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6-Thioguanine and zebularine down-regulate DNMT1 and globally demethylate canine malignant lymphoid cells
BACKGROUND: The antimetabolite 6-thioguanine (6-TG) has been used to treat both human and canine lymphoid malignancies. 6-TG has been shown to be epigenetically active as a demethylating agent in a human lymphoma cell line, causing downregulation of DNA methyltransferase 1 (DNMT1) through ubiquitin-...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272768/ https://www.ncbi.nlm.nih.gov/pubmed/25480665 http://dx.doi.org/10.1186/s12917-014-0290-8 |
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author | Flesner, Brian K Kumar, Senthil R Bryan, Jeffrey N |
author_facet | Flesner, Brian K Kumar, Senthil R Bryan, Jeffrey N |
author_sort | Flesner, Brian K |
collection | PubMed |
description | BACKGROUND: The antimetabolite 6-thioguanine (6-TG) has been used to treat both human and canine lymphoid malignancies. 6-TG has been shown to be epigenetically active as a demethylating agent in a human lymphoma cell line, causing downregulation of DNA methyltransferase 1 (DNMT1) through ubiquitin-targeted degradation. Zebularine (Zeb), a similar cytidine analog, also has demethylating activity as well as oral bioavailability. The hypothesis of the present study was that 6-TG and Zeb would cause downregulation of DNMT1 and globally demethylate the genomic DNA of canine lymphoma cells. The secondary hypothesis was that these agents would cause a dose-dependent decrease in cell proliferation in canine lymphoma cells. Canine CLGL-90 malignant T cells and CLL 17–7 cells were incubated in modified RPMI media. They were treated with 6-TG, Zeb, or control media at biologically relevant concentrations. RESULTS: Following treatment with each agent, DNMT1 protein and global DNA methylation were significantly decreased. A dose-dependent decrease in cell survival was also observed, with apoptosis being the primary mode of cell death in the CLGL-90 cell line. CONCLUSIONS: These results confirm the demethylating action of 6-TG and Zeb in canine cells which is similar to that shown in human cell lines. Confirmation of this mechanism supports the clinical application of these compounds as demethylating drugs in veterinary patients. |
format | Online Article Text |
id | pubmed-4272768 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-42727682014-12-31 6-Thioguanine and zebularine down-regulate DNMT1 and globally demethylate canine malignant lymphoid cells Flesner, Brian K Kumar, Senthil R Bryan, Jeffrey N BMC Vet Res Research Article BACKGROUND: The antimetabolite 6-thioguanine (6-TG) has been used to treat both human and canine lymphoid malignancies. 6-TG has been shown to be epigenetically active as a demethylating agent in a human lymphoma cell line, causing downregulation of DNA methyltransferase 1 (DNMT1) through ubiquitin-targeted degradation. Zebularine (Zeb), a similar cytidine analog, also has demethylating activity as well as oral bioavailability. The hypothesis of the present study was that 6-TG and Zeb would cause downregulation of DNMT1 and globally demethylate the genomic DNA of canine lymphoma cells. The secondary hypothesis was that these agents would cause a dose-dependent decrease in cell proliferation in canine lymphoma cells. Canine CLGL-90 malignant T cells and CLL 17–7 cells were incubated in modified RPMI media. They were treated with 6-TG, Zeb, or control media at biologically relevant concentrations. RESULTS: Following treatment with each agent, DNMT1 protein and global DNA methylation were significantly decreased. A dose-dependent decrease in cell survival was also observed, with apoptosis being the primary mode of cell death in the CLGL-90 cell line. CONCLUSIONS: These results confirm the demethylating action of 6-TG and Zeb in canine cells which is similar to that shown in human cell lines. Confirmation of this mechanism supports the clinical application of these compounds as demethylating drugs in veterinary patients. BioMed Central 2014-12-06 /pmc/articles/PMC4272768/ /pubmed/25480665 http://dx.doi.org/10.1186/s12917-014-0290-8 Text en © Flesner et al.; licensee BioMed Central Ltd. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Flesner, Brian K Kumar, Senthil R Bryan, Jeffrey N 6-Thioguanine and zebularine down-regulate DNMT1 and globally demethylate canine malignant lymphoid cells |
title | 6-Thioguanine and zebularine down-regulate DNMT1 and globally demethylate canine malignant lymphoid cells |
title_full | 6-Thioguanine and zebularine down-regulate DNMT1 and globally demethylate canine malignant lymphoid cells |
title_fullStr | 6-Thioguanine and zebularine down-regulate DNMT1 and globally demethylate canine malignant lymphoid cells |
title_full_unstemmed | 6-Thioguanine and zebularine down-regulate DNMT1 and globally demethylate canine malignant lymphoid cells |
title_short | 6-Thioguanine and zebularine down-regulate DNMT1 and globally demethylate canine malignant lymphoid cells |
title_sort | 6-thioguanine and zebularine down-regulate dnmt1 and globally demethylate canine malignant lymphoid cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4272768/ https://www.ncbi.nlm.nih.gov/pubmed/25480665 http://dx.doi.org/10.1186/s12917-014-0290-8 |
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