Abstract
During recent decades, selenium-containing compounds, as with the chemically similar sulfur-containing compounds, have gained considerable interest as cytotoxic and anticancer agents. Selenocyanates represent a well-established class of organic selenium compounds. These agents exhibit a wide range of biological activities. Classically, selenocyanates may cause an increase in the intracellular levels of reactive oxygen species (ROS) and exert cytotoxic activities, thus, acting as pro-oxidants. In this study, chemogenetic profiling was carried out to decipher the resistance mechanisms as central part of the antifungal mode of action against two selected selenocyanates. If a mutant line is less resistant against a compound compared to the wildtype, the gene deleted in that strain seems to be correlated with the resistance. Yeast mutants carrying gene deletions for specific redox-related protein function were employed in the chemogenetic screening. The results of screening reveal the hypersensitivity of mutants carrying deletions for glutathione pool and metabolism. To confirm the results, Arabidopsis mutants deficient in glutathione were subjected to various concentrations of selenocyanates to observe their effects on mutants and the wildtype. A significant dose dependent inhibition in Arabidopsis mutants compared to the wildtype confirmed the findings of the chemogenetic screening. The data suggest that the two representatives of organoselenium compounds cause oxidative stress in yeast cells and glutathione participates towards the development of resistance against the chemicals.
Highlights
Selenium (Se) is a vital nutritional trace element involved in antioxidative metabolism with antitumor and chemo-preventive properties [1]
The increase in oxidative stress has been implicated as a pivotal mechanism in the microbial growth inhibition in the presence of selenium compounds
Chemogenetic profiling with selected yeast mutants resulted in the inhibition of growth of mutants deficient in genes coding for glutathione metabolism and oxidative stress tolerance proteins
Summary
Selenium (Se) is a vital nutritional trace element involved in antioxidative metabolism with antitumor and chemo-preventive properties [1]. Se, being a chalcogen, exhibits a similar chemical behavior as sulfur, which is the central redox active element in biochemistry. Chemical derivatives of selenium consist of organic compounds, like selenomethione and selenomethyl-selenocysteine, and inorganic compounds, such as selenite [2]. The modulation of the cellular redox-environment is an increasing target for compounds that are employed as antibiotic or selective targeting of cancer cells in chemotherapy. Sulfur containing compounds, including natural products, such as thiosulfinates or polysulfanes are well-established examples of agents affecting the cellular redox status, exhibiting cytotoxic effects [3]. Selenium-containing compounds or Reactive Selenium Species (RSeS) can redox modulate the oxidative stress (OS) present in various cancer cells [4].
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