Handbook of oxidative stress in cancer--Volume 1. Mechanistic aspects

Preface Contents About the Editors About the Section Editors Contributors Part I: Oxidative Stress in Carcinogenesis 1 Reactive Species and ER-Mitochondrial Performance for Glioblastoma Multiforme Treatment Strategy Introduction Current Status of Glioblastoma Multiforme (GBM) Reactive Species and [Ca2+]i on ER Stress and Mitochondrial Performance ER Stress, Mitochondria, and GBM Genetic Alteration by Reactive Species in GBM Angiogenesis, NADPH Oxidase, and GBM Implications in the Treatment of Gliomas Maintenance of Reactive Species Steady State Targeting ER Components and Autophagy Other Molecular Targets Conclusion References 2 Oxidative Stress and Thyroid Disorders Introduction Hyperthyroidism and OS Papillary Thyroid Carcinoma and OS Medullary Thyroid Carcinoma and OS Anaplastic Thyroid Carcinoma and OS Conclusion References 3 Skin Cancer Induced by Pollution-Mediated ROS Introduction Solar Ultraviolet (UV) Radiation Synergy: UVA Photo-Chemo Pollution Ozone Particulate Matter (PM) Tobacco Smoke The Aryl Hydrocarbon Receptor (AHR) The Aryl Hydrocarbon Receptor (AHR) and Skin Cancer Squamous Cell Carcinoma (SCC) Basal Cell Carcinoma (BCC) Malignant Melanoma Topical Antioxidants to Protect from Environmental Pollution Conclusion Cross-References References 4 Roles of β-Glucans in Oxidative Stress and Cancer Introduction Cancer Carcinogenesis and Cachexia-Anorexia Syndrome Risk Factors Cancer Therapy Oxidative Stress Sources and Effects of Reactive Oxygen Species ROS and Antioxidant Mechanisms Cancer and Oxidative Stress β-Glucans Structural Characterization of β-D-Glucans Anticancer Effects of β-Glucans β-Glucans, Oxidative Stress, and Cancer Conclusions References 5 Oral Cancer and Oxidative Stress Introduction Oral Carcinogenesis Oxidative Stress Oxidative Stress and Oral Carcinogenesis Conclusion Cross-References References 6 Oxidative Stress in Genitourinary Cancer Introduction Kidney Cancer Urothelial Cancer Prostate Cancer Anticancer Therapy for Genitourinary Cancer and Oxidative Stress Conclusions References 7 Oxidative Stress, Microenvironment, and Oral Cancer Introduction Inflammation, Reactive Oxygen Species, and Cancer Reactive Oxygen Species and Inflammation Inflammation, Reactive Oxygen Species, and Cancer Tumor Cell Survival Tumor Cell Proliferation Tumor Cell Invasion Angiogenesis Oral Squamous Cell Carcinoma and Reactive Oxygen Species Tumor Microenvironment and Reactive Oxygen Species Reactive Oxygen Species in Oral Cancer Oncoviruses, Oral Squamous Cell Carcinoma, and Reactive Oxygen Species Reactive Oxygen Species as an Appealing Target for Intervention (Table 8) Reactive Oxygen Species as Alluring Targets for Therapeutic Intervention Reactive Oxygen Species and Oral Potentially Malignant Disorders References 8 Oxidative Stress and Glyoxalase Pathway in Cancer Introduction Glyoxalase System Glyoxalase I (GLOI) Glyoxalase II (GLOII) Glyoxalase III (GLOIII) Methyglyoxal and Cancer Methylglyoxal-Induced Reactive Oxygen Species (ROS) Glyoxalase Enzymes and Cancer Tumor Hypoxia, Cancer Cell Stemness, and Glyoxalase Expression Dual Role of Glyoxalase I in Cancer Modulation of Cellular Pathways by GLOI Overexpression Effect of Ionizing Radiation on Glyoxalase Expression Therapeutic Potential of Glyoxalase Pathway in Cancer Exogenous Application of Methylgloxal for Cancer Therapy Inhibition of Glyoxalase Enzymes as Treatment Modality in Cancer Phytochemicals as Modulators of Glyoxalase Pathway Naringin Galangin Curcumin Oleuropein (OP) Conclusions and Future Directions References 9 The Implication of ROS Homeostasis in the Modulation of EMT Signaling and Its Role in Manipulating Tumor Microenvironment Introduction The Implication of Reactive Oxygen Species in Favoring Epithelial-to-Mesenchymal Transition (EMT) ROS as a Signaling Molecule Controlling Pro-metastatic Responses Regulation of Cytoskeletal Proteins by Reactive Oxygen Species: Consequences on Cellular Motility Manipulations of Tumor Microenvironment by Reactive Oxygen Species to Expedite Metastasis The Integrative Role of ROS During Hypoxia in Facilitating Tumor Metastasis and Angiogenesis Conclusion References 10 Functional Regulation Between Matrix Metalloproteases and Cell Junction Proteins in Gastric Cancer Introduction Matrix Metalloproteinases (MMPs) and Gastric Cancer Cell Junction Proteins in Gastric Cancer Tight Junctions Gap Junction Adherens Junction Crosstalk Between of MMPs and Cell Junction Proteins MMP and Adherence Junction Proteins MMPs and Tight Junction Proteins MMPs and Gap Junction Proteins Conclusion and Future Directions References 11 Association of Oxidative Stress and Mitochondrial Dysfunction to Gynecological Malignancies Introduction Oxidative Stress, ROS, and Antioxidants ROS Paradox: Dual Effect on Cancer Cells Mitochondria as a Hub of Intrinsic ROS Generation mtROS: Prime Oncogenic Factor ROS: A Key Driver of Gynecological Cancer Progression ROS-Driven Metabolic Reprogramming: A Prime Hallmark of Cancer Implications of ROS-Induction on Signaling Aberrations in Cancer ROS Synchronizes Tumor Microenvironment Components in Gynecological Cancers ROS-Based Therapeutic Implications in Cancer Conclusion References 12 Impact of Caenorhabditis elegans in Cancer Drug Resistance Development Introduction Hormesis Cancer and Chemoresistance Hormetic Stressors