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Special Issue "Epigenetic Therapies and Biomarkers"

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (31 July 2012)

Special Issue Editors

Guest Editor
Dr. Gordon Strathdee

Crucible Laboratory, Institute for Ageing and Health, Newcastle University, UK
E-Mail
Interests: epigenetics; DNA methylation; histone acetylation; Histone methylation; leukaemia; biomarkers; drug resistance
Guest Editor
Dr. Philippe Bertrand

Institut de Chimie des Milieux et Matériaux de Poitiers, Université de Poitiers, CNRS-UMR 6514, 40 Avenue du Recteur Pineau, Poitiers, F-86022, France
E-Mail
Interests: chemistry for epigenetic targets; (asymetric) organic synthesis; click chemistry; drug delivery systems; organic functionalization of organic and inorganic materials

Special Issue Information

Dear Colleagues,

The last 15 years has seen a dramatic increase in our understanding of epigenetics, how epigenetic factors and enzymes regulate gene expression and how this can go awry during the development of disease. Much of this research has focussed on the development of cancer and it is now clear that epigenetic factors are crucial in the development of this disease. This understanding was swiftly followed by a major push to develop novel drugs and to re-examine known drugs for their ability to therapeutically target epigenetic changes. The first epigenetically targeted drugs are already approved for use in patients and many more are currently in clinical trials or pre-clinical development. With our ever increasing understanding of the many genes and pathways required for epigenetic regulation of the human genome the number of potential therapeutic targets for epigenetic therapies continues to rise.

Epigenetic changes also represent a potentially rich source of novel biomarkers, from potential uses in early diagnosis and screening to multiple studies showing links to prognosis or prediction of therapeutic responses. Epigenetic biomarkers are likely to play an important role in the increasing push towards personalised medicine and the rapid advancement in technologies for measuring epigenetic changes should allow increasingly sophisticated combinatorial approaches. Furthermore, there is increasing interest in the role of epigenetic changes as the basis not just for cancer, but for many other common chronic conditions and epigenetic changes associated with these conditions are already being identified. Consequently, it is likely that epigenetic based therapies and biomarkers are going to be of increasing medical importance.

Dr. Gordon Strathdee
Dr. Philippe Bertrand
Guest Editors

Supported Conference
http://epigeneticsymphony.conference.univ-poitiers.fr/

Keywords

  • Epigenetic
  • DNA methylation
  • DNMT
  • Histone acetylation
  • Histone methylation
  • HDAC
  • 5-azacytidine
  • 5-methylcytosine
  • Chromatin
  • Biomarker

Published Papers (6 papers)

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Research

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Open AccessArticle Differential Cellular and Molecular Effects of Butyrate and Trichostatin A on Vascular Smooth Muscle Cells
Pharmaceuticals 2012, 5(9), 925-943; doi:10.3390/ph5090925
Received: 21 July 2012 / Revised: 22 August 2012 / Accepted: 23 August 2012 / Published: 4 September 2012
Cited by 5 | PDF Full-text (1142 KB) | HTML Full-text | XML Full-text
Abstract
The histone deacetylase (HDAC) inhibitors, butyrate and trichostatin A (TSA), are epigenetic histone modifiers and proliferation inhibitors by downregulating cyclin D1, a positive cell cycle regulator, and upregulating p21Cip1 and INK family of proteins, negative cell cycle regulators. Our recent study indicated cyclin
[...] Read more.
The histone deacetylase (HDAC) inhibitors, butyrate and trichostatin A (TSA), are epigenetic histone modifiers and proliferation inhibitors by downregulating cyclin D1, a positive cell cycle regulator, and upregulating p21Cip1 and INK family of proteins, negative cell cycle regulators. Our recent study indicated cyclin D1 upregulation in vascular smooth muscle cells (VSMC) that are proliferation-arrested by butyrate. Here we investigate whether cyclin D1 upregulation is a unique response of VSMC to butyrate or a general response to HDAC inhibitors (HDACi) by evaluating the effects of butyrate and TSA on VSMC. While butyrate and TSA inhibit VSMC proliferation via cytostatic and cytotoxic effects, respectively, they downregulate cdk4, cdk6, and cdk2, and upregulate cyclin D3, p21Cip1 and p15INK4B, and cause similar effects on key histone H3 posttranslational modifications. Conversely, cyclin D1 is upregulated by butyrate and inhibited by TSA. Assessment of glycogen synthase 3-dependent phosphorylation, subcellular localization and transcription of cyclin D1 indicates that differential effects of butyrate and TSA on cyclin D1 levels are linked to disparity in cyclin D1 gene expression. Disparity in butyrate- and TSA-induced cyclin D1 may influence transcriptional regulation of genes that are associated with changes in cellular morphology/cellular effects that these HDACi confer on VSMC, as a transcriptional modulator. Full article
(This article belongs to the Special Issue Epigenetic Therapies and Biomarkers)
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Review

