DNA single-strand breakage in mammalian cells induced by redox cycling quinones in the absence of oxidative stress.
Quinone-induced cell death is often attributed to oxidative stress during which the formation of DNA strand breaks is thought to play an important role. In this study, extensive DNA damage was observed in human chronic myelogenous leukemic cells (K562) exposed for 15 minutes to low concentrations (15-100 microM) of the redox cycling quinones 2,3-dimethoxy-1,4-naphthoquinone (2,3-diOMe-1,4-NQ) and menadione. However, DNA strand breakage and cell death could not be attributed to oxidative stress as the intracellular level and redox status of the reducing equivalents NADP(H) and GSH were unaffected. The intracellular level of NAD+ was found to correlate well with the extent of DNA repair (r = 0.93, P < 0.02) and cell proliferation (r = 0.96, P < 0.01) in cells exposed to the quinones. In contrast, a significant decrease in the level of intracellular ATP was only observed in cells exposed to menadione (50-100 microM). These results suggest that redox cycling quinones are capable of inducing DNA damage in mammalian cells by a mechanism that does not involve oxidative stress. Following DNA damage, cell death is dependent on the availability of NAD+, which may be key to the rapid repair of strand breaks.
Morgan
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Interdisciplinary Centre for Cell Modulation Studies, Faculty of Science and Health, University of East London, Stratford.
D000255:Adenosine Triphosphate / Q000032:analysis; D016923:Cell Death; D002455:Cell Division; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects*; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D009243:NAD / Q000032:analysis; D009285:Naphthoquinones / Q000633:toxicity*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D015219:Substrate Cycling; D014407:Tumor Cells, Cultured; D014812:Vitamin K / Q000633:toxicity*
D004273:DNA, Neoplasm; D009285:Naphthoquinones; D009243:NAD; D014812:Vitamin K; C063002:2,3-dimethoxy-1,4-naphthoquinone; D000255:Adenosine Triphosphate