Potentiation of hydrogen peroxide toxicity: From catalase inhibition to stable DNA-iron complexes

Abstract

Hydrogen peroxide (H2O2) is unique among general toxins, because it is stable in abiotic environments at ambient temperature and neutral pH, yet rapidly kills any type of cells by producing highly-reactive hydroxyl radicals. This life-specific reactivity follows distribution of soluble iron, Fe(II) (which combines with H2O2 to form the famous Fenton’s reagent), — Fe(II) is concentrated inside cells, but is virtually absent outside them. Because of the immediate danger of H2O2, all cells have powerful H2O2 scavengers, the equally famous catalases, which enable cells to survive thousand-fold higher concentrations of H2O2 and, in combination with adequate movement of H2O2 across membranes, make the killing H2O2 concentrations virtually impractical to generate in vivo. And yet, low concentrations of H2O2 are somehow used as an efficient biological weapon. Here we review several examples of how cells potentiate H2O2 toxicity with other chemicals. At first, these potentiators were thought to simply inhibit catalases, but recent findings with cyanide suggest that potentiators mostly promote the other side of Fenton’s reaction, recruiting iron from cell depots into stable DNA-iron complexes that, in the presence of elevated H2O2, efficiently break duplex DNA, pulverizing the chromosome. This multifaceted potentiation of H2O2 toxicity results in robust and efficient killing.

CNP mediated selective toxicity on melanoma cells is accompanied by mitochondrial dysfunction

“…This activity might be able to shift the balance from superoxide to hydrogen peroxide within the cell, with superoxide serving as a prerequisite to generate H 2 O 2 . Although both superoxide and H 2 O 2 are damaging the cells after surpassing a certain threshold, H 2 O 2 is more stable and, therefore, considered to be more toxic [74]. If the nanoceria initiated increase of endogenous H 2 O 2 is responsible for melanoma cell death, the tumor cells should be more sensitive to exogenously supplied H 2 O 2 than the normal (healthy) cells.…”

Reactive Oxygen Species and Mitochondrial Dynamics: The Yin and Yang of Mitochondrial Dysfunction and Cancer Progression

“…As a membrane-diffusible species, mitochondrially-generated H 2 O 2 has been implicated in cell-wide redox signal transduction [ 72 , 73 , 74 , 75 , 76 , 77 ]. H 2 O 2 can be further reduced by divalent metal ions or superoxide in the Fenton [ 78 ] or Haber-Weiss reactions [ 79 ], respectively, to produce the hydroxyl radical ( ● OH). This highly toxic molecule promiscuously reacts with a broad range of metabolites, thus inducing oxidative damage [ 80 ].…”

Live and let die: Hydrogen peroxide production by the commensal flora and its role in maintaining a symbiotic microbiome

“…H 2 O 2 is the second intermediate formed by the addition of one electron and two protons to the highly unstable superoxide anion. H 2 O 2 is relatively stable and unreactive in an abiotic environment 22,23 . Pure solutions of macromolecules like nucleic acids, proteins (metal-free), lipids, and polysaccharides are typically resistant to H 2 O 2 oxidation.…”