Selenium (Se) is an essential dietary component for animals including humans and is regarded as a protective agent against cancer. Although the mode of anticancer action of Se is not fully understood yet, several mechanisms, such as antioxidant protection by selenoenzymes, specific inhibition of tumor cell growth by Se metabolites, modulation of cell cycle and apoptosis, and effect on DNA repair have all been proposed. Despite the unsupported results of the last SELECT trial, the cancer-preventing activity of Se was demonstrated in majority of the epidemiological studies. Moreover, recent studies suggest that Se has a potential to be used not only in cancer prevention but also in cancer treatment where in combination with other anticancer drugs or radiation, it can increase efficacy of cancer therapy. In combating cancer cells, Se acts as pro-oxidant rather than antioxidant, inducing apoptosis through the generation of oxidative stress. Thus, the inorganic Se compound, sodium selenite (SeL), due to its prooxidant character, represents a promising alternative for cancer therapy. However, this Se compound is highly toxic compared to organic Se forms. Thus, the unregulated intake of dietary or pharmacological Se supplements mainly in the form of SeL has a potential to expose the body tissues to the toxic levels of Se with subsequent negative consequences on DNA integrity. Hence, due to a broad interest to exploit the positive effects of Se on human health and cancer therapy, studies investigating the negative effects such as toxicity and DNA damage induction resulting from high Se intake are also highly required. Here, we review a role of Se in cancer prevention and cancer therapy, as well as mechanisms underlying Se-induced toxicity and DNA injury. Since Saccharomyces cerevisiae has proven a powerful tool for addressing some important questions regarding Se biology, a part of this review is devoted to this model system.
Redox-modulating compounds derived from natural sources, such as redox active secondary metabolites, are currently of considerable interest in the field of chemoprevention, drug and phytoprotectant development. Unfortunately, the exact and occasionally even selective activity of such products, and the underlying (bio-)chemical causes thereof, are often only poorly understood. A combination of the nematode-and yeast-based assays provides a powerful platform to investigate a possible biological activity of a new compound and also to explore the "redox link" which may exist between its activity on the one side and its chemistry on the other. Here, we will demonstrate the usefulness of this platform for screening several selenium and tellurium compounds for OPEN ACCESSMolecules 2014, 19 12259 their activity and action. We will also show how the nematode-based assay can be used to obtain information on compound uptake and distribution inside a multicellular organism, whilst the yeast-based system can be employed to explore possible intracellular mechanisms via chemogenetic screening and intracellular diagnostics. Whilst none of these simple and easy-to-use assays can ultimately substitute for in-depth studies in human cells and animals, these methods nonetheless provide a first glimpse on the possible biological activities of new compounds and offer direction for more complicated future investigations. They may also uncover some rather unpleasant biochemical actions of certain compounds, such as the ability of the trace element supplement selenite to induce DNA strand breaks.
Selenium (Se) is a trace element that is essential for human health as it takes part in many cellular processes. The cellular response to this compound elicits very diverse processes including DNA damage response and repair. Because an inorganic form of Se, sodium selenite (SeL), has often been a part of numerous studies and because this form of Se is used as a dietary supplement by the public, here, we elucidated mechanisms of SeL-induced toxicity in yeast Saccharomyces cerevisiae using a combination of systematic genetic and transcriptome analysis. First, we screened the yeast haploid deletion mutant library for growth in the presence of this Se compound. We identified 39 highly SeL sensitive mutants. The corresponding deleted genes encoded mostly proteins involved in DNA damage response and repair, vacuole function, glutathione (GSH) metabolism, transcription, and chromatin metabolism. DNA damage response and repair mutants were examined in more detail: a synergistic interaction between postreplication (PRR) and homologous recombination (HRR) repair pathways was revealed. In addition, the effect of combined defects in HRR and GSH metabolism was analyzed, and again, the synergistic interaction was found. Second, microarray analysis was used to reveal expression profile changes after SeL exposure. The gene process categories "amino acid metabolism" and "generation of precursor metabolites and energy" comprised the greatest number of induced and repressed genes, respectively. We propose that SeL-induced toxicity markedly results from DNA injury, thereby highlighting the importance of DNA damage response and repair pathways in protecting cells against toxic effects of this Se compound. In addition, we suggest that SeL toxicity also originates from damage to cellular proteins, including those acting in DNA damage response and repair.
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