Conclusion References 13 Scaffold-Based Selective ROS Generation as Viable Therapeutic Strategies Against Cancer Introduction Background Molecular Basis of ROS Production ROS Paradox in Cancer Modulation of ROS as a Therapeutic Target Reduction of ROS Levels: Antioxidants and Nutraceuticals Induction of ROS Levels: Scaffold-Based Chemotherapeutics Quinone Nitrogen Mustard Nitrosoureas Organic Endoperoxides Organic Di- and Polysulfides: Diallyl Trisulfide and Varacin Organosulfur Isothiocyanate: Sulforaphane and β-Phenylethylisothiocyanate Peptide and Nucleoside Taxane, Alkaloid, and Steroid Non-metal and Metal Miscellaneous Scaffolds (Procarbazine, Elesclomol, Erastin, Celecoxib) Prodrug (Masking-Demasking) Conclusion and Future Direction Cross-References References 14 Targeting Oxidative Stress in Cancer Introduction Mechanism of Oxidative Stress Toward Carcinogenesis Amelioration of Oxidative Stress Toward Prevention of Cancer Natural Compounds Some Natural Compounds Act as Antioxidants (Table 1) Role of Synthetic Compounds Biomimic or Nanoflowers Advanced Therapeutics Targeted Therapy Conclusion References 15 Targeting Mitochondria as a Novel Disease-Modifying Therapeutic Strategy in Cancer Introduction Etiology of Cancer Tobacco Environmental Carcinogens Diet, Obesity, and Physical Activity Mitochondrion-Structural Components and Functions Structure of Mitochondria Mitochondrial DNA Functions of Mitochondria Electron Transport Chain in Mitochondria Reactive Oxygen Species in Mitochondria Mitochondrial Dysfunction Therapeutic Targets in Cancer Pathology Mitochondrial Medicine in Cancer Bioenergetic Therapy in Cancer Conclusion and Future Perspective References 16 Cutaneous Unfolded Protein Response (UPR) and Endoplasmic Reticulum (ER) Stress Introduction Sensor-Transducers of the Cutaneous UPR: A Mechanistic Overview The Cutaneous UPR and Environmental Stressors: An Overview The UPR and Skin Photodamage The Cutaneous UPR and Ionizing Radiations The Cutaneous UPR and Toxic Metals The Cutaneous UPR and Paraquat The Cutaneous UPR and Cigarette Smoking The UPR and Particulate Matter The UPR and Chlorine Exposure The UPR and Phenolics The Cutaneous UPR and Cosmetic Products The UPR and the Lewisite The Cutaneous UPR and Sulfur Mustard The Cutaneous UPR and Formaldehyde Exposure Viruses and Cutaneous UPR Bacteria and Cutaneous UPR The UPR Link with Cutaneous Pathologies Role of UPR in Skin Keratinization and Darier´s Disease Role of UPR in Keratosis Linearis with Ichthyosis Cogenita and Keratoderma (KLICK) Syndrome Role of UPR in Erythrokeratoderma Variabilis (EKV) Role of UPR in Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) Syndrome Role of UPR in Keratosis Follicularisspinulosa Decalvans (KFSD) Role of UPR in Rosacea Role of UPR in Epidermolysis Bullosa Simplex Targeting ER Stress for Therapy Therapeutic Targeting of Abnormal UPR in Hereditary Keratosis Enhancing Protein Folding Capacity Targeting Individual UPR Pathways IRE1α Inhibitors PERK Inhibitors ERAD Modulators Modulators of ER Chaperones of ER Stress Signaling Concluding Remarks and Future Directions References 17 Iron Sulfur Clusters and ROS in Cancer Introduction Iron Sulfur Clusters Proteins: Types of Fe-S Biochemistry of Fe-S Proteins Major Proteins Containing Iron Sulfur Clusters in Biological Systems Fe-S Cluster Biosynthetic Machinery Mitochondrial Iron-Sulfur Cluster (ISC) Assembly Machinery: Proteins and Steps Oxidative Stress and Fe-S Cluster Damage How Iron-Sulfur Clusters Generate Reactive Oxygen Species Iron Sulfur Cluster Proteins Linked with Cancer MitoNEET- the Redox Sensor Iron-Sulfur Cluster Assembly Enzyme Aconitase -the Fe-S Regulator Frataxin Nutrient-Deprivation Autophagy Factor-1 (NAF-1) Ferredoxin Reductase Therapeutic Drugs for Cancer That Use or Target Fe-S Clusters Drugs That Generate ROS Via Fe-S Clusters Conclusion References 18 Free Radicals, Reactive Oxygen Species, and Their Biomarkers Introduction Free Radicals and Reactive Oxygen Species Radicals and Free Radicals Reactive Oxygen Species and Oxygen Free Radicals Metal Free Radicals Iron Copper Manganese Zinc Oxidative Stress Biomarkers in Cancer Single Oxidation or Antioxidant Total Oxidant Status, Total Antioxidant Status, and Oxidant Stress Index Measurement of Total Antioxidant Status Measurement of Total Oxidant Status Calculation of Oxidant Stress Index End Products of Lipid Hydroperoxide Conclusions References 19 Zymographic Techniques Introduction Matrix Metalloproteinases in Cancer Types of Zymographic Techniques Basic Protocol of Zymography to Map MMP Activities Materials for Zymography Experiment Sample Preparation Preparation of Gel Sample Loading and Gel Electrophoresis Analysis Antioxidative Enzymes as Cancer Target Zymographic Techniques for Antioxidative Enzymes Zymography Protocol for Catalase Enzyme Zymography Method for SOD Enzyme Conclusion References 20 Biomarkers of Oxidative Stress and Its Dynamics in Cancer Introduction Mitochondrial Biomarkers of Oxidative Stress Regulation of Mitochondrial Dynamics and Its Biogenesis Oxidative Stress in Mitochondrial Dynamics and Its Pathophysiology Pharmacological Strategies to Target Oxidative Stress Biomarkers Impact of Oxidative Stress in Mitochondrial Dynamics Conclusions References 21 Glutathione as Oxidative Stress Marker in Cancer Introduction Reduced and Oxidized Glutathione Prodrugs and Co-drugs of GSH Cancer