Current Medicinal Chemistry - Volume 18, Issue 12, 2011

Epigenetics is defined as heritable changes in gene expression which do not alter the DNA sequence. This is achieved through changes to chromatin structure: genes are inactivated when chromatin is condensed and expressed when chromatin is extended. These dynamic chromatin states are controlled by reversible epigenetic patterns of DNA methylation and histone modification. There is now increasing evidence that environmental events can directly modify the epigenetic state of the genome. Since most human diseases are related, in some way, to alterations in gene function, disruption of the balance of epigenetic networks can cause several major pathologies such as cancer, syndromes involving chromosomal instability, mental retardation and neurodegenerative diseases, imprinting disorders, a variety of cardiovascular diseases and a great number of other human life-threatening situations. Limited amount of research has also implicated epigenetics in drug toxicity and addiction. The possibility of reversing epigenetic marks may provide new pharmacological targets for emerging therapeutic interventions. Such epigenetic drugs would be novel, possibly possessing higher therapeutic potential and fewer adverse effects in comparison to current, conventional treatments. In this special issue titled “Epigenetic mechanisms and therapeutic strategies” five review manuscripts present and discuss both the epigenetic mechanisms implicated in the pathogenesis of various disorders and diseases as well as the currently available therapeutic strategies for controlling or reversing epigenetic lesions. In the first manuscript Liakopoulos et al. provide an overview of the role of epigenetic mechanisms in the pathogenesis of renal diseases. Demars et al. in the second review discuss epigenetic and genetic mechanisms of abnormal 11p15 genomic imprinting in Silver-Russell and Beckwith-Wiedemann syndromes. A comprehensive review by Daniilidou et al. summarizes the recent findings on synaptic dysfunction and cognitive decline caused by common epigenetic modifications. The authors also discuss potential treatment strategies targeting on the epigenetic machinery. Georgiou and Kouidou discuss the currently available epigenetic therapies for the treatment of hematological malignancies. Last but not least, the review by Kovatsi et al. discusses the advances in the field of epigenetics towards the understanding of the mechanisms underlying toxicity and addiction for ethanol, cocaine, amphetamines and heroin. As guest editors of this special issue, we would like to express our appreciation to all the contributors for their imperative work, as well as to the referees for their help towards publishing review articles of high quality. We believe that the aim of this special thematic issue has been fulfilled and we hope that the readers of the journal find it interesting and helpful for their own field of scientific interest and expertise.

In recent years, molecular research has brought to light a series of mechanisms involved in the regulation of gene function without altering the DNA sequence. These mechanisms are described with the term “epigenetics” and include modifications in the structure of the human genome, leading to heritable and potentially reversible changes in gene expression. There is now increasing evidence suggesting that several characteristic features of chronic kidney disease such as hyperhomocysteinemia, subclinical inflammation, increased oxidative stress and others may affect the human epigenome. In addition, animal studies have suggested a possible link between nutrition and environmental exposure during the periconceptional period and epigenetic changes in the expression of major genes implicated in kidney organogenesis; these changes result in a diminished number of nephrons in the developing kidney, which predisposes to an increased risk for hypertension and chronic kidney disease in future life. The understanding of the role of epigenetic phenomena in the pathogenesis of chronic kidney disease opens new avenues for future therapeutic strategies, through the development of pharmaceutical agents that target directly with the changes in the human epigenome. Such epigenetic drugs are already in clinical use for the treatment of cancer as well as under investigation for the use in other diseases. This review will summarize the existing data on the link between epigenetic mechanisms and chronic uremic milieu, as well as the promising results of ongoing research in the field of epigenetic drugs that could represent additional options in our therapeutic armamentarium for patients with chronic kidney disease.

Fetal growth is a complex process depending on the genetics of the fetus, the availability of nutrients to the fetus, maternal nutrition and various growth factors and hormones of maternal, fetal and placental origin. The IGF system, and more particularly IGF2, is one of the most important endocrine and paracrine growth systems regulating fetal and placental growth (reviewed in [1]). The IGF2 gene is regulated by genomic imprinting and is expressed only from the paternally-inherited allele in most tissues during fetal development and after birth. Imprinted genes are tightly regulated and are therefore particularly susceptible to changes, including environmental and nutritional changes. Dysregulation of a cluster of imprinted genes, including the IGF2 gene within the 11p15 region, results in two fetal growth disorders (Silver-Russell and Beckwith-Wiedemann syndromes) with opposite growth phenotypes. Those two syndromes are model imprinting disorders to decipher the regulation of genomic imprinting.

