Dual targeting of the thioredoxin and glutathione systems in cancer and HIV
Moran Benhar, Iart Luca Shytaj, Jonathan S. Stamler, Andrea Savarino
Moran Benhar, Iart Luca Shytaj, Jonathan S. Stamler, Andrea Savarino
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Dual targeting of the thioredoxin and glutathione systems in cancer and HIV

Abstract

Although the use of antioxidants for the treatment of cancer and HIV/AIDS has been proposed for decades, new insights gained from redox research have suggested a very different scenario. These new data show that the major cellular antioxidant systems, the thioredoxin (Trx) and glutathione (GSH) systems, actually promote cancer growth and HIV infection, while suppressing an effective immune response. Mechanistically, these systems control both the redox- and NO-based pathways (nitroso-redox homeostasis), which subserve innate and cellular immune defenses. Dual inhibition of the Trx and GSH systems synergistically kills neoplastic cells in vitro and in mice and decreases resistance to anticancer therapy. Similarly, the population of HIV reservoir cells that constitutes the major barrier to a cure for AIDS is exquisitely redox sensitive and could be selectively targeted by Trx and GSH inhibitors. Trx and GSH inhibition may lead to a reprogramming of the immune response, tilting the balance between the immune system and cancer or HIV in favor of the former, allowing elimination of diseased cells. Thus, therapies based on silencing of the Trx and GSH pathways represent a promising approach for the cure of both cancer and AIDS and warrant further investigation.

Authors

Moran Benhar, Iart Luca Shytaj, Jonathan S. Stamler, Andrea Savarino

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Figure 3

Hypothesized bottleneck mechanism for the enhancement of cell-mediated immunity following inhibition of the Trx and GSH systems.

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Hypothesized bottleneck mechanism for the enhancement of cell-mediated i...
A professional APC (DC) can phagocytize a foreign pathogen (HIV), degrade it into peptidic antigens, and present these antigens to naive lymphocytes. Because of high mutation rates, HIV antigens are characterized by high variability, with the exception of highly conserved, essential proteins, which are consequently well represented in a typical viral population. Following antigen presentation, the lymphocyte becomes activated and primed toward a specific antigen. During the progression of HIV infection (upper panel), the lymphocyte clones specific for conserved antigens (red halo in the figure) are reduced in frequency due to the accumulation of “nonfunctional clones” directed against increasingly mutated antigens (green and gold halos). When Trx and GSH systems are inhibited, lymphocyte activation is impaired, and the majority of activated lymphocyte clones undergo stochastic apoptosis. The more frequently represented clones have a selective advantage in survival as a result of their numbers. This leads to a bottleneck effect that can favor repopulation by those lymphocytes primed against the most frequently represented (conserved) antigens.