and Oxidative Stress Mechanism Phase 1 and Phase 2 Detoxification Pathways Phase 1 Pathway Phase 2 Pathway Metal Homeostasis Chromium Copper Iron Glutathione, Metallothionein, and Cancer Glutathione, Free Radicals, and Antioxidants Free Radicals and Reactive Oxygen Antioxidants ROS and Antioxidants Balance Cancer and Glutathione Glutathione, Cancer, and Oxidative Stress Type of Mechanism on Glutathione as a Marker for Cancer Other Oxidative Stress Markers Resembling Glutathione (Benedette 2018; Payal et al. 2016) (Table 3) The Role of Selenoproteins and Glutathione in Cancer Antioxidants May Make Cancer Worse Conclusion Cross-References References 22 Salivary Oxidative Stress Biomarkers in Oral Potentially Malignant Disorders and Squamous Cell Carcinoma Introduction Salivary Diagnostics Tumor Biomarkers and Its Significance Oral Squamous Cell Carcinoma and Oral Potentially Malignant Disorders Oxidative Stress Biomarkers Salivary Oxidative Stress Biomarkers in Oral Cancer Conclusion Cross-References References 23 Recent Development of Monoclonal Antibodies Targeting Tyrosine Kinase in ROS-Mediated Cancer Introduction Reactive Oxygen Species (ROS) and Its Importance in Cancer and Its Treatment MAbs-Based Therapy for ROS-Mediated Cancer Recent Development of mAbs Targeting Tyrosine Kinase of ROS-Mediated Cancer Anti-EGFR Monoclonal Antibodies Anti-HER2 Monoclonal Antibodies Future Scope and Conclusion References 24 Fluoride as a Carcinogen: A Myth or Fact? Introduction Fluoride and Cancer Fluoride and Apoptosis Conclusions References 25 The Role of ROS in Chemical Carcinogenesis Induced by Lead, Nickel, and Chromium Introduction The Role of ROS in Chemical Carcinogenesis Induced by Lead The Role of ROS in Chemical Carcinogenesis Induced by Nickel The Role of ROS in Chemical Carcinogenesis Induced by Chromium Concluding Remarks References 26 Environmental Contaminants, Oxidative Stress, and Reproductive Cancer Introduction Epidemiological Aspect of Reproductive Cancer Environmental Causes of Female Reproductive Cancer Environmental Causes of Male Reproductive Cancer Endocrine Disruptors and Reproductive Cancer Pesticides and Reproductive Cancer Obesogens and Reproductive Cancer Oxidative Stress and Reproductive Cancer Antioxidants and Reproductive Cancer Conclusions References 27 Environmental Toxicants and Carcinogenicity: Role of Oxidative Stress Introduction Heavy Metals, Oxidative Stress, and Cancer Pesticides, Oxidative Stress, and Cancer Conclusion References 28 Environmental and Occupational Exposure to Pesticides and Cancer Development Introduction Environmental and Occupational Exposure to Pesticides Herbicides Organochlorine Pesticides Organophosphate Pesticides Conclusion References 29 Benzo(a)Pyrene-Induced ROS-Mediated Lung Cancer Introduction Benzo(a)Pyrene and Lung Cancer Source and Route of B(a)P B(a)P Metabolism B(a)P and Oxidative Stress Radical Cations and B(a)P Redox-Active Quinone Radical DNA Adducts Oxygen Free Radicals and DNA Adducts Role of Free Radicals in Cigarette Smoking Role of Oxygen Radicals in Initiating Tumors Oxygen Radicals as Tumor Promoters Conclusion References 30 Essential Role of Occupational Hazards in Cancer Among Women Introduction Breast Cancer Colon Cancer Gastrointestinal Cancers Ovarian and Uterine Cancers Lung Cancer Skin Cancer Conclusion References 31 Arsenic: An Environmental Toxicant-Induced Oxidative Stress and Carcinogenesis Introduction Skin Cancer Lung Cancer Bladder Cancer Liver Cancer Kidney Cancer Cellular Metabolism of Arsenic Role of ROS in Arsenic Carcinogenicity Conclusion Cross-References References 32 ROS in Apoptosis of Cancer Cells Introduction Definitions for Cancer Cells, ROS, and Apoptosis Relationship Between Apoptosis and ROS ROS in Regulation of the Mitochondrial or Intrinsic Apoptotic Pathway ROS in Regulation of the Death Receptor or Extrinsic Apoptotic Pathway Apoptosis of Cancer Cells Triggered by ROS Conclusion References 33 Role of ROS in Triggering Death Receptor-Mediated Apoptosis Introduction to Apoptosis Apoptosis Signaling Pathways General Features of Apoptosis Caspase Main Mechanisms of Apoptosis Regulation and Execution The Mitochondrial or Intrinsic Pathway The Death Receptor or Extrinsic Pathway Endoplasmic Reticulum Pathway ROS and Apoptosis The Intrinsic Pathway and ROS ROS and the Extrinsic Pathway The ER Pathway and ROS ROS in Apoptosis and Cell Survival in Cancer Cells ROS Mediator and Executor of Apoptosis Conclusions References 34 Advanced Glycation End Products-Mediated Oxidative Stress and Regulated Cell Death Signaling in Cancer Introduction Receptor for Advanced Glycation End Products (RAGE) AGES and RAGE in Cancer Oxidative Stress and AGE/RAGE Signaling in Cancer AGE/RAGE and Regulated Cell Death Signaling in Cancer Conclusion References 35 Helping Leukemia Cells to Die with Natural or Chemical Compounds Through H2O2 Signaling Introduction An Enemy Within Myself Making Fun of Death Oxidative Distress: The Dose Makes Life or Death Signals H2O2: ``A match that starts bush fires´´ Quo Vadis? Conclusion References 36 Microtubule-Targeting Agents Induce ROS-Mediated Apoptosis in Cancer Introduction Importance of Microtubules in Anticancer Therapy ROS: A Friend or Foe ROS in Cancer Development and Metastasis Cytotoxic Role of ROS in Cancer Cells Mitochondria: The Missing Link Between MTAs and ROS Generation in Cancer Cells Modulation