Zebularine: a new drug for epigenetic therapy

2004 ◽  
Vol 32 (6) ◽  
pp. 910-912 ◽  
Author(s):  
C.B. Yoo ◽  
J.C. Cheng ◽  
P.A. Jones
Keyword(s):  
Dna Methylation ◽  
Regulatory Genes ◽  
Epigenetic Therapy ◽  
Clinical Use ◽  
Novel Therapies ◽  
New Drug ◽  
Dna Methylation Inhibitors

Regulatory genes are often hypermethylated at their promoter 5′ regions and silenced in cancer. Epigenetic therapy with DNA methylation inhibitors have been shown to result in the demethylation and reactivation of these genes. Zebularine is a recently discovered mechanism-based inhibitor of DNA methylation, and has received much attention for its potential in clinical use. Further studies exploring the effectiveness of zebularine in a variety of settings could allow the development of novel therapies for cancer.

scholarly journals Aberrant DNA Methylation in Cholangiocarcinoma

2017 ◽  
Author(s):  
Toshiaki Nakaoka ◽  
Yoshimasa Saito ◽  
Hidetsugu Saito
Keyword(s):  
Dna Methylation ◽  
Immune Response ◽  
Tumor Suppressor ◽  
Tumor Suppressor Genes ◽  
Ampulla Of Vater ◽  
Endogenous Retroviruses ◽  
Epigenetic Therapy ◽  
Suppressor Genes ◽  
Aberrant Dna Methylation ◽  
Dna Methylation Inhibitors

Cholangiocarcinoma is an epithelial malignancy arising in the region between the intrahepatic bile ducts and the ampulla of Vater at the distal end of the common bile duct. The effect of current chemotherapy regimens against cholangiocarcinoma is limited, and the prognosis of patients with cholangiocarcinoma is poor. Aberrant DNA methylation and histone modification induce silencing of tumor suppressor genes and chromosomal instability during carcinogenesis. Studies have shown that the tumor suppressor genes and microRNAs (miRNAs) including MLH1, p14, p16, DAPK, miR-370 and miR-376c are frequently methylated in cholangiocarcinoma. Silencing of these tumor suppressor genes and miRNAs plays critical roles in the initiation and progression of cholangiocarcinoma. In addition, recent studies have demonstrated that DNA methylation inhibitors induce expression of endogenous retroviruses and exert the anti-tumor effect of via an anti-viral immune response. Aberrant DNA methylation of tumor suppressor genes and miRNAs could be a powerful biomarker for diagnosis and treatment of cholangiocarcinoma. Epigenetic therapy with DNA methylation inhibitors hold considerable promise for the treatment of cholangiocarcinoma through re-activation of tumor suppressor genes and miRNAs as well as induction of an anti-viral immune response.

scholarly journals Epigenetic Events in Ovarian Cancer

2021 ◽  
Author(s):  
Yanisa Rattanapan ◽  
Takol Chareonsirisuthigul
Keyword(s):  
Ovarian Cancer ◽  
Dna Methylation ◽  
Epigenetic Therapy ◽  
Dna Mutations ◽  
Epigenetic Events ◽  
Pharmacodynamic Biomarkers ◽  
Dna Methylation Inhibitors ◽  
Microrna Dysregulation ◽  
Aberrant Gene ◽  
Progressive Accumulation

Epigenetic aberrations are now well established in the development and progression of ovarian cancer, including DNA methylation, histone modifications, and microRNA dysregulation, and their progressive accumulation is correlated with the progression of the stage grade of disease. Epigenetic aberrations are relatively stable, linked to various subtypes of the disease, and present in circulating serum, representing promising diagnostic, prognostic, and pharmacodynamic biomarkers. Unlike DNA mutations and deletions, aberrant gene-repressive epigenetic changes, including DNA methylation inhibitors or histone-modifying enzymes, are theoretically reversible by epigenetic therapies. While no action against solid tumors, including ovarian cancer, has been shown in epigenetic monotherapies, preclinical studies indicate that they may be successful when used in conjunction with one another or with conventional chemotherapy, and combinatorial epigenetic therapy regiments are being investigated in cancer clinical trials. Improved interventions against this debilitating malignancy will provide a greater understanding of epigenetics’ role in ovarian cancer.

