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Examination of the Impact of Copper(II) α-(N)-Heterocyclic Thiosemicarbazone Complexes on DNA Topoisomerase IIα
Examination of the Impact of Copper(II) α-(N)-Heterocyclic Thiosemicarbazone Complexes on DNA Topoisomerase IIα
- Source :
- Chemical Research in Toxicology. 29:649-658
- Publication Year :
- 2016
- Publisher :
- American Chemical Society (ACS), 2016.
-
Abstract
- Type II DNA topoisomerases resolve topological knots and tangles in DNA that result from routine cellular processes and are effective targets for anticancer therapeutics. To this end, thiosemicarbazones have been identified as having the ability to kill cancer cells from several cell lines. Literature evidence suggests that at least some thiosemicarbazones have an impact on topoisomerase II activity. However, the mechanism is not as clearly defined. Therefore, we set out to analyze the activity of four α-(N)-heterocyclic thiosemicarbazone compounds against topoisomerase IIα. The ligands, acetylpyridine-ethylthiosemicarbazone (APY-ETSC) and acetylpyrazine-methylthiosemicarbazone (APZ-MTSC), and their copper(II) [Cu(II)] complexes [Cu(APY-ETSC)Cl] and [Cu(APZ-MTSC)Cl] were examined for the ability to impact the catalytic cycle of human topoisomerase IIα. Both [Cu(APY-ETSC)Cl] and [Cu(APZ-MTSC)Cl] were more effective at inhibiting DNA relaxation compared with the ligands alone. Further, both [Cu(APY-ETSC)Cl] and [Cu(APZ-MTSC)Cl] increased double-stranded DNA cleavage levels without inhibiting topoisomerase IIα-mediated DNA ligation. The Cu(II) complexes inactivate enzyme activity over time suggesting a critical interaction with the enzyme. Additionally, we found that the Cu(II)-thiosemicarbazone complexes do not significantly impact DNA cleavage by the catalytic core of the enzyme. This evidence is supported by the fact that both [Cu(APY-ETSC)Cl] and [Cu(APZ-MTSC)Cl], and to a lesser extent the ligands, inhibit topoisomerase IIα-mediated ATP hydrolysis. Based upon kinetic analysis, the Cu(II) complexes appear to be noncompetitive inhibitors of the ATPase domain of topoisomerase IIα. Taken together, our results provide evidence that Cu(II) complexes of α-(N)-heterocyclic thiosemicarbazones catalytically inhibit the enzyme through the ATPase domain but also promote double-stranded DNA cleavage by the enzyme.
- Subjects :
- Thiosemicarbazones
0301 basic medicine
Topoisomerase iiα
Stereochemistry
chemistry.chemical_element
Toxicology
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Antigens, Neoplasm
Coordination Complexes
Humans
Topoisomerase II Inhibitors
DNA Cleavage
Semicarbazone
biology
Chemistry
Topoisomerase
General Medicine
Copper
DNA-Binding Proteins
DNA Topoisomerases, Type II
030104 developmental biology
Catalytic cycle
Cell culture
030220 oncology & carcinogenesis
Cancer cell
biology.protein
DNA
Subjects
Details
- ISSN :
- 15205010 and 0893228X
- Volume :
- 29
- Database :
- OpenAIRE
- Journal :
- Chemical Research in Toxicology
- Accession number :
- edsair.doi.dedup.....fc10f73d0b844d934191d5e953aa770b
- Full Text :
- https://doi.org/10.1021/acs.chemrestox.5b00471