Abstract | BACKGROUND: METHODS: Human WIL2-NS cells were maintained in complete medium containing 0, 0.2 or 1.0 μM 5azadC for four days, and analysed daily for telomere length (flow cytometry), chromosomal stability (cytokinesis-block micronucleus cytome (CBMN-cyt) assay), and global methylation (%5me-C). RESULTS: DNA methylation decreased significantly in 1.0 μM 5azadC, relative to control (p < 0.0001). Exposure to 1.0 μM 5azadC resulted in 1.7-fold increase in telomere length (p < 0.0001), in parallel with rapid increase in biomarkers of DNA damage; (micronuclei (MN, 6-fold increase), nucleoplasmic bridges ( NPB, a 12-fold increase), and nuclear buds (NBud, a 13-fold increase) (all p < 0.0001). Fused nuclei (FUS), indicative of mitotic dysfunction, showed a 5- and 13-fold increase in the 0.2 μM and 1.0 μM conditions, respectively (p = 0.001) after 4 days. CONCLUSIONS: These data show that (i) clinically relevant concentrations of 5azadC are highly genotoxic; (ii) hypomethylation was associated with increased TL and DNA damage; and (iii) longer TL was associated with chromosomal instability. These findings suggest that lower doses of 5azdC may be effective as a hypomethylating agent, while potentially reducing DNA damage and risk for secondary disease.
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Authors | Caroline Bull, Graham Mayrhofer, Michael Fenech |
Journal | Mutation research. Genetic toxicology and environmental mutagenesis
(Mutat Res Genet Toxicol Environ Mutagen)
2021 Aug-Sep
Vol. 868-869
Pg. 503385
ISSN: 1879-3592 [Electronic] Netherlands |
PMID | 34454691
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved. |
Chemical References |
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Topics |
- Biomarkers
(metabolism)
- Cell Line
- Chromosomal Instability
(drug effects)
- Cytokinesis
(drug effects)
- DNA Damage
(drug effects)
- DNA Methylation
(drug effects)
- Decitabine
(pharmacology)
- Humans
- Lymphocytes
(drug effects)
- Micronucleus Tests
(methods)
- Mitosis
(drug effects)
- Telomere
(drug effects)
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