Review Chromatin-modifying agents in anti-cancer therapy Carole Seidel 1 , Cristina Florean 1 , Michael Schnekenburger, Mario Dicato, Marc Diederich * Laboratoire de Biologie Moléculaire et Cellulaire de Cancer, Hôpital Kirchberg, 9, rue Edward Steichen, L-2540 Luxembourg, Luxembourg article info Article history: Received 13 February 2012 Accepted 14 May 2012 Available online 22 May 2012 Keywords: Epigenetic inhibitors HDAC DNMT Anti-cancer therapy Clinical trials Combinatory treatments abstract Epigenetic alterations are involved in every step of carcinogenesis. The development of chromatin- modifying agents (CMAs) has provided the ability to fight cancer by reversing these alterations. Currently, four CMAs have been approved for cancer treatment; two DNA demethylating agents and two deacetylase inhibitors. A number of promising CMAs are undergoing clinical trials in several cancer types. Moreover, already approved CMAs are still under clinical investigation to improve their efficacy and to extend their use to a broader panel of cancers. Combinatorial treatments with CMAs are already considered a promising strategy to improve clinical benefits and to limit side effects. The real mecha- nisms by which these CMAs allow the improvement and remission of patients are still obscure. A deeper analysis of the molecular features expressed by responding patients should be performed to reveal this information. In this review, we focus on clinical trials with CMAs, discussing the success and the pitfalls of this new class of anti-cancer drugs. Ó 2012 Elsevier Masson SAS. All rights reserved. 1. Introduction Epigenetics (literally meaning “what stands above genetics”) refers to all the changes in gene expression independent of DNA sequence alterations. DNA methylation, histone modification and small RNA-mediated gene silencing are considered the three main epigenetic mechanisms [1]. These mechanisms work synergisti- cally to regulate the chromatin structure and to establish the precise pattern of gene expression required for normal physiolog- ical cell functions and a wide variety of biological processes. In particular, DNA methylation and histone modification regulate the access of the transcription machinery to their target genes, modulating transitions from euchromatin to heterochromatin and vice versa [2]. Together with genetic alterations, aberrant epigenetic modifi- cations are responsible for the development of many diseases, including cancer [3e5]. Unlike mutations and other structural alterations of DNA, epigenetic modifications can be reversed. This important feature explains the increasing interest of scientists in a better understanding of the epigenetic mechanisms and the increasing role of research in the development of new drugs able to restore normal epigenetic gene regulation. Currently, only a few chromatin-modifying agents (CMAs) have been approved for clin- ical use, and relatively few other molecules are undergoing clinical trials. The preclinical development of more new compounds provides the hope for a larger panel of therapeutic CMAs in the future. In this review, we will describe the currently known CMAs, with a special focus on clinical trials of these drugs either alone or in combination, and discuss the alternative strategies of epigenetic modulation for anti-cancer therapeutic purposes. 2. DNA demethylation as an anti-cancer strategy DNA methylation was discovered decades ago as a covalent DNA modification that was clearly implicated in many physiological mechanisms. DNA methylation, together with specific histone residue modifications, is a mark typical of heterochromatin. The methylation of gene promoters results in the transcriptional silencing of the targeted genes. Repetitive DNA regions and mobile sequences (i.e., retrotransposons) are also subject to methylation; this prevents retrotransposon activation and promotes chromo- somal stability, acting as a guardian of the genome. Altogether, DNA methylation is implicated in tissue-specific gene transcription both during development and in adult life as well as in female X-chro- mosome inactivation, parental imprinting and the maintenance of genomic stability [6]. Abbreviations: AML, acute myeloid leukemia; AZA, 5-azacytidine; CMA, chro- matin-modifying agent; CML, chronic myeloid leukemia; CMML, chronic myelo- monocytic leukemia; CTCL, cutaneous T-cell lymphoma; DAC, 2 0 -deoxy-5- azacytidine; DHAC, 5,6-dihydro-5-azacytidine; DHDAC, 2 0 -deoxy-5,6-di-hydro-5- azacytidine; DNMTi, DNMT inhibitor; FDA, Food and Drug Administration; HDACi, HDAC inhibitor; MDS, myelodysplastic syndrome; TSG, tumor suppressor gene; VPA, valproic acid. * Corresponding author. Tel.: þ352 24684040; fax: þ352 2468 4060. E-mail address: marc.diederich@lbmcc.lu (M. Diederich). 1 These authors contributed equally to this work. Contents lists available at SciVerse ScienceDirect Biochimie journal homepage: www.elsevier.com/locate/biochi 0300-9084/$ e see front matter Ó 2012 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.biochi.2012.05.012 Biochimie 94 (2012) 2264e2279