The novel DNA methylation inhibitor zebularine is effective against the development of murine T-cell lymphoma

Blood ◽  
2006 ◽  
Vol 107 (3) ◽  
pp. 1174-1177 ◽  
Author(s):  
Michel Herranz ◽  
Juan Martín-Caballero ◽  
Mario F. Fraga ◽  
Jesús Ruiz-Cabello ◽  
Juana Maria Flores ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Cpg Island ◽  
Promoter Hypermethylation ◽  
Dna Hypomethylation ◽  
Chemotherapy Drugs ◽  
Positron Emission ◽  
Methylation Inhibitor ◽  
Dna Methylation Inhibitor ◽  
T Lymphomas

AbstractGene silencing by CpG island promoter hypermethylation has awakened the interest for DNA demethylating agents as chemotherapy drugs. Zebularine (1-[β-D-ribofuranosil]-1,2-dihydropyrimidin-2-1) has been recently described as a new DNA methylation inhibitor. Here we have studied its effects in a mouse model of radiation-induced lymphomagenesis using nuclear magnetic resonance (NMR) and positron emission tomography (PET). All control animals presented large thymic T lymphomas and died between 4 and 5.5 months. In contrast, 40% (12 of 30) of zebularine-treated animals were still alive after 1 year (Kaplan-Meier P < .001). NMR and PET imaging showed that surviving animals presented a thymus structure/volume similar to normal mice of the same age. Most important, zebularine demonstrated a complete lack of toxicity in nonirradiated control mice. DNA hypomethylation induced by zebularine occurred in association with depletion in extractable DNA methyltransferase 1 protein. Thus, our data support the role of zebularine as a DNA demethylating agent with antitumor activity and little toxicity.

scholarly journals Naturally occurring methylation inhibitor: DNA hypomethylation and hemoglobin synthesis in human K562 cells.

1987 ◽  
Vol 7 (5) ◽  
pp. 1759-1763 ◽  
Author(s):  
S B Lyon ◽  
L Buonocore ◽  
M Miller
Keyword(s):  
Dna Methylation ◽  
Genomic Dna ◽  
Dna Methyltransferase ◽  
Globin Gene ◽  
K562 Cells ◽  
Gene Probe ◽  
Dna Hypomethylation ◽  
Naturally Occurring ◽  
Methylation Inhibitor

A naturally occurring methylation inhibitor isolated from rabbit liver and named methinin inhibits a number of methyltransferases. Methinin is a low-molecular-weight compound (1,400) that has an active amine group. This compound inhibits the DNA methyltransferase of human erythroleukemia cells (K562) in vitro. When the K562 cells were grown in medium containing methinin, fetal hemoglobin was produced. Small but detectable amounts of adult hemoglobin were also produced. Methinin was not toxic to these cells. The overall rate of genomic DNA methylation was reduced by 60% in cells grown in medium containing methinin. Southern blots of genomic DNA from methinin-treated cells and untreated cells hybridized to a 32P-labeled globin gene probe showed that one site in the globin gene region was hypomethylated. Methinin is a naturally occurring compound which inhibits DNA methylation both in vitro and in vivo.

Naturally occurring methylation inhibitor: DNA hypomethylation and hemoglobin synthesis in human K562 cells

1987 ◽  
Vol 7 (5) ◽  
pp. 1759-1763
Author(s):  
S B Lyon ◽  
L Buonocore ◽  
M Miller
Keyword(s):  
Dna Methylation ◽  
Genomic Dna ◽  
Dna Methyltransferase ◽  
Globin Gene ◽  
K562 Cells ◽  
Gene Probe ◽  
Dna Hypomethylation ◽  
Naturally Occurring ◽  
Methylation Inhibitor

A naturally occurring methylation inhibitor isolated from rabbit liver and named methinin inhibits a number of methyltransferases. Methinin is a low-molecular-weight compound (1,400) that has an active amine group. This compound inhibits the DNA methyltransferase of human erythroleukemia cells (K562) in vitro. When the K562 cells were grown in medium containing methinin, fetal hemoglobin was produced. Small but detectable amounts of adult hemoglobin were also produced. Methinin was not toxic to these cells. The overall rate of genomic DNA methylation was reduced by 60% in cells grown in medium containing methinin. Southern blots of genomic DNA from methinin-treated cells and untreated cells hybridized to a 32P-labeled globin gene probe showed that one site in the globin gene region was hypomethylated. Methinin is a naturally occurring compound which inhibits DNA methylation both in vitro and in vivo.

