Abstract
Redox cancer therapeutics target the increased reliance on intracellular antioxidant systems and enhanced susceptibility to oxidant-induced stress of some cancer cells compared to normal cells. Many of these therapeutics are thought to perturb intracellular levels of the oxidant hydrogen peroxide (H2O2), a signaling molecule that modulates a number of different processes in human cells. However, fluorescent probes for this species remain limited in their ability to detect the small perturbations induced during successful treatments. We report a fluorescent sensor based upon human peroxiredoxin-2, which acts as the natural indicator of small H2O2 fluctuations in human cells. The new probe reveals peroxide-induced oxidation in human cells below the detection limit of current probes, as well as peroxiredoxin-2 oxidation caused by two different redox cancer therapeutics in living cells. This capability will be useful in elucidating the mechanism of current redox-based therapeutics and in developing new ones.
Highlights
Redox cancer therapeutics target the increased reliance on intracellular antioxidant systems and enhanced susceptibility to oxidant-induced stress of some cancer cells compared to normal cells
Several small molecule cancer therapeutics, such as piperlongumine[13], are thought to result in elevated intracellular H2O2 that is central to their toxicity mechanisms; due to the small perturbations produced in response to several of these drugs, it remains difficult to detect H2O2 fluctuations in response to these treatments[14]
Cytosolic H2O2 levels are controlled by a powerful network of specific reductive reactions primarily accomplished by peroxiredoxins (Prxs), thioredoxin (Trx), and thioredoxin reductase (TrxR), with reducing equivalents supplied by nicotinamide adenine dinucleotide phosphate (NADPH)[15,16]
Summary
Redox cancer therapeutics target the increased reliance on intracellular antioxidant systems and enhanced susceptibility to oxidant-induced stress of some cancer cells compared to normal cells. Many of these therapeutics are thought to perturb intracellular levels of the oxidant hydrogen peroxide (H2O2), a signaling molecule that modulates a number of different processes in human cells. After dimer formation, Trx reduces the disulfide bond between the two Prx[2] monomers and regenerates the original proteins, while TrxR reduces oxidized Trx using electrons from NADPH19,20 This set of reactions maintains a large amount of reduced Prx[2] in the cytosol of cells[16], poised to respond to very small changes in cytosolic H2O2 fluxes.
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