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• W2133711255 abstract "Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone possesses potent and selective antitumor activity. Its cytotoxicity has been attributed to iron chelation leading to inhibition of the iron-containing enzyme ribonucleotide reductase (RR). Thiosemicarbazone iron complexes have been shown to be redox-active, although their effect on cellular antioxidant systems is unclear. Using a variety of antioxidants, we found that only <i>N</i>-acetylcysteine significantly inhibited thiosemicarbazone-induced antiproliferative activity. Thus, we examined the effects of thiosemicarbazones on major thiol-containing systems considering their key involvement in providing reducing equivalents for RR. Thiosemicarbazones significantly (<i>p</i> < 0.001) elevated oxidized trimeric thioredoxin levels to 213 ± 5% (<i>n</i> = 3) of the control. This was most likely due to a significant (<i>p</i> < 0.01) decrease in thioredoxin reductase activity to 65 ± 6% (<i>n</i> = 4) of the control. We were surprised to find that the non–redox-active chelator desferrioxamine increased thioredoxin oxidation to a lower extent (152 ± 9%; <i>n</i> = 3) and inhibited thioredoxin reductase activity (62 ± 5%; <i>n</i> = 4), but at a 10-fold higher concentration than thiosemicarbazones. In contrast, only the thiosemicarbazones significantly (<i>p</i> < 0.05) reduced the glutathione/oxidized-glutathione ratio and the activity of glutaredoxin that requires glutathione as a reductant. All chelators significantly decreased RR activity, whereas the NADPH/NADP_total ratio was not reduced. This was important to consider because NADPH is required for thiol reduction. Thus, thiosemicarbazones could have an additional mechanism of RR inhibition via their effects on major thiol-containing systems." @default.
• W2133711255 created "2016-06-24" @default.
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• W2133711255 date "2011-03-09" @default.
• W2133711255 modified "2023-09-25" @default.
• W2133711255 title "The Potent and Novel Thiosemicarbazone Chelators Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone and 2-Benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone Affect Crucial Thiol Systems Required for Ribonucleotide Reductase Activity" @default.
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• W2133711255 doi "https://doi.org/10.1124/mol.111.071324" @default.
• W2133711255 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/21389104" @default.
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