of ROS-Mediated Apoptotic Signaling by MTAs Microtubule Targeting Agent Kills Cancer Cells by Modulating ROS Induced Autophagy Conclusion References 37 ROS Induced by Chemo- and Targeted Therapy Promote Apoptosis in Cancer Cells Introduction ROS: A Double-Edged Sword ROS as an Oncogene ROS as a Tumor Suppressor ROS-Mediated Apoptosis in Malignant Cells by Targeted Therapy Tyrosine Kinase Inhibitors PIM Kinase Inhibitors ROS-Mediated Apoptosis in Malignant Cells by Chemotherapy Strategies and Drugs Targeted to Increases ROS-Mediated Apoptosis in Malignant Cells Conclusion Cross-References References 38 ROS-Mediated Apoptosis in Cancer Introduction ROS in the Mitochondria-Mediated Intrinsic Apoptotic Pathway ROS in the Death Receptor-Mediated Apoptotic Pathway ROS in p53-Mediated Apoptosis ROS in ER Stress-Induced Apoptosis ROS in Calcium-Mediated Apoptosis Prooxidant-Based Cancer Therapy Conclusion Cross-References References 39 Genomic Instability in Carcinogenesis Introduction Genomic Instability - An Overview Genomic Instability and Cancer The Role of Oxidative Stress in Genomic Instability in Cancer Oxidative Stress Induced Genomic Instability in Carcinogenesis: Mechanism and Evidences The Role of Oxidative Stress-Induced Lipid Peroxidation in Genomic Instability Cellular Defense Mechanism against Oxidative Stress-Induced Genomic Instability Conclusion and Future Perspectives References 40 Impact of Environmental and Occupational Exposures in Reactive Oxygen Species-Induced Pancreatic Cancer Introduction Epidemiology of Pancreatic Cancer with Incidence and Prevalence Prevalence/Geographic Distribution of Pancreatic Cancer Environmental, Occupational, Lifestyle, and Genetic Risk Factors for Pancreatic Cancer Age, Gender, and Race Smoking and Tobacco Alcohol Dietary Factors Vitamin D and UVB Irradiation Obesity Occupational Exposures of Heavy Metals Chronic Pancreatitis Infections Genetic Risk Factors Current Treatment of Pancreatic Cancer Reactive Oxygen Species (ROS)/Oxidative Stress Promotes Cancer Development Reactive Oxygen Species (ROS) in Relation to Pancreatic Adenocarcinoma Environmental Risk Factor of Pancreatic Cancer: Tobacco Smoking in Relation to Reactive Oxygen Species Occupational Risk Factor of Pancreatic Cancer: Cadmium Heavy Metal in Pesticide in Relation to Reactive Oxygen Species (ROS) Cadmium Conclusions References 41 Reactive Oxygen Species: Central Regulators of the Tumor Microenvironment Introduction The Origin of ROS: Mitochondrial and Nonmitochondrial Sources Major Producers of ROS in the TME Molecular Events Triggered by ROS: Impact on Tumorigenesis Modulation of Immune Cells by Tumor Microenvironment-Associated Oxidative Stress Natural Killer Cells Dendritic Cells T-Cells Treg Cells ROS Involvement on Immunomodulation by Antitumor Therapeutics Immunotherapy Conclusion References 42 Biomarkers of Oxidative Stress-Induced Cancer Introduction Oxidative Stress and Cancer Biomarkers of Oxidative Stress and Role in Cancer Diagnosis and Treatment Oxidative Stress Biomarker Research in Breast Cancer Oxidative Stress Biomarker Research in Gastro-Intestinal and Colorectal Cancer Oxidative Stress Biomarker Research in Prostate Cancer Biomarkers of Oxidative Stress Research in Lung Cancer Biomarkers of Oxidative Stress Research in Ovarian Cancer Biomarker of Oxidative Stress in Cervical Cancer Conclusion References 43 Reactive Oxygen Species in Male Reproductive Cancers Introduction ROS in Prostate Cancer Development Imbalance in ROS Generation and Antioxidant Protection in Prostate Leads to mtDNA Mutations Mutations in Mitochondrial Genome and Correlation with Prostate Cancer NADPH Oxidase Is a Source of ROS for Prostatic Cancer Cells Androgens in Regulation of ROS Generation in Prostate Cancer Ageing and ROS in Incidence of Prostate Cancer Cancer Prevention by Dietary Antioxidants? Testicular Cancer Regulation of ROS and Aerobic Glycolysis in Testicular Cancer Heat Stress and Testicular Cancers Penile Cancer SOD2 as a Marker for Penile Cancer Metastasis Targeting ROS for Cancer Therapy Conclusions and Future Directions Cross-References References 44 Biomarkers of Oxidative Stress in Cancer and Their Clinical Implications Introduction Reactive Oxygen Species and Oxidative Stress Cellular Sources of ROS Cellular Signaling Mediated by ROS The Antioxidant System ROS Influences Signaling Pathways in Cancer Inflammation and Oxidative Stress in Cancer Biomarkers of Oxidative Stress End Products of Lipid Oxidation By-products of DNA Oxidation By-products of Protein Oxidation Other Biomarkers of Oxidative Stress in Cancer ROS Markers: Methods of Measurement Direct Measurement of ROS Superoxide Hydrogen Peroxide Nitric Oxide Peroxy-Nitrite Assessing the Damage to Macromolecules Such as DNA, Proteins, and Lipids Protein Damage Lipid Damage DNA Damage Measurement of Antioxidant Levels Enzymatic Antioxidants Superoxide Dismutase Catalase Glutathione Peroxidase Nonenzymatic Antioxidants Glutathione Vitamin-C Vitamin-E Clinical Implications of Oxidative Stress Markers in Cancer ROS-Induced Apoptosis ROS-Induced Autophagy and Necrosis ROS-Induced Necrosis ROS-Mediated Resistance to Cancer Therapy ROS as a Marker of Risk Prediction and Prognosis in Cancer Conclusion References 45 The Role of Reactive Oxygen Species on Cellular Fate and Function of Tumor-Infiltrating Lymphocytes Introduction Role of ROS as Signaling