scholarly journals Cancer Epigenetics: New Therapies and New Challenges

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Eleftheria Hatzimichael ◽  
Tim Crook
Keyword(s):  
Dna Methylation ◽  
Epigenetic Modification ◽  
Hdac Inhibitors ◽  
Clinical Impact ◽  
Clinical Use ◽  
Cancer Epigenetics ◽  
Dnmt Inhibitors ◽  
Epigenetic Effects ◽  
New Challenges ◽  
Neoplastic Disorders

Cancer is nowadays considered to be both a genetic and an epigenetic disease. The most well studied epigenetic modification in humans is DNA methylation; however it becomes increasingly acknowledged that DNA methylation does not work alone, but rather is linked to other modifications, such as histone modifications. Epigenetic abnormalities are reversible and as a result novel therapies that work by reversing epigenetic effects are being increasingly explored. The biggest clinical impact of epigenetic modifying agents in neoplastic disorders thus far has been in haematological malignancies, and the efficacy of DNMT inhibitors and HDAC inhibitors in blood cancers clearly attests to the principle that therapeutic modification of the cancer cell epigenome can produce clinical benefit. This paper will discuss the most well studied epigenetic modifications and how these are linked to cancer, will give a brief overview of the clinical use of epigenetics as biomarkers, and will focus in more detail on epigenetic drugs and their use in solid and blood cancers.

Comparison of biological effects of non-nucleoside DNA methylation inhibitors versus 5-aza-2′-deoxycytidine

2005 ◽  
Vol 4 (10) ◽  
pp. 1515-1520 ◽  
Author(s):  
Jody C. Chuang ◽  
Christine B. Yoo ◽  
Jennifer M. Kwan ◽  
Tony W.H. Li ◽  
Gangning Liang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Biological Effects ◽  
Dna Methylation Inhibitors

Effect of DNA Methylation Inhibitors on the Developmental Competence of Cloned Buffalo (Bubalus bubalis) Embryos.

2011 ◽  
Vol 85 (Suppl_1) ◽  
pp. 781-781 ◽  
Author(s):  
Ambikaprasanna Saha ◽  
Naresh Lalaji Selokar ◽  
Sudeepta Kumar Panda ◽  
Aman George ◽  
Musharifa Muzaffar ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bubalus Bubalis ◽  
Developmental Competence ◽  
Dna Methylation Inhibitors

scholarly journals Environmental Epigenetics and Genome Flexibility: Focus on 5-Hydroxymethylcytosine

2020 ◽  
Vol 21 (9) ◽  
pp. 3223 ◽  
Author(s):  
Olga A. Efimova ◽  
Alla S. Koltsova ◽  
Mikhail I. Krapivin ◽  
Andrei V. Tikhonov ◽  
Anna A. Pendina
Keyword(s):  
Dna Methylation ◽  
Environmental Factors ◽  
Environmental Exposure ◽  
Dna Sequences ◽  
Molecular Mechanisms ◽  
Epigenetic Therapy ◽  
Special Focus ◽  
Stable Form ◽  
Dna Hydroxymethylation ◽  
Genome Regulation