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders affecting elderly people (over 65 years old). Only a small percentage (less than 5%) of the disease is consistent with the Mendelian form of inheritance. The rest, named as Late Onset Alzheimer's Disease (more than 95%), is characterized as a complex multi-factorial disorder, missing familial traits. Although some genes have been implicated in the pathogenesis and the risk of developing sporadic AD, they only account for the minority of LOAD cases. Thus, over the past few years emerging data suggest a potential role of epigenetic mechanisms and chromatin remodeling on neurodegenerative processes leading to dementia. Alterations on the epigenomic machinery cause aberrant DNA methylation and histone acetylation. Therefore, these changes trigger alterations on the transcrpiptional level of genes involved in the pathogenesis of AD, such as APP. In this review we summarize recent advances on synaptic dysfunction and cognitive decline caused by common epigenetic modifications. We also discuss potential treatment strategies targeting on the epigenetic machinery.

Epigenetic modifications, which are heritable changes in gene expression not involving DNA sequence alterations, are important early events in the multi -step process of tumorigenesis. Among them, DNA methylation and histone acetylation are the most extensively studied. Although they are, by definition, somatically heritable, epigenetic modifications of DNA and histones are also reversible. This characteristic difference from genetic alterations makes them interesting targets for therapeutic intervention. The huge amount of knowledge gathered in the field of epigenetics the last decade, was followed by the development of novel therapies: old drugs finding new identity and new targets and an increasing list of novel compounds for the treatment of malignant diseases. Hematological malignancies offer a broad spectrum of diseases where epigenetic therapies are shown to be active, providing encouraging results. Some of the more recent reports on this field of therapeutic interventions are reviewed below.

The abuse of substances such as ethanol, cocaine, amphetamines and heroin is associated with toxic effects on almost every system of the organism. Furthermore, the transition from occasional-recreational use to chronic abuse and addiction is a serious psychiatric disorder with only few chances for effective and definitive treatment since most individuals relapse, even after long periods of abstinence. It is therefore of utmost importance to elucidate the mechanisms by which these substances exert their toxicity and mediate addiction, in order to develop new, efficient therapeutic strategies with a long-term outcome, which are currently lacking. We already know that in a great number of these mechanisms, altered gene function is involved. But, with the new field of epigenetics, there is increasing evidence that changes in the epigenome are responsible for the altered gene function. The advances in the field of epigenetics towards elucidation of the mechanisms underlying toxicity and addiction for ethanol, cocaine, amphetamines and heroin are currently presented and discussed in this review.

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), characterized by inflammation, demyelination and axonal loss underlying progressive clinical disability. The chronic inflammatory tissue damage involving myelin and axons is driven by autoreactive T cells and represents a key mechanism in the immunopathogenesis of MS. Over the last few years, evidence from MS and experimental models of neuroinflammation has suggested that autoimmune responses could exert neuroprotective effects through the release of neurotrophins by autoreactive T cells. Specifically, the role of the Brain-derived neurotrophic factor (BDNF) in facilitating brain tissue repair in experimental traumatic injury has been well recognized. Support for this hypothesis comes from recent studies showing that glatiramer acetate, a currently approved treatment for MS, promotes the expansion of T cell clones crossing the blood-brain barrier and releasing BDNF in situ. A small subset of autoreactive T cells expresses the high-affinity full-length receptor for BDNF (TrkB-TK) in the periphery. In MS patients, T cells show reduced susceptibility to activation-induced apoptosis, a crucial mechanism eliminating autoreactive T clones and contributing to peripheral immunologic tolerance. These findings suggest the existence of a dual effect exerted by BDNF, which not only provides neuroprotection in the CNS but also promotes the survival of autoreactive T cells through an autocrine/paracrine loop. The aim of this review is to discuss the neuroprotective effects of currently approved immunomodulatory treatments for MS and their role in regulating neurotrophin production. We will also describe novel therapeutic strategies arising from new insights on “neuroprotective autoimmunity”.

