Abstract |
The DNA damage induced by 7-chloro-3-[[(N,N-dimethylamino)propyl]amino]-2-quinoxalinecarbonitrile 1,4-di-N-oxide hydrochloride (Q-85 HCl) in Caco-2 cells under hypoxic and well-oxygenated conditions has been studied by using the comet assay. This compound has shown a good in vitro profile of high selective toxicity in hypoxia, but its mechanism of action is unknown. The DNA damage has been evaluated by performing the comet assay after a 2-h treatment with Q-85 HCl (0.1, 0.2, 0.4 microM in hypoxia; 20, 40 microM in well-oxygenated conditions). The number of cells in apoptosis has also been assessed by flow cytometry analysis of Annexin V-FITC staining. The capability of the cells to repair the DNA damage and the proliferation rate was evaluated at different times after the treatment (24-168 h). Under hypoxic conditions, a clear dose-dependent increase in the number of nuclei with a comet was observed (comet score: 132 +/- 13, 343 +/- 30 and 399 +/- 1; control comet score: 42 +/- 14). Under well-oxygenated conditions, the number of nuclei with comet increased significantly with respect to the control (comet score: 273 +/- 14 and 312 +/- 9; control comet score: 27 +/- 4). Cells in apoptosis were not detected by the comet assay nor by flow cytometry. The recovery from DNA damage was time- and concentration-dependent in hypoxia (cells treated with the highest concentration still showed DNA damage after 72 h) and rather time-dependent in well-oxygenated conditions ( DNA was completely repaired after 24 h). In conclusion, Q-85 HCl acts by DNA damage and not only the reduced intermediate is genotoxic but also some other derivatives and Q-85 HCl itself may be acting.
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Authors | Amaia Azqueta, Gisela Pachón, Marta Cascante, Edmond E Creppy, Adela López de Cerain |
Journal | Mutagenesis
(Mutagenesis)
Vol. 20
Issue 3
Pg. 165-71
(May 2005)
ISSN: 0267-8357 [Print] England |
PMID | 15817574
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- 7-chloro-3-(((N,N-dimethylamino)propyl)amino)-2-quinoxalinecarbonitrile-1,4-di-N-oxide
- Mutagens
- Quinoxalines
- DNA
- quindoxin
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Topics |
- Apoptosis
- Caco-2 Cells
- Cell Hypoxia
- Cell Nucleus
(drug effects)
- Cell Proliferation
(drug effects)
- Cell Survival
(drug effects)
- Comet Assay
- DNA
(drug effects)
- DNA Damage
- DNA Repair
- Humans
- Mutagens
(toxicity)
- Oxidation-Reduction
- Quinoxalines
(chemistry, toxicity)
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