Histone Deacetylase Inhibitors: Recent Insights from Basic to Clinical Knowledge & Patenting of Anti-Cancer Actions

Abstract

Epigenetic modifications have been causally linked to cancer development and progression, and are potentially reversible by drug treatments. The N-terminal tails of histones contain amino acid residues modifiable by post-translational modifications such as acetylation. Given that HDAC inhibitors induce cancer cell differentiation and death, an increasing number of these compounds has been synthesized in the last ten years. Many HDAC inhibitors are in clinical trials for the treatment of cancer. Two of them, the hydroxamic acid (SAHA) and Romidepsin (FK 228), are approved in the second line treatment of refractory, persistent or relapsed Cutaneous T Cell Lymphoma (CTCL). The growing evidence of the potential benefits of an anti-cancer treatment based on the use of HDAC inhibitors have led to a large number of patent applications all over the world. The aim of this review is to give an overview of the basic current knowledge and molecular mechanisms of HDAC inhibitors and their clinical trials as well as to focus on the recent patent applications existing in the field of HDAC inhibitors and cancer treatment between 2008 and 2010 in USA.

Gene expression signature-based approach identifies a pro-resolving mechanism of action for histone deacetylase inhibitors

“…The selective FPR2 antagonist WRW 4 was purchased from Calbiochem, Nottingham, UK. The PKC inhibitor (PKC [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] ) and the protein phosphatase 2 inhibitor (okadaic acid) were purchased from Tocris Bioscience, Bristol, UK.…”

“…[16][17][18] Using the gene expression profile produced by the antiinflammatory pro-resolving molecule annexin A1 (AnxA1), 19 we found very strong positive connections with several members of the histone deacetylase inhibitors (HDACIs) class of drugs. HDACIs are being actively investigated for the treatment of cancer owing to their pro-apoptotic effect, 20,21 although a substantial body of evidence indicates that this chemically-unrelated family of molecules affords potent anti-inflammatory properties 22,23 with potential therapeutic in pathologies including rheumatoid arthritis, 24,25 inflammatory bowel disease 26 and heart disease. 27,28 The mechanisms underlying these anti-inflammatory properties of HDACIs are largely not understood.…”

Current Status of Healthy Human Skin Models: Can Histone Deacetylase Inhibitors Potentially Improve the Present Replacement Models?

“…Based on their tight phylogenetic preservation (structural homology even to yeast orthologs), HDACs can be divided into 4 different classes [7,14,15,16,17]. Class I HDACs, represented by HDAC-1- to -3 and -8, show resemblance at the structural level with the yeast Rpd 3.…”

Proteasome inhibitor MG-132 enhances histone deacetylase inhibitor SAHA-induced cell death of chronic myeloid leukemia cells by an ROS-mediated mechanism and downregulation of the Bcr-Abl fusion protein

“…Histone deacetylase inhibitors (HDACi) represent a novel class of anticancer agents that are currently under investigation in preclinical models and in phase I-III clinical trials (3,4). Suberoylanilide hydroxamic acid (SAHA) is an orally bioavailable, well-tolerated pan-HDACi, which exhibits strong anticancer activity in hematological and solid malignancies (3)(4)(5)(6)(7).…”

“…Suberoylanilide hydroxamic acid (SAHA) is an orally bioavailable, well-tolerated pan-HDACi, which exhibits strong anticancer activity in hematological and solid malignancies (3)(4)(5)(6)(7). Recently, SAHA has been shown to exhibit anti-CML activity, when administered either alone or in combination with other agents (8)(9)(10).…”