Molecules in Cancer ROS and the Immune System ROS and Innate Immunity ROS in Adaptive Immunity ROS Production in the Tumor Microenvironment MDSCs Tumor-Associated Macrophages Tumor Cells ROS and Tumor-Infiltrating Lymphocytes Mechanisms of Action of ROS on Tumor-Infiltrating T Lymphocytes T Cell Hyporesponsiveness Altered T Cell Activation T Cell Death Therapeutic Strategies that Affect ROS and Influence Anti-tumor Immunity Conclusions References 46 ROS-Mediated Inflammatory Response in Cancer Introduction Production of ROS ROS from Mitochondria ROS from Oxidase Activity ROS from Peroxisomes Chronic Inflammation and Cancer Oxidative-Stress-Induced Inflammation Molecular Mechanisms of ROS-Induced Carcinogenesis DNA Damage Role of ROS in DNA Damage Induced by Replication Stress/Other Factors Cell Signaling Cascades in ROS-Mediated Inflammation and Cancer Transcription Factors - NF-κB, STAT, AP-1, HIF-1 Apoptosis and Survival Inflammatory Markers and ROS Tumor Microenvironment Components and Characteristics of TME Hypoxia, Angiogenesis, and Metastasis ROS in Cancer Metastasis Angiogenesis and ROS Regulation of ROS Conclusion References 47 Food Colors and Associated Oxidative Stress in Chemical Carcinogenesis Introduction Use of Synthetic Dyes International Legislations Regulation in the European Union Regulation in the USA, Japan, and China Regulatory Measures in India Carcinogenicity of Food Dyes Oxidative Stress Genotoxicity Neurotoxicity Biotransformation Oxidative Effects and Associated Health Risks of Synthetic Dyes Health Concerns of Approved Dyes Health Concerns of Illegal Dyes Conclusions Cross-References References 48 Benzo(a)Pyrene-Induced Oxidative Stress During Lung Cancer and Treatment with Baicalein Introduction Lung Cancer Epidemiology and Incidence Statistics Known Risk Factors Polycyclic Aromatic Hydrocarbons (PAHs) Benzo(a)pyrene [B(a)P] B(a)P: A Potent Inducer of Oxidative Stress B(a)P-Induced Inflammatory Responses Mechanisms of B(a)P-Induced Lung Cancer Lung Cancer Progression Stages Traditional Treatment for Oxidative Damage and Lung Cancer Free Radical Scavenging and Antioxidant Activity of Baicalein Anti-Inflammatory Activity of Baicalein Conclusion References 49 Assessing the Contributions of Lipid Profile and Oxidative Lipid Damage to Carcinogenesis Introduction Lipids: Key Macromolecules with Structural and Functional Diversities Body Carcinogenesis Through Inflammation Redox Homeostasis: Oxidative Stress and Antioxidant Defense ROS and Lipid Peroxidation in Physiological and Pathophysiological Conditions Dietary, Blood, and Biomembrane Lipid Composition and LPO Products Mechanism of Carcinogenesis Through LPO and Inflammation Organelle Dysfunction Caused by LPO Products Lipid Peroxidation and Its Products: Structure, Signalling, and Cellular Biochemical Effects Conclusion References 50 Oxidative Stress in Hepatocarcinogenesis and Role of Antioxidant Therapy Introduction Liver Cells and Inflammatory Cytokines Mitochondrial Roles in ROS-Induced Hepatocarcinogenesis Viral Hepatitis Increases Free Radicals: Toward HCC Induction Alcohol and Oxidants Cause HCC Warburg Effect Increases Oxidative Stress in HCC Cells Current Preventive and Treatment Modalities of HCC and Related Limitations Antioxidant Therapy for HCC Natural Honey Nigella sativa Ajwa Date Fruit Costus Fennel (Foeniculum vulgare Mill) Conclusion References Part II: ROS- Induced Cancer Progression and Metastasis 51 Oxidative Stress in Orchestrating Genomic Instability-Associated Cancer Progression Introduction Oxidative Stress: Its Generation and Implication in Cancer Oxidative Stress-Mediated DNA Damage Leads to Genomic Instability Chromosomal Instability Telomere Shortening Centrosome Amplification, Multipolarity, and Centrosome Clustering Microsatellite Instability Epigenetic Modifications Oncogenic Replication Stress Oxidative Stress Manipulates DNA Damage Response to Facilitate Genomic Instability Therapeutic Strategies to Mitigate Genomic Instability in Cancer Progression Amelioration of Oxidative Stress to Prohibit Establishment of Genomic Instability Increasing Oxidative Stress to Kill Cancer Cells Via Comprehensive Genomic Degradation Conclusion References 52 Hypoxic Stress Perturb DNA Repair Mechanisms Leading to Genetic Instability Introduction: The Hypoxic Tumor Microenvironment Hypoxia and Reoxygenation Induces Oxidative Stress Through Reactive Oxygen Species (ROS) Hypoxia and the Activation of DNA Damage Response Downregulation of DNA Repair Pathways Under Hypoxia Base Excision Repair (BER) Nucleotide Excision Repair (NER) Mismatch Repair (MMR) Pathway Homology-Directed Repair (HDR) Non-Homologous End Joining (NHEJ) Fanconi Anemia (FA) Pathway Hypoxia Induced Replication Stress Hypoxia Induced Genetic Instability Conclusion References 53 DNA Lesions Induced by Lipid Peroxidation Products in Cancer Progression Introduction DNA Lesions Induced by Reactive Lipid Peroxidation Products Malondialdehyde α,β-Unsaturated Aldehydes Propano Adducts Etheno Adducts Ketoaldehydes DNA Lesions from Lipid Peroxidation in Cancer Development Conclusion Cross-References References 54 Understanding ROS-Induced DNA Damage for Therapeutics Introduction Relevance of ROS-Induced Oxidation in Pathogenesis of Cancer ROS Interaction with Lipids Generation Cytosolic ROS from Proteins Ras Signaling PI3-K/Akt Pathway IKK/NF-κB Pathway Regulation by ROS ROS and