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The role of oxidative stress in activity of anticancer thiosemicarbazones.

ABSTRACT: 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.

SUBMITTER: Malarz K

PROVIDER: S-EPMC5915149 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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The role of oxidative stress in activity of anticancer thiosemicarbazones.

Malarz Katarzyna K Mrozek-Wilczkiewicz Anna A Serda Maciej M Rejmund Marta M Polanski Jaroslaw J Musiol Robert R

Oncotarget 20180403 25

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 m ...[more]

PMID: 29707141

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Project description:Persisters are dormant phenotypic variants of regular cells that are tolerant to antibiotics and play an important role in recalcitrance of chronic infections to therapy. Persisters can be produced stochastically in a population untreated with antibiotics. At the same time, a deterministic component of persister formation has also been documented in a population of cells with DNA damaged by fluoroquinolone treatment. Expression of the SOS response under these conditions induces formation of persisters by increasing expression of the TisB toxin. This suggests that other stress responses may also contribute to persister formation. Of particular interest is oxidative stress that pathogens encounter during infection. Activated macrophages produce reactive oxygen and nitrogen species which induce the SoxRS and OxyR regulons. Genes controlled by these regulons deactivate the oxidants and promote repair. We examined the ability of oxidative stress induced by paraquat (PQ) to affect persister formation. Preincubation of cells with PQ produced a dramatic increase in the number of persisters surviving challenge with fluoroquinolone antibiotics. PQ did not affect killing by kanamycin or ampicillin. Persisters in a culture treated with PQ that survived a challenge with a fluoroquinolone were also highly tolerant to other antibiotics. PQ induces SoxRS, which in turn induces expression of the AcrAB-TolC multidrug-resistant (MDR) pump. Fluoroquinolones are extruded by this MDR pump, and the effect of PQ on antibiotic tolerance was largely abolished in a mutant that was defective in the pump. It appears that PQ, acting through AcrAB-TolC, reduces the concentration of fluoroquinolones in the cells. This allows a larger fraction of cells to become persisters in the presence of a fluoroquinolone. Analysis of a lexA3 mutant indeed showed a dependence of persister induction under these conditions on SOS. These findings show that induction of a classical resistance mechanism, MDR efflux, by oxidative stress leads to an increase in multidrug-tolerant persister cells.

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The role of oxidative stress in activity of anticancer thiosemicarbazones.

Publications

The role of oxidative stress in activity of anticancer thiosemicarbazones.

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