Redox Dependence of the Rate of Interaction of Hydroxyl Radical Adducts of DNA Nucleobases with Oxidants:  Consequences for DNA Strand Breakage

Abstract

Oxidants and oxygen enhance the sensitivity of cells to radiation. To understand this effect at the mechanistic level, the kinetics of interaction of the OH adducts of pyrimidines and 2‘-deoxynucleosides with oxidants (quinones, viologens, nitroarenes) of differing one-electron reduction potentials (−447 to 99 mV) have been determined in aqueous solution at pH 7.5−8 using the technique of pulse radiolysis. With quinones and viologens, this interaction produces the one-electron-reduced species of the oxidants, with rate constants (3.0 × 106 to 2.0 × 109 dm3 mol-1 s-1), which depend significantly on the redox potential of the oxidant. This dependence is consistent with an outer-sphere electron-transfer mechanism. In contrast, an addition (nitroxyl) adduct is formed with nitroarenes with rate constants that are weakly if at all dependent on the one-electron redox potentials of the nitroarenes. Using poly C as a probe for strand breakage, the resulting nitroxyl adduct of the nucleobase radical species in the absence of oxygen leads to strand breakage involving a base to sugar transfer of the radical site with a rate constant of 2.7 s-1. In contrast with benzoquinone, the resulting carbocation of the cytosine moiety of poly C does not result in strand breakage but leads to a decrease in the yield of ssb by ∼60%. Therefore nitroarenes mimic the effects of oxygen in leading to ssb on interaction with hydroxyl radical damage of nucleobases.

Effects of Ionizing Radiation on Biological Molecules—Mechanisms of Damage and Emerging Methods of Detection

“…Radiation damage to deoxyriboses is the primary event underlying strand breakages, which occur in a high frequency and randomly along the DNA backbone in response to both direct OH attack and the activity of nucleic acid-binding enzymes (46). DSBs, in particular, originate through the coordinated reactivity of two OH radicals at nearby ribose sites, ultimately leading to strand breaks through subsequent radical pathways (14,24,350). Both the nucleobases and deoxyribose are targets for OH -mediated damage.…”

Glutaminase inhibitor CB-839 increases radiation sensitivity of lung tumor cells and human lung tumor xenografts in mice

“…Most radiosensitizers are small molecules that inhibit the repair of radiation-induced DNA damage and directly or indirectly increase oxidative stress or related mechanisms (Wang et al 2018). Antioxidants such as GSH directly counteract these mechanisms, and GSH depletion is expected to enhance RT outcome (Bamatraf et al 1998). Here we report the efficacy of CB-839 for GSH depletion and the subsequent increased response to radiation therapy in vitro and in vivo.…”

Enhancement of the radiation response of EMT-6 tumours by a copper octabromotetracarboranylphenylporphyrin

“…For this reason, the total dose administered was reduced to levels that were not associated with significant hypoxic cell radiosensitisation. It is postulated that such compounds react with the hydroxyl adducts of DNA bases and form new radicals, which ultimately result in double strand DNA scission [13,28].…”