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Abstract
2,2'-diselenyldibenzoic acid (DSBA) is a chemical probe produced to explore the pharmacological properties of diphenyldiselenide-derived agents with seleno-hormetic activity undergoing preclinical development. The present study was designed to verify in vivo the drug’s properties and to determine mechanistically how these may mediate the protection of tissues against stress conditions, exemplified by ionizing radiation induced damage in mouse bone marrow. In murine bone marrow hematopoietic cells, the drug initiated the activation of the Nrf2 transcription factor resulting in enhanced expression of downstream stress response genes. This type of response was confirmed in human liver cells and included enhanced expression of glutathione S-transferases (GST), important in the metabolism and pharmacological function of seleno-compounds. In C57 BL/6 mice, DSBA prevented the suppression of bone marrow hematopoietic cells caused by ionizing radiation exposure. Such in vivo prevention effects were associated with Nrf2 pathway activation in both bone marrow cells and liver tissue. These findings demonstrated for the first time the pharmacological properties of DSBA in vivo, suggesting a practical application for this type of Se-hormetic molecules as a radioprotective and/or prevention agents in cancer treatments.
Highlights
IntroductionInorganic and organic forms of selenium have been investigated as pharmacological agents with applications in either cancer chemoprevention (cytoprotective effects) or therapy of drug-resistant tumors (recently reviewed in [1])
Inorganic and organic forms of selenium have been investigated as pharmacological agents with applications in either cancer chemoprevention or therapy of drug-resistant tumors
To characterize the metabolism and effects of diselenyldibenzoic acid (DSBA) on cellular redox, ROS and thiol levels were assessed in two human liver cell lines, HepaRG and HepG2 after treatment with this and other Se-compounds that were used for comparison
Summary
Inorganic and organic forms of selenium have been investigated as pharmacological agents with applications in either cancer chemoprevention (cytoprotective effects) or therapy of drug-resistant tumors (recently reviewed in [1]). In vitro findings suggested that the hormetic effects of DSBA are achieved through activation of the transcription factor NF-E2-Related Factor 2 (Nrf2) [2], step-wise influencing the expression of gene products that protect against oxidative damage These include isoform P of the enzyme glutathione S-transferase (GSTP) [4]. GSTP has been characterized as an unusual member of this family, insofar as its functions transcend detoxification and include regulation of signal transduction pathways by means of S-glutathionylation, a post-translational modification of susceptible Cys residues [8] In this context, S-glutathionylation of estrogen receptor alpha [9], is an indication of the general importance of GST family members in controlling myeloproliferation events [10]. These cells can be considered “a reporter cell model” for Se-hormetic activity of DSBA and other Se-compounds [2, 3]
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