PS02.176: LINE-1 METHYLATION LEVEL AND LOCAL IMMUNE RESPONSE IN ESOPHAGEAL CANCER

2018 ◽  
Vol 31 (Supplement_1) ◽  
pp. 172-172
Author(s):  
Yoshifumi Baba ◽  
Taisuke Yagi ◽  
Yuki Kiyozumi ◽  
Yukiharu Hiyoshi ◽  
Masaaki Iwatsuki ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Immune Response ◽  
Esophageal Cancer ◽  
Methylation Level ◽  
Cpg Island ◽  
Surrogate Marker ◽  
Esophageal Tumor ◽  
Local Immune Response ◽  
Dna Hypomethylation ◽  
Response Status

Abstract Background In cancer cells, DNA methylation may be altered in two principle ways; global DNA hypomethylation and site-specific CpG island promoter hypermethylation. Since Long interspersed element-1 (LINE-1 or L1; a repetitive DNA retrotransposon) constitutes a substantial portion (approximately 17%) of the human genome, the extent of LINE-1 methylation is regarded as a surrogate marker of global DNA methylation. In previous studies, we demonstrated that LINE-1 hypomethylation was strongly associated with a poor prognosis in esophageal cancer, supporting its potential role as a prognostic marker (Ann Surg 2012). We also found that LINE-1-hypomethylated tumors showed highly frequent genomic gains at various loci containing candidate oncogenes such as CDK6 (Clin Cancer Res 2014). Given that immunotherapy, as represented by PD-1/PD-L1-targeting antibodies, has increasingly gained attention as a novel treatment strategy for esophageal cancer, better understanding of local immune response status in esophageal cancer is important. The aim of this study is to evaluate the relationship between LINE-1 methylation level and local immune response in esophageal cancer. Methods Using a non-biased database of 305 curatively resected esophageal cancers, we evaluated PD-L1 expression and TIL status (CD8 expression) by immunohistochemical analysis (Ann Surg 2017). Results TIL positivity was significantly correlated with longer overall survival (log-rank P < 0.0001). TIL-negative cases demonstrated significantly lower LINE-1 methylation level compared with TIL-positive cases (P = 0.012). This finding certainly supports that LINE-1 methylation level may influence the local immune response status. Conclusion PD-L1 expression was not related with LINE-1 methylation level. Further investigations in this field would provide deeper insights into esophageal tumor immunology and assist the development of new therapeutic strategies against esophageal cancer. Disclosure All authors have declared no conflicts of interest.

scholarly journals Zebularine: A Novel DNA Methylation Inhibitor that Forms a Covalent Complex with DNA Methyltransferases

2002 ◽  
Vol 321 (4) ◽  
pp. 591-599 ◽  
Author(s):  
L. Zhou ◽  
X. Cheng ◽  
B.A. Connolly ◽  
M.J. Dickman ◽  
P.J. Hurd ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferases ◽  
Methylation Inhibitor ◽  
Dna Methylation Inhibitor ◽  
Covalent Complex

scholarly journals DNA methylation inhibitor attenuates polyglutamine‐induced neurodegeneration by regulating Hes5

2019 ◽  
Vol 11 (5) ◽  
Author(s):  
Naohide Kondo ◽  
Genki Tohnai ◽  
Kentaro Sahashi ◽  
Madoka Iida ◽  
Mayumi Kataoka ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Methylation Inhibitor ◽  
Dna Methylation Inhibitor

Combination of DNA methylation inhibitor 5-azacytidine and arsenic trioxide has synergistic activity in myeloma

2009 ◽  
Vol 82 (3) ◽  
pp. 176-183 ◽  
Author(s):  
Guanghua Chen ◽  
Yi Wang ◽  
Haiwen Huang ◽  
Fengru Lin ◽  
Depei Wu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Arsenic Trioxide ◽  
Synergistic Activity ◽  
Methylation Inhibitor ◽  
Dna Methylation Inhibitor

Methylation Profile of B-Chronic Lymphocytic Leukemia Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2951-2951
Author(s):  
Jun Fan ◽  
Asou Norio ◽  
Masao Matsuoka
Keyword(s):  
Dna Methylation ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Lines ◽  
Mammalian Cells ◽  
Mononuclear Cells ◽  
Cpg Island ◽  
Methylation Status ◽  
Lymphocytic Leukemia ◽  
Dna Hypomethylation ◽  
Peripheral Blood Mononuclear

Abstract DNA methylation plays an important role in the development and aging of mammalian cells, and its dysregulation has been frequently observed in cancer cells. The purpose of this study is to investigate the involvement of aberrant DNA methylation in B chronic lymphocytic leukemia (B-CLL) cells. We compared methylation status of B-CLL cells isolated from patients with that of normal CD19+ cells isolated from health donors by methylated CpG island amplification/representative difference analysis method. 5 hypermethylated and 27 hypomethylated DNA regions were identified in B-CLL sample. Among the 27 hypomethylated regions, 5 located on chromosome 9q34, 3 on 10q25-26 and 4 on 19q13. Methylation status was confirmed by sequencing using sodium bisulfite-treated DNA samples. By comparing DNA samples from same patients at different clinical stages, we found that lower methylation density in these regions is linked with disease progression. Expression of 15 genes surrounding hypomethylated regions was studied by RT-PCR. Expression of laminin beta3 gene and melanotransferrin gene was found to be upregulated in all B-CLL cell lines as well as lymphoma cell lines comparing with normal CD19+ peripheral blood mononuclear cells. B-cell CLL/lymphoma 11b gene showed increased expression in only 2 B-CLL cell lines. For other genes, no transcriptional change was found regardless of changed DNA methylation. This study showed the predominance of DNA hypomethylation in B-CLL cells compared with hypermethylation. Hypomethylated regions clustered in a limited number of chromosomes and methylation density appeared to be inversely correlated with disease progress. Figure Figure

Sign in / Sign up

Export Citation Format

Share Document