Role of Reactive Oxygen Species ROS in Therapeutics and Drug Resistance in Cancer and Bacteria Allimuthu T Dharmaraja Department of Genetics and Genome Sciences and Comprehensive Cancer Center School of Medicine Case Western Reserve University Cleveland Ohio 44106 United States ABSTRACT Evading persistent drug resistance in cancer and bacteria is quintessential to restore health in humans and impels intervention strategies A distinct property of the cancer phenotype is enhanced glucose metabolism and oxidative stress Reactive oxygen species ROS are metabolic byproducts of aerobic respiration and are responsible for maintaining redox homeostasis in cells Redox balance and oxidative stress are orchestrated by antioxidant enzymes reduced thiols and NADP H cofactors which is critical for cancer cells survival and progression Similarly Escherichia coli E coli and life threatening infectious pathogens such as Staphylococcus aureus SA and Mycobacterium tuberculosis Mtb are appreciably sensitive to changes in the intracellular oxidative environment Thus small molecules that modulate antioxidant levels and or enhance intracellular ROS could disturb the cellular oxidative environment and induce cell death and hence could serve as novel therapeutics Presented here are a collection of approaches that involve ROS modulation in cells as a strategy to target cancer and bacteria INTRODUCTION Chemical genetics is one of the successful strategies widely explored for the identifi cation of drug candidates and their mechanism of action in cells 1Phenotypic screening of drug candidates exploits the genetic diff erences in cancerous cells and has identifi ed many successful FDA approved drugs including afatinib imatinib and trastuzumab and others such as neratinib that are in advanced clinical development However sustaining the effi cacy of marketed drugs has been a challenge due to the prevailing drug resistance in cancer which often necessitates intervention strategies 2During aerobic respiration and cellular metabolism oxygen is converted into water and carbon dioxide respectively to produce energy in the of adenosine triphosphate ATP in cells 3In these processes oxygen is partially reduced to reactive radical and nonradical oxygen species In cells superoxide O2 is generated by 1 e transfer to O2either from the electron transport chain ETC or by NADPH oxidase NOX enzyme O2 is known to damage iron sulfur cluster proteins Fe S which leads to release of Fe II into the extracellular matrix and as an eff ect inactivation of the function of Fe S cluster proteins Schemes 1a and 2 4 5This O2 species undergoes a dismutation to hydrogen peroxide H2O2 in a buff er or catalyzed by a family of enzymes called superoxide dismutases SOD Scheme 2 H2O2is reactive toward a variety of functional groups in biomolecules for example the thiol of the cysteine containing proteins is oxidized to sulfenic acids Scheme 1b This in turn can undergo subsequent oxidations by additional equivalents of H2O2 to sulfi nic and sulfonic acids that could permanently inactivate the protein function 5 8 Next hydroxyl radical OH one of the highly reactive ROS is generated by a metal Fe II or Cu I mediated reduction of H2O2through the Fenton reaction Schemes 1 and 2 Hydroxyl radical directly reacts with DNA which is often irreversible causing oxidative damage and eventually leading to mutations in the DNA sequence 5 7The reactive sites in DNA are the sugar backbone and nucleobases In ribose C 4 tertiary radical is generated and subsequent uncontrolled reactions lead to DNA degradation or mutations Among the nucleobases guanine is a highly reactive base that s 8 oxoguanine during its reaction with OH Thymine another nucleobase undergoes an addition reaction with OH ing thymine radical species and inducing mutations in DNA Proteins are known to be oxidized by OH mainly thiol containing amino acids including methionine and these residues are oxidized to their corresponding sulfoxides Scheme 1b Protein carbonyls are generated by a reaction of OH with amino acids such as lysine arginine proline and histidine at the carboxylic acid functional group and oxidation of histidine residues in proteins produces 2 oxo histidines 6 8 ation of hypochlorous acid HOCl from H2O2in cells is catalyzed by the enzyme myeloperoxidase MPO Scheme 2 This species HOCl is reactive toward biomolecules and found to oxidize cysteine residues to cysteine sulfenic acid and tyrosine residues to dityrosines in proteins HOCl is much more reactive 3 107M 1s 1 than H2O2 0 9 M 1s 1 as observed in oxidizing glutathione Hydroxyl radical OH is the source of a generation of hydroperoxyl or organoperoxy Received August 16 2016 Published January 30 2017 Perspective pubs acs org jmc XXXX American Chemical SocietyADOI 10 1021 acs jmedchem 6b01243 J Med Chem XXXX XXX XXX XXX radicals which can damage lipids by oxidation and peroxidation Scheme 1b 6These radical and nonradical oxygen specie