Nuclear Signaling Oxidative Stress Promotes Cancer ROS Serves Dual Purpose in Cancer Cancer Progression and Metastasis Are Promoted by CAFs ROS and Cellular Death Pathways Apoptosis Caspases Autophagy and ROS (Programmed Cell Death Type II) Necrosis and ROS Necroptosis (Programmed Cell Death: Type III) Ferroptosis and ROS Therapeutics and ROS ROS and Multidrug Resistance Nuclear ROS Induces DNA Damage ROS Targeted Nanotherapeutic Drugs Conclusion References 55 Mitochondrial Metabolism, Oxidative Stress, and the Microenvironment in Breast Cancer Development and Progression Introduction The Role of Mitochondrial Metabolism in Breast Cancer Development and Progression with Focus on Mitochondria and ROS Production The Importance of Mitochondria for Cancer Cell Metabolism Mitochondrial Functions in Non-cancer Cells and Changes in Cancer Cells The Breast Tumor Microenvironment, Metabolic Interactions and Crosstalk Between Stroma and Tumor Cells Oxidative Stress as an Essential Factor in the Pathogenesis and Progression of Breast Cancer ROS and Oxidative Stress Triggers for ROS Production and Oxidative Stress Oxidative Stress Affecting Sites Distal from Tumor Tissue Conclusions and Perspectives References 56 Role of Oxidative Stress and DNA Damage/Repair in Lung Cancer Introduction Inducers of Lung Cancer Genetic Factors Epigenetics and Lung Cancer Environmental Factors Link Between Inflammation, Oxidative Stress, and DNA Damage Vicious Cycle Between Inflammation and DNA Damage in Development of Lung Cancer (Fig. 1) Relation Between Various Chronic Inflammatory Lung Diseases and Lung Cancer Sources of Reactive Oxidative Species (ROS) in Lung Cancer DNA Repair Mechanisms in Lung Cancer Oxidative Stress/DNA Damage Markers in Lung Cancer Therapeutic Targets in Lung Cancer in Oxidative Stress, DNA Damage, and DNA Repair Controversial Role of Oxidative Stress in Lung Cancer Important Clinical Trials Targeting Redox Candidates in Lung Cancer Conclusions and Future Direction References 57 Oxidative Stress and Cancer: Role of the Nrf2-Antioxidant Response Element Signaling Pathway Introduction Oxidative Stress and Cancer Oxidative Stress Oxidative Stress and Carcinogenesis The Nrf2-Antioxidant Response Element (Nrf2-ARE) Signaling Pathway The Double Role of Nrf2 in Cancer Pro-Oncogenic Effects of Nrf2: Nrf2 as a Proto-Oncogene Nrf2 as Tumor Suppressor Mechanisms of Nrf2 Activation in Cancer Cells Somatic Mutations of Keap1, Nrf2, and Cul3 Epigenetic Modifications of Keap1 Disruption of Nrf2/Keap1 Interactions by Other Signaling Pathways Role of Nrf2 in Chemoresistance Conclusions Cross-References References 58 Role of Macrophages in Oxidative Stress-Induced Inflammatory Tumor Microenvironment Introduction Oxidative Stress and Chronic Inflammation: Important Regulators of Tumor Progression Source of Oxidative Stress Within the Tumor Microenvironment Cancer Cells Microenvironmental Factors Stromal Cells Relat Preface Contents About the Editors About the Section Editors Contributors Part I: Oxidative Stress in Carcinogenesis 1 Reactive Species and ER-Mitochondrial Performance for Glioblastoma Multiforme Treatment Strategy Introduction Current Status of Glioblastoma Multiforme (GBM) Reactive Species and [Ca2+]i on ER Stress and Mitochondrial Performance ER Stress, Mitochondria, and GBM Genetic Alteration by Reactive Species in GBM Angiogenesis, NADPH Oxidase, and GBM Implications in the Treatment of Gliomas Maintenance of Reactive Species Steady State Targeting ER Components and Autophagy Other Molecular Targets Conclusion References 2 Oxidative Stress and Thyroid Disorders Introduction Hyperthyroidism and OS Papillary Thyroid Carcinoma and OS Medullary Thyroid Carcinoma and OS Anaplastic Thyroid Carcinoma and OS Conclusion References 3 Skin Cancer Induced by Pollution-Mediated ROS Introduction Solar Ultraviolet (UV) Radiation Synergy: UVA Photo-Chemo Pollution Ozone Particulate Matter (PM) Tobacco Smoke The Aryl Hydrocarbon Receptor (AHR) The Aryl Hydrocarbon Receptor (AHR) and Skin Cancer Squamous Cell Carcinoma (SCC) Basal Cell Carcinoma (BCC) Malignant Melanoma Topical Antioxidants to Protect from Environmental Pollution Conclusion Cross-References References 4 Roles of β-Glucans in Oxidative Stress and Cancer Introduction Cancer Carcinogenesis and Cachexia-Anorexia Syndrome Risk Factors Cancer Therapy Oxidative Stress Sources and Effects of Reactive Oxygen Species ROS and Antioxidant Mechanisms Cancer and Oxidative Stress β-Glucans Structural Characterization of β-D-Glucans Anticancer Effects of β-Glucans β-Glucans, Oxidative Stress, and Cancer Conclusions References 5 Oral Cancer and Oxidative Stress Introduction Oral Carcinogenesis Oxidative Stress Oxidative Stress and Oral Carcinogenesis Conclusion Cross-References References 6 Oxidative Stress in Genitourinary Cancer Introduction Kidney Cancer Urothelial Cancer Prostate Cancer Anticancer Therapy for Genitourinary Cancer and Oxidative Stress Conclusions References 7 Oxidative Stress, Microenvironment, and Oral Cancer Introduction Inflammation, Reactive Oxygen Species, and Cancer Reactive Oxygen Species and Inflammation Inflammation, Reactive Oxygen Species, and Cancer Tumor Cell Survival Tumor Cell Proliferation Tumor Cell Invasion Angiogenesis Oral Squamous Cell Carcinoma and Reactive Oxygen Species Tumor Microenvironment and Reactive Oxygen Species Reactive Oxygen Species in Oral