Reactive Chemicals and Electrophilic Stress in Cancer

Abstract

Exogenous reactive chemicals can impair cellular homeostasis and are often associated with the progression of cancer. Significant progress has been achieved by studying the 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 remains largely unclear. Derivatives of nitro-benzoxadiazole (also referred as nitrobenzofurazan) are potent producers of hydrogen peroxide and have been used as a model to elucidate the generation of reactive species in cancer cells. This survey highlights the pivotal role of Cu/Zn superoxide dismutase 1 (SOD1) in the rapid generation of reactive oxygen and electrophilic species in cells exposed to cell-permeable chemicals. Lipophilic electrophiles 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. 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.