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dc.contributor.authorYu, Yu
dc.contributor.authorRahmanto, Y.
dc.contributor.authorHawkins, C.
dc.contributor.authorRichardson, D.
dc.date.accessioned2017-01-30T14:58:52Z
dc.date.available2017-01-30T14:58:52Z
dc.date.created2017-01-17T19:30:21Z
dc.date.issued2011
dc.identifier.citationYu, Y. and Rahmanto, Y. and Hawkins, C. and Richardson, D. 2011. 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. Molecular Pharmacology. 79 (6): pp. 921-931.
dc.identifier.urihttp://hdl.handle.net/20.500.11937/42322
dc.identifier.doi10.1124/mol.111.071324
dc.description.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 N-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 (p < 0.001) elevated oxidized trimeric thioredoxin levels to 213 ± 5% (n = 3) of the control. This was most likely due to a significant (p < 0.01) decrease in thioredoxin reductase activity to 65 ± 6% (n = 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%; n = 3) and inhibited thioredoxin reductase activity (62 ± 5%; n = 4), but at a 10-fold higher concentration than thiosemicarbazones. In contrast, only the thiosemicarbazones significantly (p < 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. Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics.

dc.titleThe 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
dc.typeJournal Article
dcterms.source.volume79
dcterms.source.number6
dcterms.source.startPage921
dcterms.source.endPage931
dcterms.source.issn0026-895X
dcterms.source.titleMolecular Pharmacology
curtin.departmentSchool of Pharmacy
curtin.accessStatusOpen access via publisher


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