The role of oxidative stress in activity of anticancer thiosemicarbazones
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Katarzyna Malarz1,2, Anna Mrozek-Wilczkiewicz2,3, Maciej Serda1, Marta Rejmund1, Jaroslaw Polanski1 and Robert Musiol1
1Institute of Chemistry, University of Silesia in Katowice, Katowice, Poland
2Silesian Center for Education and Interdisciplinary Research, University of Silesia in Katowice, Chorzów, Poland
3A. Chełkowski Institute of Physics, University of Silesia in Katowice, Katowice, Poland
Robert Musiol, email: [email protected]
Keywords: thiosemicarbazones; anticancer; iron chelators; reactive oxygen species; oxidative stress
Received: July 06, 2017 Accepted: February 28, 2018 Published: April 03, 2018
Thiosemicarbazones are chelators of transition metals such as iron or copper whose anticancer potency is intensively investigated. Although two compounds from this class have entered clinical trials, their precise mechanism of action is still unknown. Recent studies have suggested the mobilization of the iron ions from a cell, as well as the inhibition of ribonucleotide reductase, and the formation of reactive oxygen species. The complexity and vague nature of this mechanism not only impedes a more rational design of novel compounds, but also the further development of those that are highly active that are already in the preclinical phase. In the current work, a series of highly active thiosemicarbazones was studied for their antiproliferative activity in vitro. Our experiments indicate that these complexes have ionophoric properties and redox activity. They appeared to be very effective generating reactive oxygen species and deregulating the antioxidative potential of a cell. Moreover, the genes that are responsible for antioxidant capacity were considerably deregulated, which led to the induction of apoptosis and cell cycle arrest. On the other hand, good intercalating properties of the studied compounds may explain their ability to cleave DNA strands and to also poison related enzymes through the formation of reactive oxygen species. These findings may help to explain the particularly high selectivity that they have over normal cells, which generally have a stronger redox equilibrium.
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