Zebularine

Epigenetic modifier; Inhibits DNA methyltransferases (DNMT)

Zebularine

Epigenetic modifier; Inhibits DNA methyltransferases (DNMT)

From: 165 USD
Catalog #
72902_C
Epigenetic modifier; Inhibits DNA methyltransferases (DNMT)

Overview

Zebularine, a cytidine analog, is a DNA methylation inhibitor that acts by forming a covalent complex with DNA methyltransferases (DNMTs; Zhou et al.).

DIFFERENTIATION
· Induces cardiomyocyte differentiation from rat bone marrow mesenchymal stem cells (MSCs; Naeem et al.).

CANCER RESEARCH
· Reduces proliferation of the cancer cell lines TK6, Jurkat, KG-1, and HCT116 (Stresemann et al.).
· Inhibits cell proliferation in T24 bladder carcinoma cells (Ben-Kasus et al.).
· In combination with the histone deacetylase inhibitor SAHA, reduces cell proliferation and increases apoptosis in pancreatic cancer cell lines (Neureiter et al.).
· Inhibits cell proliferation and induces apoptosis in human acute myeloid leukemia cells in vitro (Scott et al.).
· Increases the proportion of cells with cancer stem cell properties in subpopulations of human cancer cells and liver cancer cell lines (Marquardt et al.).
Alternative Names
NSC 309132
Cell Type
Cancer Cells and Cell Lines, Cardiomyocytes, PSC-Derived, Leukemia/Lymphoma Cells, Mesenchymal Stem and Progenitor Cells
Species
Human, Mouse, Rat, Non-Human Primate, Other
Application
Differentiation
Area of Interest
Cancer, Stem Cell Biology
CAS Number
3690-10-6
Chemical Formula
C₉H₁₂N₂O₅
Molecular Weight
228.2 g/mol
Purity
≥ 98%
Pathway
Epigenetic
Target
DNMT

Protocols and Documentation

Find supporting information and directions for use in the Product Information Sheet or explore additional protocols below.

Document Type
Product Name
Catalog #
Lot #
Language
Product Name
Zebularine
Catalog #
72902
Lot #
All
Language
English
Document Type
Safety Data Sheet
Product Name
Zebularine
Catalog #
72902
Lot #
All
Language
English

Applications

This product is designed for use in the following research area(s) as part of the highlighted workflow stage(s). Explore these workflows to learn more about the other products we offer to support each research area.

Resources and Publications

Publications (9)

DNA methylation inhibitors, 5-azacytidine and zebularine potentiate the transdifferentiation of rat bone marrow mesenchymal stem cells into cardiomyocytes. Naeem N et al. Cardiovascular therapeutics 2013 AUG

Abstract

BACKGROUND Mesenchymal stem cells (MSCs) have immense self-renewal capability. They can be differentiated into many cell types and therefore hold great potential in the field of regenerative medicine. MSCs can be converted into beating cardiomyocytes by treating them with DNA-demethylating agents. Some of these compounds are nucleoside analogs that are widely used for studying the role of DNA methylation in biological processes as well as for the clinical treatment of leukemia and other carcinomas. AIMS To achieve a better therapeutic option for cardiovascular regeneration, this study was carried out using MSCs treated with two synthetic compounds, zebularine and 5-azacytidine. It can be expected that treated MSCs prior to transplantation may increase the likelihood of successful regeneration of damaged myocardium. METHODS The optimized concentrations of these compounds were added separately into the culture medium and the treated cells were analyzed for the expression of cardiac-specific genes by RT-PCR and cardiac-specific proteins by immunocytochemistry and flow cytometry. Treated MSCs were cocultured with cardiomyocytes to see the fusion capability of these cells. RESULTS mRNA and protein expressions of GATA4, Nkx2.5, and cardiac troponin T were observed in the treated MSCs. Coculture studies of MSCs and cardiomyocytes have shown improved fusion with zebularine-treated MSCs as compared to untreated and 5-azacytidine-treated MSCs. CONCLUSION The study is expected to put forth another valuable aspect of certain compounds, that is, induction of transdifferentiation of MSCs into cardiomyocytes. This would serve as a tool for modified cellular therapy and may increase the probability of better myocardial regeneration.
Human hepatic cancer stem cells are characterized by common stemness traits and diverse oncogenic pathways. Marquardt JU et al. Hepatology (Baltimore, Md.) 2011 SEP

Abstract

UNLABELLED Epigenetic mechanisms play critical roles in stem cell biology by maintaining pluripotency of stem cells and promoting differentiation of more mature derivatives. If similar mechanisms are relevant for the cancer stem cell (CSC) model, then epigenetic modulation might enrich the CSC population, thereby facilitating CSC isolation and rigorous evaluation. To test this hypothesis, primary human cancer cells and liver cancer cell lines were treated with zebularine (ZEB), a potent DNA methyltransferase-1 inhibitor, and putative CSCs were isolated using the side population (SP) approach. The CSC properties of ZEB-treated and untreated subpopulations were tested using standard in vitro and in vivo assays. Whole transcriptome profiling of isolated CSCs was performed to generate CSC signatures. Clinical relevance of the CSC signatures was evaluated in diverse primary human cancers. Epigenetic modulation increased frequency of cells with CSC properties in the SP fraction isolated from human cancer cells as judged by self-renewal, superior tumor-initiating capacity in serial transplantations, and direct cell tracking experiments. Integrative transcriptome analysis revealed common traits enriched for stemness-associated genes, although each individual CSC gene expression signature exhibited activation of different oncogenic pathways (e.g., EGFR, SRC, and MYC). The common CSC signature was associated with malignant progression, which is enriched in poorly differentiated tumors, and was highly predictive of prognosis in liver and other cancers. CONCLUSION Epigenetic modulation may provide a tool for prospective isolation and in-depth analysis of CSC. The liver CSC gene signatures are defined by a pernicious interaction of unique oncogene-specific and common stemness traits. These data should facilitate the identifications of therapeutic tools targeting both unique and common features of CSCs.
Mechanistic insights on the inhibition of c5 DNA methyltransferases by zebularine. Champion C et al. PloS one 2010 JAN

Abstract

In mammals DNA methylation occurs at position 5 of cytosine in a CpG context and regulates gene expression. It plays an important role in diseases and inhibitors of DNA methyltransferases (DNMTs)--the enzymes responsible for DNA methylation--are used in clinics for cancer therapy. The most potent inhibitors are 5-azacytidine and 5-azadeoxycytidine. Zebularine (1-(beta-D-ribofuranosyl)-2(1H)- pyrimidinone) is another cytidine analog described as a potent inhibitor that acts by forming a covalent complex with DNMT when incorporated into DNA. Here we bring additional experiments to explain its mechanism of action. First, we observe an increase in the DNA binding when zebularine is incorporated into the DNA, compared to deoxycytidine and 5-fluorodeoxycytidine, together with a strong decrease in the dissociation rate. Second, we show by denaturing gel analysis that the intermediate covalent complex between the enzyme and the DNA is reversible, differing thus from 5-fluorodeoxycytidine. Third, no methylation reaction occurs when zebularine is present in the DNA. We confirm that zebularine exerts its demethylation activity by stabilizing the binding of DNMTs to DNA, hindering the methylation and decreasing the dissociation, thereby trapping the enzyme and preventing turnover even at other sites.

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