Histone deacetylase inhibitors: clinical implications for hematological malignancies

Abstract

Histone modifications have widely been implicated in cancer development and progression and are potentially reversible by drug treatments. The N-terminal tails of each histone extend outward through the DNA strand containing amino acid residues modified by posttranslational acetylation, methylation, and phosphorylation. These modifications change the secondary structure of the histone protein tails in relation to the DNA strands, increasing the distance between DNA and histones, and thus allowing accessibility of transcription factors to gene promoter regions. A large number of HDAC inhibitors have been synthesized in the last few years, most being effective in vitro, inducing cancer cells differentiation or cell death. The majority of the inhibitors are in clinical trials, unlike the suberoylanilide hydroxamic acid, a pan-HDACi, and Romidepsin (FK 228), a class I-selective HDACi, which are only approved in the second line treatment of refractory, persistent or relapsed cutaneous T-cell lymphoma, and active in approximately 150 clinical trials, in monotherapy or in association. Preclinical studies investigated the use of these drugs in clinical practice, as single agents and in combination with chemotherapy, hypomethylating agents, proteasome inhibitors, and MTOR inhibitors, showing a significant effect mostly in hematological malignancies. The aim of this review is to focus on the biological features of these drugs, analyzing the possible mechanism(s) of action and outline an overview on the current use in the clinical practice.

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

“…Although reversible acetylation is the best-studied example of posttranslational modification of histone proteins, a plethora of other chemical signatures may be deposited at their N-terminal tails, evoking either transcriptional activation or suppression (Yang et al 2007; Tambaro et al 2010). All known histone phosphorylation events are associated with transcriptional activation.…”

Histone deacetylases (HDAC) in physiological and pathological bone remodelling

“…Modulation of these enzymes using HDAC inhibitors (HDACi) is emerging as a promising treatment not only for cancer [1][2][3] but also for neurodegenerative diseases, asthma, rheumatoid arthritis, viral infections and malaria [4][5][6][7][8][9][10][11]. A number of HDACi have progressed to the clinic, or are in clinical trials, for treating solid and haematological tumours [1][2][3]. These include vorinostat (SAHA) and romidepsin (Istodax), both The vast majority of HDACi are 'pan' inhibitors, targeting multiple HDACs in both class I and II.…”

Histone deacetylase inhibition in the treatment of acute myeloid leukemia: the effects of valproic acid on leukemic cells, and the clinical and experimental evidence for combining valproic acid with other antileukemic agents

“…Except for VPA, several other HDAC inhibitors have been developed, as described in a recent review article [14], and used in clinical studies [68,69]. In 2007, vorinostat was the first HDAC inhibitor to be approved as treatment for the malignant disease primary cutaneous T cell lymphoma.…”