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.

• Authors: Francesco Paolo Tambaro, Carmela Dell'aversana, Vincenzo Carafa, Angela Nebbioso, Branka Radic, Felicetto Ferrara, Lucia Altucci
• Journal: Clinical epigenetics (Clin Epigenetics) Vol. 1 Issue 1-2 Pg. 25-44 (Sep 2010) ISSN: 1868-7083 [Electronic] Germany
• PMID: 22704087 (Publication Type: Journal Article)