Cancer Oncoviruses, Oral Squamous Cell Carcinoma, and Reactive Oxygen Species Reactive Oxygen Species as an Appealing Target for Intervention (Table 8) Reactive Oxygen Species as Alluring Targets for Therapeutic Intervention Reactive Oxygen Species and Oral Potentially Malignant Disorders References 8 Oxidative Stress and Glyoxalase Pathway in Cancer Introduction Glyoxalase System Glyoxalase I (GLOI) Glyoxalase II (GLOII) Glyoxalase III (GLOIII) Methyglyoxal and Cancer Methylglyoxal-Induced Reactive Oxygen Species (ROS) Glyoxalase Enzymes and Cancer Tumor Hypoxia, Cancer Cell Stemness, and Glyoxalase Expression Dual Role of Glyoxalase I in Cancer Modulation of Cellular Pathways by GLOI Overexpression Effect of Ionizing Radiation on Glyoxalase Expression Therapeutic Potential of Glyoxalase Pathway in Cancer Exogenous Application of Methylgloxal for Cancer Therapy Inhibition of Glyoxalase Enzymes as Treatment Modality in Cancer Phytochemicals as Modulators of Glyoxalase Pathway Naringin Galangin Curcumin Oleuropein (OP) Conclusions and Future Directions References 9 The Implication of ROS Homeostasis in the Modulation of EMT Signaling and Its Role in Manipulating Tumor Microenvironment Introduction The Implication of Reactive Oxygen Species in Favoring Epithelial-to-Mesenchymal Transition (EMT) ROS as a Signaling Molecule Controlling Pro-metastatic Responses Regulation of Cytoskeletal Proteins by Reactive Oxygen Species: Consequences on Cellular Motility Manipulations of Tumor Microenvironment by Reactive Oxygen Species to Expedite Metastasis The Integrative Role of ROS During Hypoxia in Facilitating Tumor Metastasis and Angiogenesis Conclusion References 10 Functional Regulation Between Matrix Metalloproteases and Cell Junction Proteins in Gastric Cancer Introduction Matrix Metalloproteinases (MMPs) and Gastric Cancer Cell Junction Proteins in Gastric Cancer Tight Junctions Gap Junction Adherens Junction Crosstalk Between of MMPs and Cell Junction Proteins MMP and Adherence Junction Proteins MMPs and Tight Junction Proteins MMPs and Gap Junction Proteins Conclusion and Future Directions References 11 Association of Oxidative Stress and Mitochondrial Dysfunction to Gynecological Malignancies Introduction Oxidative Stress, ROS, and Antioxidants ROS Paradox: Dual Effect on Cancer Cells Mitochondria as a Hub of Intrinsic ROS Generation mtROS: Prime Oncogenic Factor ROS: A Key Driver of Gynecological Cancer Progression ROS-Driven Metabolic Reprogramming: A Prime Hallmark of Cancer Implications of ROS-Induction on Signaling Aberrations in Cancer ROS Synchronizes Tumor Microenvironment Components in Gynecological Cancers ROS-Based Therapeutic Implications in Cancer Conclusion References 12 Impact of Caenorhabditis elegans in Cancer Drug Resistance Development Introduction Hormesis Cancer and Chemoresistance Hormetic Stressors Conclusion References 13 Scaffold-Based Selective ROS Generation as Viable Therapeutic Strategies Against Cancer Introduction Background Molecular Basis of ROS Production ROS Paradox in Cancer Modulation of ROS as a Therapeutic Target Reduction of ROS Levels: Antioxidants and Nutraceuticals Induction of ROS Levels: Scaffold-Based Chemotherapeutics Quinone Nitrogen Mustard Nitrosoureas Organic Endoperoxides Organic Di- and Polysulfides: Diallyl Trisulfide and Varacin Organosulfur Isothiocyanate: Sulforaphane and β-Phenylethylisothiocyanate Peptide and Nucleoside Taxane, Alkaloid, and Steroid Non-metal and Metal Miscellaneous Scaffolds (Procarbazine, Elesclomol, Erastin, Celecoxib) Prodrug (Masking-Demasking) Conclusion and Future Direction Cross-References References 14 Targeting Oxidative Stress in Cancer Introduction Mechanism of Oxidative Stress Toward Carcinogenesis Amelioration of Oxidative Stress Toward Prevention of Cancer Natural Compounds Some Natural Compounds Act as Antioxidants (Table 1) Role of Synthetic Compounds Biomimic or Nanoflowers Advanced Therapeutics Targeted Therapy Conclusion References 15 Targeting Mitochondria as a Novel Disease-Modifying Therapeutic Strategy in Cancer Introduction Etiology of Cancer Tobacco Environmental Carcinogens Diet, Obesity, and Physical Activity Mitochondrion-Structural Components and Functions Structure of Mitochondria Mitochondrial DNA Functions of Mitochondria Electron Transport Chain in Mitochondria Reactive Oxygen Species in Mitochondria Mitochondrial Dysfunction Therapeutic Targets in Cancer Pathology Mitochondrial Medicine in Cancer Bioenergetic Therapy in Cancer Conclusion and Future Perspective References 16 Cutaneous Unfolded Protein Response (UPR) and Endoplasmic Reticulum (ER) Stress Introduction Sensor-Transducers of the Cutaneous UPR: A Mechanistic Overview The Cutaneous UPR and Environmental Stressors: An Overview The UPR and Skin Photodamage The Cutaneous UPR and Ionizing Radiations The Cutaneous UPR and Toxic Metals The Cutaneous UPR and Paraquat The Cutaneous UPR and Cigarette Smoking The UPR and Particulate Matter The UPR and Chlorine Exposure The UPR and Phenolics The Cutaneous UPR and Cosmetic Products The UPR and the Lewisite The Cutaneous UPR and Sulfur Mustard The Cutaneous UPR and Formaldehyde Exposure Viruses and Cutaneous UPR Bacteria and Cutaneous UPR The UPR Link with Cutaneous Pathologies Role of UPR in Skin Keratinization and Darier ́s Disease Role of UPR in Keratosis Linearis with Ichthyosis Cogenita and Keratoderma (KLICK) Syndrome