery and its deregulation have led to the development and use of a wide range of modulatory molecules directed not only at chromatin enzymes (histone acetyltransferases, histone deacetylases, histone methyltransferases, histone demethylases and DNA methyltransferases) but also toward the emerging class of chromatin-associated proteins, so-called "histone readers." Chromatin modifiers are attractive therapeutic targets for the development of new cancer therapies. Many are currently approved by the US Food and Drug Administration and used to treat different malignancies. Specifically, inhibitors of DNA methyltransferases, such as azacitidine and decitabine, have been approved for the treatment of myelodysplastic syndrome, while inhibitors of histone deacetylases, including vorinostat and romidepsin, have been approved for cutaneous T-cell lymphoma. The bromodomain and extra-terminal inhibitors JQ1, IBET762 and IBET151 have performed extremely well in preclinical settings, suggesting that they may be promising molecules for the treatment of some type of tumors. This review focuses on epidrugs and their possible application, with particular emphasis on their mechanism of action as well as their present status in clinical and preclinical trials.

A Succinate Ether Derivative of Tocotrienol Enhances Dickkopf-1 Gene Expression through Epigenetic Alterations in Malignant Mesothelioma Cells

“…The epigenetic factors are mainly represented by DNMT and HDAC activity. To date, drugs such as azacytidine (a DNMT inhibitor) and vorinostat (an HDAC inhibitor) have been approved by the FDA for treatment of epigenetics-related diseases [19]. However, in a recent clinical study, vorinostat therapy did not improve overall survival; therefore, it cannot be recommended as therapy for patients with advanced MM [20].…”

CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer

“…With recent findings in epigenetics research, it is now clear that DNA methylation and histone modification are reversible processes that can be targeted for therapeutic intervention using small-molecule inhibitors of the epigenetic writers (methyltransferases, acetyltransferases, kinases), readers (bromodomain-or chromodomain-containing genes), and erasers (demethylases, deacetylases, phosphatases) (28)(29)(30)(31). For example, the histone acetyl-lysine reader BRD4 can be targeted for inhibition using drugs that disrupt bromodomain binding to acetylated histones (32,33).…”

ARHGEF3 controls HDACi-induced differentiation via RhoA-dependent pathways in acute myeloid leukemias

“…The acetylation status of histones is dynamically controlled by competing activities of 2 enzymatic super-families: histone acetyltransferases (HATs) and histone deacetylases (HDACs). 4 HATs and HDACs acetylate and deacetylate both histone and non-histone proteins, such as TFs, cytoskeletal proteins, and molecular chaperones, which in turn control cell cycle progression, differentiation, and apoptosis. HAT and HDAC alterations are involved in several human diseases, as their imbalance causes dysregulation of proliferation and differentiation.…”