Clinical studies provide overwhelming evidence for the importance of proteolytic imbalance and the upregulation of diverse protease classes in diseases such as cancer and arthritis. While the complex nature of proteolytic networks has hampered the development of protease inhibitors for these indications, aberrant enzyme activity could be successfully exploited for the development of proteasesensitive drug delivery systems and fluorescent in vivo imaging agents. More recently, these concepts have also been translated into photomedical applications to develop dual modality prodrugs for the simultaneous treatment and imaging of disease. After an introductory overview of proteases and their role in cancer, we present and discuss different strategies to exploit upregulated protease activity for the development of drug delivery systems, fluorescent in vivo reporter probes, and photosensitizer-prodrugs with respect to their potential and limitations. The main approaches used for targeting proteases in all three areas can be roughly divided into peptide-based and macromolecular strategies. Both involve the use of a short, peptide-based protease substrate, which is either directly tagged to the therapeutic agent or dye/quencher pair, or alternatively, serves as a linker between the polymeric carrier and a functional unit. In the latter case, the pharmacokinetic properties of peptide-based protease-sensitive prodrugs and imaging probes can be further ameliorated by the passive targeting capacity of macromolecular drug delivery systems for neoplastic and inflammatory lesions.

Micro- and macro-vascular complications are the leading causes of morbidity and mortality in type 1 and type 2 diabetic patients. Despite the vast clinical experience linking diabetic metabolic abnormalities to cardiovascular lesions, the molecular basis of individual susceptibility to diabetic cardiovascular injury is still largely unknown. Significant advances in this area may come from studies on suitable animal models. Although no animal model can accurately reproduce the human disease, experimental studies in animals have the great advantage to eliminate factors such as ethnicity, economic and geographic variables, drug interactions, diet, gender and age differences that importantly limit clinical studies. Indeed, appropriate animal models have provided important information on genetic and environmental risks of diabetes, and helped to dissect molecular mechanisms underlying the development, progression and therapeutic control of this disease. Unfortunately, none of the diabetic models presently available fully mimics the human syndrome. Therefore, the current knowledge on the pathogenesis of cardiovascular complications relies on the evaluation of distinct phenotypes from various diabetic models. In addition to strains prone to diabetes, this disease can be induced by surgical, pharmacological or genetic manipulation in several animal species. Rodents are the most used, although some studies are still performed in larger animals as rabbits, cats, pigs or monkeys. Far from being exhaustive, this work should serve as a general overview of the most relevant clues provided by major species and models for the overall comprehension of cardiovascular complications in type 1 and type 2 diabetes.

The neuropeptide substance P (SP) shows a widespread distribution in both the central and peripheral nervous systems and it is known that after binding to the neurokinin-1 (NK-1) receptors, SP regulates many biological functions in the central nervous system such as emotional behaviour, stress, depression, anxiety, emesis, migraine, alcohol addiction and neurodegeneration. SP has been also implicated in pain, inflammation, hepatotoxicity and in virus proliferation, and it plays an important role in cancer (e.g., tumour cell proliferation, angiogenesis, and the migration of tumour cells for invasion and metastasis). By contrast, it is known that after binding to NK-1 receptors, NK-1 receptor antagonists specifically inhibit the above-mentioned biological functions mediated by SP. Thus, these antagonists exert an anxyolitic, antidepressant, antiemetic, antimigraine, antialcohol addiction or neuroprotector effect in the central nervous system, and they play a role in analgesic, antiinflammatory, hepatoprotector processes and in antivirus proliferation. Regarding cancer, NK-1 receptor antagonists exert an antitumour action (inducing tumour cell death by apoptosis), and induce antiangiogenesis and inhibit the migration of tumour cells. It is also known that NK-1 receptors have a widespread distribution and that they are overexpressed in tumour cells. Thus, NK-1 receptor antagonists are molecularly targeted agents. In general, current drugs have a single therapeutic effect, although less commonly they may exert several. However, the data reported above indicate that NK-1 receptor antagonists are promising drugs, exerting many therapeutic effects (the action of such antagonists is dose-dependent and, depending on the concentration, has more positive effects). In this review, we update the multiple therapeutic effects exerted by NK-1 receptor antagonists.

