Abstract
Exogenous reactive chemicals can impair cellular homeostasis and are often associated with the development of cancer. Significant progress has been achieved by studying the macromolecular interactions of chemicals that possess various electron-withdrawing groups and the elucidation of the protective responses of cells to chemical interventions. However, the formation of electrophilic species inside the cell and the relationship between oxydative and electrophilic stress remain largely unclear. Derivatives of nitro-benzoxadiazole (also referred as nitro-benzofurazan) are potent producers of hydrogen peroxide and have been used as a model to study the generation of reactive species in cancer cells. This survey highlights the pivotal role of Cu/Zn superoxide dismutase 1 (SOD1) in the production of reactive oxygen and electrophilic species in cells exposed to cell-permeable chemicals. Lipophilic electrophiles rapidly bind to SOD1 and induce stable and functionally active dimers, which produce excess hydrogen peroxide leading to aberrant cell signalling. Moreover, reactive oxygen species and reactive electrophilic species, simultaneously generated by redox reactions, behave as independent entities that attack a variety of proteins. It is postulated that the binding of the electrophilic moiety to multiple proteins leading to impairing different cellular functions may explain unpredictable side effects in patients undergoing chemotherapy with reactive oxygen species (ROS)-inducing drugs. The identification of proteins susceptible to electrophiles at early steps of oxidative and electrophilic stress is a promising way to offer rational strategies for dealing with stress-related malignant tumors.
Highlights
The emergence of redox cycling of molecular oxygen in cells serve as safeguarding mechanisms against the toxicity of reactive oxygen species
Numerous studies for nearly five decades have contributed to understanding the role of reactive oxygen species (ROS) in oxidative stress, when the overwhelming production of ROS exceeds the ability of the cellular antioxidant system to neutralize reactive molecules [1,2]
H2O2 can be converted to a short lifetime and more reactive hydroxyl radical (OH), which is responsible for the formation of oxidized DNA base products, such as hydroxy-2 -deoxyguanosine, resulting in mutations and development of cancer [6]
Summary
The emergence of redox cycling of molecular oxygen in cells serve as safeguarding mechanisms against the toxicity of reactive oxygen species. A weak inhibition of EGFR phosphorylation with a neutralizing antibody and the activation of a larger set of RTKs when compared to a cognate ligand EGF (see Figure 1) were in favour of the generation of H2O2 with NBD compounds differently from the binding EGF, without implication of the extracellular region dimerization of the receptor. In any case, these data demonstrate the vulnerability of EGFR in the perception of external chemical signals leading to aberrant activation of downstream pathways. In the absence of appropriate downstream reactions, catalyzed by catalase and/or glutathione peroxidase, the induced by lipophilic NBD compounds dimers of SOD1 produced an excessive amount of H2O2, which rapidly impair the signaling functions of protein kinases
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