Mini-reviewThioredoxin reductase as a novel molecular target for cancer therapy
Section snippets
Pro-survival signaling factors as molecular targets
Eukaryotic, and more importantly tumor cells, evolve adaptive responses to multiple forms of environmental stress by initiating genetically preprogrammed signaling pathways [1], [2]. These adaptive responses include the activation of cellular machinery involved in DNA repair, cell cycle arrest, apoptosis, gene induction, and pro-proliferative/survival [3], [4]. The potential relationship of intracellular pro-survival factors, observed with malignant progression, is critical to predicting how
Oxidative stress
It has long been appreciated that actively dividing and metabolically hyperactive cells produce free radicals and reactive oxygen species (ROS) that are involved in a number of intracellular processes. These include oxygen metabolism, immune-mediated attack of pathogens, inflammation, signal transduction/gene expression pathways, and a number of human diseases [14], [15], [16], [17]. In the presence of O2, free radicals give rise to ROS including hydrogen peroxide (H2O2) and organic
Redox and thioredoxin reductase
Tumor cells primarily derive energy via altered glucose utilization from increasing glycolysis and pentose phosphate cycle activity resulting in the loss of regulation between glycolytic metabolism and respiration [32], [33], [34], [35]. It has been suggested that tumor cells increase glycolytic metabolism resulting from the excess ROS production due to the accelerated cell processes required to support division. When a cell ‘senses’ oxidative stress it can respond by decreasing ROS production,
TR as a molecular target
The use of modern technologies and high throughput screening allows the identification of agents that can inhibit specific intracellular factors/proteins that may be fundamental to tumor cell proliferation and growth. These signaling cascades are frequently activated or distorted by mutations in cancer cells, thus presenting the possibility that they may be potential molecular targets for new therapeutic agents. As such, identifying potential molecular targets to be used in high throughput drug
Other redox signaling factors as molecular targets
It also seems logical to determine if other redox-sensitive signaling factors downstream of TR would also meet parts of the criteria designed to identify potential molecular targets. Since, TRX is a major target of redox regulation by TR, it would be reasonable to examine if it would also be a potential anticancer target. In this regard, groups have recently reported that TR and other related redox-sensitive signaling factors are increased in tumors versus normal cells or found in higher levels
Conclusions
Oxidative stress has been suggested to play a role in various clinical diseases, including neurodegenerative disorders, endocrine abnormalities, and cancer. While the understanding of the specific signals that are sensitive to changes in the cellular oxidation/reduction status of the cell is rapidly expanding, the specific mechanism(s) and molecules that bridge the gap between cellular kinases, phosphatases and small redox-sensitive molecules remains unclear. However, it appears that many types
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Au<inf>4</inf> cluster inhibits human thioredoxin reductase activity via specifically binding of Au to Cys189
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