Prospects: Histone deacetylase inhibitors

Abstract

Histone deacetylase (HDAC), inhibitors represent a new class of targeted anti-cancer agents. Several of these compounds are in clinical trials with significant activity against a spectrum of both hematologic and solid tumors at doses that are well tolerated by the patients. The HDAC inhibitors are a structurally diverse group of molecules that can induce growth arrest, differentiation, apoptosis, and autophagocytic cell death of cancer cells. While the base sequence of DNA provides the genetic code for proteins, the expression of genes is regulated, in large part, by the structure of the chromatin proteins around which the DNA is wrapped (epigenetic gene regulation). The acetylation and deacetylation of the lysines in the tails of the core histones, among the most extensively studied aspects of chromatin structure, is controlled by the action of two families of enzymes, histone deacetylases (HDACs) and histone acetyltransferases (HATs). Protein components of transcription factor complexes and many other non-histone proteins are also substrates for HDACs and HATs. The structure and activity of these non-histone proteins may be altered by acetylation/deacetylation with consequent effects on various cell functions including gene expression, cell cycle progression, and cell death pathways. This review focuses on several key questions with respect to the mechanism of action of HDACi, including, what are the different cell phenotypes induced by HDACi, why are normal cells compared to transformed cells relatively resistant to HDACi induced cell death, why are certain tumors more responsive to HDACi than others, and what is the basis of the selectivity of HDACi in altering gene expression. The answers to these questions will have therapeutic importance since we will identify targets for enhancing the efficacy and safety of HDACi.

DNA demethylation and histone deacetylation inhibition co‐operate to re‐express estrogen receptor beta and induce apoptosis in prostate cancer cell‐lines

“…Although a number of HDAC inhibitors have shown promising antitumour activity in animal models of prostate cancer (36,43,44), as yet there are no published clinical trials in humans. A number of phase I trials have however reported good clinical efficacy and a favourable side-effect profile for HDAC inhibitors in a range of other solid and haematological malignancies (45). It is thus tempting to speculate that combination therapy with HDAC and DNMT inhibitors may improve response rates in prostate cancer over that seen with DNMT inhibitors alone.…”

Modulation of cellular radiation responses by histone deacetylase inhibitors

“…It is evident that the anticancer effects of HDAC inhibitors are caused in part by the accumulation of acetylated histones that results in the altered transcription of a finite number of genes (Jenuwein and Allis, 2001;Zhang and Reinberg, 2001;Butler et al, 2002;Spotswood and Turner, 2002;Marks et al, 2004). Alternatively, HDAC inhibitors alter gene transcription by modulating the acetylation status of transcription regulating proteins, such as NK-kB, GATA1, E2F-1 and MyoD or components of the transcriptional machinery (Kouzarides, 2000;Lagger et al, 2002;Dokmanovic and Marks, 2005). The net result is the activation and repression of specific genes resulting in antiproliferative or proapoptotic effects.…”

Histone deacetylase 7, a potential target for the antifibrotic treatment of systemic sclerosis

“…HDAC inhibitors alter the balance of acetylation and affect many aspects of cellular function, including cell growth, differentiation, cell death, cell-cell and cell-matrix interactions, and inflammatory responses (10). One of the first discovered HDAC inhibitors with antitumor activity was trichostatin A (TSA).…”