Review Reactive Chemicals and Electrophilic Stress in Cancer Vehary SAKANYAN Université de Nantes, Faculté de Pharmacie, Faculté des Sciences et des Techniques, IICiMed, 2 rue de la Houssinière, 44322 Nantes, France * Correspondence: vehary.sakanyan@univ-nantes.fr; Tel : +33-(0)25-112-5620 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 nitro- benzofurazan) 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. Keywords: cancer; electrophilic stress; oxidative stress; reactive molecules; high-throughput screening; microarrays; nitro-benzoxadiazole; fluorescence detection. 1. Introduction The emergence of redox cycling of molecular oxygen in cells had been apparently accompanied by the evolution of 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. The abundance of intracellular hydrogen peroxide (H2O2) appears to be the main cause of oxidative stress, which is frequently associated with the development of cancer, neurodegenerative disorders, and autoimmune diseases [1]. In animal cells, metal-dependent superoxide dismutases (SOD) are considered as key enzymes that convert a short half-life superoxide anion (O2 − ) to the neutrally charged and more stable H2O2, which moves easily through membranes [2]. In high doses, H2O2 reacts with DNA, lipids, and proteins, leading to tissue damage and cell death, whereas in low doses, this molecule functions as a secondary signal transmitter in cells [3]. Chemical substances synthesized for industry, agriculture, and medicine are potential sources of ROS, and therefore, the exposure of the human organism to pollutants over many years can lead to the development of cancer [4]. Reactive chemicals cause oxidative stress, to which the cell responds by activating chemo-protective mechanisms, which are regulated mainly at the transcriptional level through the Nrf2/Keap1/ARE pathway [5]. The excessive production of ROS is not the only cause associated with pathological processes in cells exposed to chemicals. Exogenous chemicals also generate reactive electrophilic species (referred to as RES) in cells, which react with intracellular nucleophilic substrates including DNA, lipids, and proteins. Investigations of various aspects of electrophilic stress revealed a correlation between the formation of DNA adducts, induction of Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 5 March 2018 doi:10.20944/preprints201803.0028.v1 © 2018 by the author(s). Distributed under a Creative Commons CC BY license.