Aberrant oxidative pathways of catecholamine neurotransmitters, i.e. dopamine and norepinephrine, are an important biochemical correlate of catecholaminergic neuron loss in some disabling neurodegenerative diseases of the elderly, notably Parkinson's disease. In an oxidative stress setting, under conditions of elevated lipid peroxidation, iron accumulation, impaired mitochondrial functioning and antioxidant depletion, catecholamines are oxidatively converted to the corresponding o-quinones, which may initiate a cascade of spontaneous reactions, including intramolecular cyclization, aminoethyl side chain fission and interaction with molecular targets. The overall outcome of the competing pathways may vary depending on contingent factors and the biochemical environment, and may include formation of nitrated derivatives, neuromelanin deposition, generation of chain fission products, conjugation with L-cysteine leading eventually to cytotoxic responses and altered cellular function. In addition, catecholamines may interact with products of lipid peroxidation and other species derived from oxidative breakdown of biomolecules, notably glyoxal and other aldehydes, leading e.g. to tetrahydroisoquinolines via Pictet-Spengler chemistry. After a brief introductory remark on oxidative stress biochemistry, the bulk of this review will deal with an overview of the basic chemical pathways of catecholamine oxidation, with special emphasis on the analogies and differences between the central neurotransmitters dopamine and norepinephrine. This chemistry will form the basis for a concise discussion of the latest advances in the mechanisms of catecholamine-associated neurotoxicity in neuronal degeneration.

Dietary intakes of tomatoes and tomato products containing lycopene have been shown to be associated with decreased risk of chronic diseases, such as cancer. Although several mechanisms, including modulation of gap junction communication and enhancement of immune system, are thought to be implicated in its beneficial activities, evidence is accumulating to suggest that lycopene may act as a modulator of intracellular reactive oxygen species (ROS) and, therefore, control ROS-mediated cell growth. According with this, at high concentration, ROS have been reported to be hazardous for living organisms, whereas at moderate concentrations, they play an important role as regulatory mediators in signaling processes regulating cell growth. In this review, we report the available evidence on a role of lycopene as a redox agent in cell proliferation, differentiation and apoptosis. In particular, we focused our attention on lycopene prevention of cell oxidative damage and its influence in cell growth as well as on lycopene modulation of redox-sensitive molecular targets in cell signalling: growth factors and growth factor receptors, antioxidant response elements, MAPKs, transcription factors, such as NF-κB and AP-1, and cytokine expression. Moreover, we speculate on the possible influence that lycopene may have as a redox agent in cancer.

Tight junctions (TJs) play pivotal roles in the fence and barrier functions of epithelial and endothelial cell sheets. Since the 1980s, the modulation of the TJ barrier has been utilized as a method for drug absorption. Over the last decade, the structural and functional biochemical components of TJs, such as occludin and claudin, have been determined, providing new insights into TJ-based pharmaceutical therapy. For example, the modulation of the claudin barrier enhances the jejunal absorption of drugs, and claudin expression is deregulated in cancer cells. Claudin is a co-receptor for the hepatitis C virus. Moreover, claudin is modulated during inflammatory conditions. These findings indicate that claudins are promising drug targets. In this review, we discuss the seeds of claudin-based drug development, which may provide potential pharmaceutical breakthroughs in the future.

Autophagy is a self-renewal process in cells by recycling redundant materials through lysosomal machinery. The basal level of autophagy in eukaryotic cells plays a “housekeeping” role by degrading redundant cellular materials and providing nutrients and energy. However acute and sustained autophagy may cause autophagic cell death. These two features of autophagy are consistent with its complex roles in both oncogenesis and cancer development. Many small molecule autophagy regulators are developed to turn autophagy on/off for therapeutic purpose. The roles of chemotherapeutic agents in regulating autophagy and facilitating cancer treatment can be classified into three categories: direct autophagy enhancers, indirect autophagy enhancers and autophagy inhibitors. The representative autophagy regulators and their roles in cancer treatment were reviewed.

There is an urgent need for the design and development of new and selective drugs for the treatment of malaria and bacterial infections as these pathogens are developing resistance to presently available therapies. Malaria is a life threatening disease in many countries and responsible for almost one million deaths annually. In particular, drug-resistant malarial parasites are hindering effective control of malaria and prompting to find novel druggable targets and develop compounds with mechanism of action different from the conventional drugs. In this quest, efforts were made to determine three-dimensional structures of Plasmodium falciparum and Plasmodium vivax FK506 binding proteins which bind the macrolides (FK506 and rapamycin) and also demonstrate peptidylprolyl cis-trans isomerase activity in a similar manner as human FKBP12. Previous studies revealed that the immunosuppressive drug FK506 exhibits potential anti-malarial activity by binding FK506 binding domains (FKBD). This review focuses on three different types of FK506 binding proteins/domains in pathogens, their structural characteristics and biological roles. Binding ability of these proteins with the macrolides has opened new possibilities to develop selective inhibitors for these novel targets to combat the life threatening infections.