Pharmacological Research 62 (2010) 18–34 Contents lists available at ScienceDirect Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs Review Histone deacetylases and epigenetic therapies of hematological malignancies Ciro Mercurio a,b , Saverio Minucci b,c,∗ , Pier Giuseppe Pelicci b,c a DAC-Genextra Group, Via Adamello 16, 20100 Milan, Italy b IFOM-IEO-Campus, Via Adamello 16, 20100 Milan, Italy c University of Milan, Via Festa del Perdono 7, 20100 Milan, Italy article info Article history: Received 29 January 2010 Accepted 22 February 2010 Keywords: HDACi Epigenetic therapy Chromatin Leukemia Lymphoma Acute myeloid leukemia abstract Histone deacetylase inhibitors (HDACi) represent a novel class of targeted drugs which alter the acety- lation status of several cellular proteins. These agents, modulating both chromatin structure through histone acetylation, and the activity of several non-histone substrates, are at the same time able to deter- mine changes in gene transcription and to induce a plethora of biological effects ranging from cell death induction, to differentiation, angiogenesis inhibition or modulation of immune responses. The impressive anticancer activity observed in both in vitro and in vivo cancer models, together with their preferential effect on cancer cells, have led to a huge effort into the identification and development of HDACi with different characteristics. To date, several clinical trials of HDACi conducted in solid tumors and hematological malignancies have shown a preferential clinical efficacy of these drugs in hematological malignancies, and in particular in cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), Hodgkin lymphoma (HL) and myeloid malignancies. Several agents are also beginning to be tested in combination therapies, either as chemo sensitizing agents in association with standard chemotherapy drugs or in combination with DNA methyltransferase inhibitors (DNMTi) in the context of the so-called “epigenetic therapies”, aimed to revert epigenetic alterations found in cancer cells. Herein, we will review HDACi data in hematological malignancies ques- tioning the molecular basis of observed clinical responses, and highlighting some of the concerns raised on the use of these drugs for cancer therapy. © 2010 Elsevier Ltd. All rights reserved. Contents 1. Introduction .......................................................................................................................................... 19 2. HDACs and their biological role ...................................................................................................................... 19 2.1. HDACs and their biological role .............................................................................................................. 19 2.2. Aberrant expression and activity of HDACs in hematological malignancies ................................................................ 20 2.3. Rationale for the use of HDAC inhibitors in hematological malignancies ................................................................... 22 3. HDAC inhibitors and their clinical use in hematological malignancies ............................................................................. 23 3.1. HDAC inhibitors and their clinical use in hematological malignancies ..................................................................... 23 3.2. Mechanisms of action of HDACi .............................................................................................................. 23 4. Clinical experiences with HDACi in hematological malignancies ................................................................................... 25 4.1. Vorinostat (SAHA) ............................................................................................................................ 25 4.2. Belinostat (PXD101) .......................................................................................................................... 26 4.3. Panobinostat (LBH589) ....................................................................................................................... 26 4.4. Givinostat (ITF2375) .......................................................................................................................... 27 4.5. Mocetinostat (MGCD0103) ................................................................................................................... 27 4.6. Entinostat (MS275-SNDX275) ................................................................................................................ 27 4.7. Romidepsin (Depsipeptide) .................................................................................................................. 28 ∗ Corresponding author at: IFOM-IEO-Campus, Via Adamello 16, 20100 Milan, Italy. E-mail address: saverio.minucci@ifom-ieo-campus.it (S. Minucci). 1043-6618/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2010.02.010