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Open AccessReview Strategies To Modulate Heritable Epigenetic Defects in Cellular Machinery: Lessons from Nature
Pharmaceuticals 2013, 6(1), 1-24; doi:10.3390/ph6010001
Received: 21 August 2012 / Revised: 20 November 2012 / Accepted: 18 December 2012 / Published: 27 December 2012
Cited by 14 | PDF Full-text (665 KB) | HTML Full-text | XML Full-text
Abstract
Natural epigenetic processes precisely orchestrate the intricate gene network by expressing and suppressing genes at the right place and time, thereby playing an essential role in maintaining the cellular homeostasis. Environment-mediated alteration of this natural epigenomic pattern causes abnormal cell behavior and shifts
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Natural epigenetic processes precisely orchestrate the intricate gene network by expressing and suppressing genes at the right place and time, thereby playing an essential role in maintaining the cellular homeostasis. Environment-mediated alteration of this natural epigenomic pattern causes abnormal cell behavior and shifts the cell from the normal to a diseased state, leading to certain cancers and neurodegenerative disorders. Unlike heritable diseases that are caused by the irreversible mutations in DNA, epigenetic errors can be reversed. Inheritance of epigenetic memory is also a major concern in the clinical translation of the Nobel Prize-winning discovery of induced pluripotent stem cell technology. Consequently, there is an increasing interest in the development of novel epigenetic switch-based therapeutic strategies that could potentially restore the heritable changes in epigenetically inherited disorders. Here we give a comprehensive overview of epigenetic inheritance and suggest the prospects of therapeutic gene modulation using epigenetic-based drugs, in particular histone deacetylase inhibitors. This review suggests that there is a need to develop therapeutic strategies that effectively mimic the natural environment and include the ways to modulate the gene expression at both the genetic and epigenetic levels. The development of tailor-made small molecules that could epigenetically alter DNA in a sequence-specific manner is a promising approach for restoring defects in an altered epigenome and may offer a sustainable solution to some unresolved clinical issues. Full article
(This article belongs to the Special Issue Epigenetic Therapies and Biomarkers)
Open AccessReview Epigenetic Control and Cancer: The Potential of Histone Demethylases as Therapeutic Targets
Pharmaceuticals 2012, 5(9), 963-990; doi:10.3390/ph5090963
Received: 26 June 2012 / Revised: 21 July 2012 / Accepted: 17 August 2012 / Published: 12 September 2012
Cited by 5 | PDF Full-text (617 KB) | HTML Full-text | XML Full-text
Abstract
The development of cancer involves an immense number of factors at the molecular level. These factors are associated principally with alterations in the epigenetic mechanisms that regulate gene expression profiles. Studying the effects of chromatin structure alterations, which are caused by the addition/removal
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The development of cancer involves an immense number of factors at the molecular level. These factors are associated principally with alterations in the epigenetic mechanisms that regulate gene expression profiles. Studying the effects of chromatin structure alterations, which are caused by the addition/removal of functional groups to specific histone residues, are of great interest as a promising way to identify markers for cancer diagnosis, classify the disease and determine its prognosis, and these markers could be potential targets for the treatment of this disease in its different forms. This manuscript presents the current point of view regarding members of the recently described family of proteins that exhibit histone demethylase activity; histone demethylases are genetic regulators that play a fundamental role in both the activation and repression of genes and whose expression has been observed to increase in many types of cancer. Some fundamental aspects of their association with the development of cancer and their relevance as potential targets for the development of new therapeutic strategies at the epigenetic level are discussed in the following manuscript. Full article
(This article belongs to the Special Issue Epigenetic Therapies and Biomarkers)
Open AccessReview A Perspective on the Comparative Antileukemic Activity of 5-Aza-2′-deoxycytidine (Decitabine) and 5-Azacytidine (Vidaza)
Pharmaceuticals 2012, 5(8), 875-881; doi:10.3390/ph5080875
Received: 31 May 2012 / Revised: 16 August 2012 / Accepted: 17 August 2012 / Published: 21 August 2012
Cited by 3 | PDF Full-text (282 KB) | HTML Full-text | XML Full-text
Abstract
5-Aza-2′-deoxycytidine (5-AZA-CdR, decitabine, Dacogen®) and 5-azacytidine (5-AC, Vidaza®) are epigenetic agents that have been approved for the clinical treatment of the hematological malignancy myelodysplastic syndrome (MDS) and are currently under clinical evaluation for the treatment of acute myeloid leukemia (AML). Most investigators currently
[...] Read more.