Convincing evidence accumulated over the last decades demonstrates the crucial role of epigenetic modifications for mammalian genome regulation and its flexibility. DNA methylation and demethylation is a key mechanism of genome programming and reprogramming. During ontogenesis, the DNA methylome undergoes both programmed changes and those induced by environmental and endogenous factors. The former enable accurate activation of developmental programs; the latter drive epigenetic responses to factors that directly or indirectly affect epigenetic biochemistry leading to alterations in genome regulation and mediating organism response to environmental transformations. Adverse environmental exposure can induce aberrant DNA methylation changes conducive to genetic dysfunction and, eventually, various pathologies. In recent years, evidence was derived that apart from 5-methylcytosine, the DNA methylation/demethylation cycle includes three other oxidative derivatives of cytosine—5-hydroxymethylcytosine (5hmC), 5-formylcytosine, and 5-carboxylcytosine. 5hmC is a predominantly stable form and serves as both an intermediate product of active DNA demethylation and an essential hallmark of epigenetic gene regulation. This makes 5hmC a potential contributor to epigenetically mediated responses to environmental factors. In this state-of-the-art review, we consolidate the latest findings on environmentally induced adverse effects on 5hmC patterns in mammalian genomes. Types of environmental exposure under consideration include hypnotic drugs and medicines (i.e., phenobarbital, diethylstilbestrol, cocaine, methamphetamine, ethanol, dimethyl sulfoxide), as well as anthropogenic pollutants (i.e., heavy metals, particulate air pollution, bisphenol A, hydroquinone, and pentachlorophenol metabolites). We put a special focus on the discussion of molecular mechanisms underlying environmentally induced alterations in DNA hydroxymethylation patterns and their impact on genetic dysfunction. We conclude that DNA hydroxymethylation is a sensitive biosensor for many harmful environmental factors each of which specifically targets 5hmC in different organs, cell types, and DNA sequences and induces its changes through a specific metabolic pathway. The associated transcriptional changes suggest that environmentally induced 5hmC alterations play a role in epigenetically mediated genome flexibility. We believe that knowledge accumulated in this review together with further studies will provide a solid basis for new approaches to epigenetic therapy and chemoprevention of environmentally induced epigenetic toxicity involving 5hmC patterns.

scholarly journals CRISPR-mediated modification of DNA methylation pattern in the new era of cancer therapy

Epigenomics ◽  
2020 ◽  
Vol 12 (20) ◽  
pp. 1845-1859
Author(s):  
Faezeh Maroufi ◽  
Amirhosein Maali ◽  
Meghdad Abdollahpour-Alitappeh ◽  
Mohammad Hossein Ahmadi ◽  
Mehdi Azad
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Cancer Progression ◽  
Methylation Pattern ◽  
Epigenetic Therapy ◽  
Special Importance ◽  
New Era ◽  
Major Mechanism ◽  
Aberrant Dna Methylation ◽  
Normal Status

In the last 2 decades, a wide variety of studies have been conducted on epigenetics and its role in various cancers. A major mechanism of epigenetic regulation is DNA methylation, including aberrant DNA methylation variations such as hypermethylation and hypomethylation in the promoters of critical genes, which are commonly detected in tumors and mark the early stages of cancer development. Therefore, epigenetic therapy has been of special importance in the last decade for cancer treatment. In epigenetic therapy, all efforts are made to modulate gene expression to the normal status. Importantly, recent studies have shown that epigenetic therapy is focusing on the new gene editing technology, CRISPR-Cas9. This tool was found to be able to effectively modulate gene expression and alter almost any sequence in the genome of cells, resulting in events such as a change in acetylation, methylation, or histone modifications. Of note, the CRISPR-Cas9 system can be used for the treatment of cancers caused by epigenetic alterations. The CRISPR-Cas9 system has greater advantages than other available methods, including potent activity, easy design and high velocity as well as the ability to target any DNA or RNA site. In this review, we described epigenetic modulators, which can be used in the CRISPR-Cas9 system, as well as their functions in gene expression alterations that lead to cancer initiation and progression. In addition, we surveyed various species of CRISPR-dead Cas9 (dCas9) systems, a mutant version of Cas9 with no endonuclease activity. Such systems are applicable in epigenetic therapy for gene expression modulation through chemical group editing on nucleosomes and chromatin remodeling, which finally return the cell to the normal status and prevent cancer progression.

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