5-Aza-2′-deoxycytidine (5-AZA-CdR, decitabine, Dacogen®) and 5-azacytidine (5-AC, Vidaza®) are epigenetic agents that have been approved for the clinical treatment of the hematological malignancy myelodysplastic syndrome (MDS) and are currently under clinical evaluation for the treatment of acute myeloid leukemia (AML). Most investigators currently classify 5-AZA-CdR and 5-AC as inhibitors of DNA methylation, which can reactivate tumor suppressor genes silenced by this epigenetic event. Examination of the pharmacology of these analogues reveals important differences with respect to their molecular mechanism of action. The action of 5-AZA-CdR is due to its incorporation into DNA. 5-AC is a riboside analogue that is incorporated primarily into RNA. A small fraction of 5-AC is converted to its deoxyribose form by ribonucleotide reductase and subsequently incorporated into DNA. The incorporation of 5-AC into RNA can interfere with the biological function of RNA and result in an inhibition protein synthesis. Microarray analysis revealed that both these analogues target the expression of different cohorts of genes. Preclinical studies show that 5-AZA-CdR is a more effective antileukemic agent than 5-AC. One explanation for this observation is that 5-AC blocks the progression of some leukemic cells from G1 into S phase, and this protects these cells from the chemotherapeutic action of this riboside analogue related to its incorporation into DNA. However, differences in chemotherapeutic efficacy of these related analogues have not been clearly demonstrated in clinical trials in patients with hematological malignancies. These observations should be taken into consideration in the design of new clinical trials using 5-AZA-CdR or 5-AC in patients with MDS and AML. Full article
(This article belongs to the Special Issue Epigenetic Therapies and Biomarkers)
Open AccessReview Epigenetic Mechanisms and Therapeutic Perspectives for Neurodevelopmental Disorders
Pharmaceuticals 2012, 5(4), 369-383; doi:10.3390/ph5040369
Received: 29 February 2012 / Revised: 23 March 2012 / Accepted: 27 March 2012 / Published: 5 April 2012
Cited by 9 | PDF Full-text (211 KB) | HTML Full-text | XML Full-text
Abstract
The number of children with mild neurodevelopmental disorders, such as autism, has been recently increasing in advanced countries. This increase is probably caused by environmental factors rather than genetic factors, because it is unlikely that genetic mutation rates suddenly increased within a short
[...] Read more.
The number of children with mild neurodevelopmental disorders, such as autism, has been recently increasing in advanced countries. This increase is probably caused by environmental factors rather than genetic factors, because it is unlikely that genetic mutation rates suddenly increased within a short period. Epigenetics is a mechanism that regulates gene expression, depending not on the underlying DNA sequence but on the chemical modifications of DNA and histone proteins. Because mental stress can alter the epigenetic status in neuronal cells, environmental factors may alter brain function through epigenetic changes. However, one advantage of epigenetic changes is their reversibility. Therefore, diseases due to abnormal epigenetic regulation are theoretically treatable. In fact, several drugs for treating mental diseases are known to have restoring effects on aberrant epigenetic statuses, and a novel therapeutic strategy targeting gene has been developed. In this review, we discuss epigenetic mechanisms of congenital and acquired neurodevelopmental disorders, drugs with epigenetic effects, novel therapeutic strategies for epigenetic diseases, and future perspectives in epigenetic medicine. Full article
(This article belongs to the Special Issue Epigenetic Therapies and Biomarkers)
Open AccessReview DNA Methylation as Clinically Useful Biomarkers—Light at the End of the Tunnel
Pharmaceuticals 2012, 5(1), 94-113; doi:10.3390/ph5010094
Received: 6 December 2011 / Revised: 10 January 2012 / Accepted: 11 January 2012 / Published: 18 January 2012
Cited by 21 | PDF Full-text (225 KB) | HTML Full-text | XML Full-text
Abstract
A recent expansion of our knowledge about epigenetic changes strongly suggests that epigenetic rather than genetic features better reflect disease development, and consequently, can become more conclusive biomarkers for the detection and diagnosis of different diseases. In this paper we will concentrate on
[...] Read more.
A recent expansion of our knowledge about epigenetic changes strongly suggests that epigenetic rather than genetic features better reflect disease development, and consequently, can become more conclusive biomarkers for the detection and diagnosis of different diseases. In this paper we will concentrate on the current advances in DNA methylation studies that demonstrate a direct link between abnormal DNA methylation and a disease. This link can be used to develop diagnostic biomarkers that will precisely identify a particular disease. It also appears that disease-specific DNA methylation patterns undergo unique changes in response to treatment with a particular drug, thus raising the possibility of DNA methylation-based biomarkers for the monitoring of treatment efficacy, for prediction of response to treatment, and for the prognosis of outcome. While biomarkers for oncology are the most obvious applications, other fields of medicine are likely to benefit as well. This potential is demonstrated by DNA methylation-based biomarkers for neurological and psychiatric diseases. A special requirement for a biomarker is the possibility of longitudinal testing. In this regard cell-free circulating DNA from blood is especially interesting because it carries methylation markers specific for a particular disease. Although only a few DNA methylation-based biomarkers have attained clinical relevance, the ongoing efforts to decipher disease-specific methylation patterns are likely to produce additional biomarkers for detection, diagnosis, and monitoring of different diseases in the near future. Full article
(This article belongs to the Special Issue Epigenetic Therapies and Biomarkers)

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