Role of UPR in Erythrokeratoderma Variabilis (EKV) Role of UPR in Ichthyosis Follicularis with Atrichia and Photophobia (IFAP) Syndrome Role of UPR in Keratosis Follicularisspinulosa Decalvans (KFSD) Role of UPR in Rosacea Role of UPR in Epidermolysis Bullosa Simplex Targeting ER Stress for Therapy Therapeutic Targeting of Abnormal UPR in Hereditary Keratosis Enhancing Protein Folding Capacity Targeting Individual UPR Pathways IRE1α Inhibitors PERK Inhibitors ERAD Modulators Modulators of ER Chaperones of ER Stress Signaling Concluding Remarks and Future Directions References 17 Iron Sulfur Clusters and ROS in Cancer Introduction Iron Sulfur Clusters Proteins: Types of Fe-S Biochemistry of Fe-S Proteins Major Proteins Containing Iron Sulfur Clusters in Biological Systems Fe-S Cluster Biosynthetic Machinery Mitochondrial Iron-Sulfur Cluster (ISC) Assembly Machinery: Proteins and Steps Oxidative Stress and Fe-S Cluster Damage How Iron-Sulfur Clusters Generate Reactive Oxygen Species Iron Sulfur Cluster Proteins Linked with Cancer MitoNEET- the Redox Sensor Iron-Sulfur Cluster Assembly Enzyme Aconitase -the Fe-S Regulator Frataxin Nutrient-Deprivation Autophagy Factor-1 (NAF-1) Ferredoxin Reductase Therapeutic Drugs for Cancer That Use or Target Fe-S Clusters Drugs That Generate ROS Via Fe-S Clusters Conclusion References 18 Free Radicals, Reactive Oxygen Species, and Their Biomarkers Introduction Free Radicals and Reactive Oxygen Species Radicals and Free Radicals Reactive Oxygen Species and Oxygen Free Radicals Metal Free Radicals Iron Copper Manganese Zinc Oxidative Stress Biomarkers in Cancer Single Oxidation or Antioxidant Total Oxidant Status, Total Antioxidant Status, and Oxidant Stress Index Measurement of Total Antioxidant Status Measurement of Total Oxidant Status Calculation of Oxidant Stress Index End Products of Lipid Hydroperoxide Conclusions References 19 Zymographic Techniques Introduction Matrix Metalloproteinases in Cancer Types of Zymographic Techniques Basic Protocol of Zymography to Map MMP Activities Materials for Zymography Experiment Sample Preparation Preparation of Gel Sample Loading and Gel Electrophoresis Analysis Antioxidative Enzymes as Cancer Target Zymographic Techniques for Antioxidative Enzymes Zymography Protocol for Catalase Enzyme Zymography Method for SOD Enzyme Conclusion References 20 Biomarkers of Oxidative Stress and Its Dynamics in Cancer Introduction Mitochondrial Biomarkers of Oxidative Stress Regulation of Mitochondrial Dynamics and Its Biogenesis Oxidative Stress in Mitochondrial Dynamics and Its Pathophysiology Pharmacological Strategies to Target Oxidative Stress Biomarkers Impact of Oxidative Stress in Mitochondrial Dynamics Conclusions References 21 Glutathione as Oxidative Stress Marker in Cancer Introduction Reduced and Oxidized Glutathione Prodrugs and Co-drugs of GSH Cancer and Oxidative Stress Mechanism Phase 1 and Phase 2 Detoxification Pathways Phase 1 Pathway Phase 2 Pathway Metal Homeostasis Chromium Copper Iron Glutathione, Metallothionein, and Cancer Glutathione, Free Radicals, and Antioxidants Free Radicals and Reactive Oxygen Antioxidants ROS and Antioxidants Balance Cancer and Glutathione Glutathione, Cancer, and Oxidative Stress Type of Mechanism on Glutathione as a Marker for Cancer Other Oxidative Stress Markers Resembling Glutathione (Benedette 2018; Payal et al. 2016) (Table 3) The Role of Selenoproteins and Glutathione in Cancer Antioxidants May Make Cancer Worse Conclusion Cross-References References 22 Salivary Oxidative Stress Biomarkers in Oral Potentially Malignant Disorders and Squamous Cell Carcinoma Introduction Salivary Diagnostics Tumor Biomarkers and Its Significance Oral Squamous Cell Carcinoma and Oral Potentially Malignant Disorders Oxidative Stress Biomarkers Salivary Oxidative Stress Biomarkers in Oral Cancer Conclusion Cross-References References 23 Recent Development of Monoclonal Antibodies Targeting Tyrosine Kinase in ROS-Mediated Cancer Introduction Reactive Oxygen Species (ROS) and Its Importance in Cancer and Its Treatment MAbs-Based Therapy for ROS-Mediated Cancer Recent Development of mAbs Targeting Tyrosine Kinase of ROS-Mediated Cancer Anti-EGFR Monoclonal Antibodies Anti-HER2 Monoclonal Antibodies Future Scope and Conclusion References 24 Fluoride as a Carcinogen: A Myth or Fact? Introduction Fluoride and Cancer Fluoride and Apoptosis Conclusions References 25 The Role of ROS in Chemical Carcinogenesis Induced by Lead, Nickel, and Chromium Introduction The Role of ROS in Chemical Carcinogenesis Induced by Lead The Role of ROS in Chemical Carcinogenesis Induced by Nickel The Role of ROS in Chemical Carcinogenesis Induced by Chromium Concluding Remarks References 26 Environmental Contaminants, Oxidative Stress, and Reproductive Cancer Introduction Epidemiological Aspect of Reproductive Cancer Environmental Causes of Female Reproductive Cancer Environmental Causes of Male Reproductive Cancer Endocrine Disruptors and Reproductive Cancer Pesticides and Reproductive Cancer Obesogens and Reproductive Cancer Oxidative Stress and Reproductive Cancer Antioxidants and Reproductive Cancer Conclusions References 27 Environmental Toxicants and Carcinogenicity: Role of Oxidative Stress Introduction Heavy Metals, Oxidative Stress, and Cancer Pesticides, Oxidative Stress, and Cancer Conclusion References 28 Environmental and Occupational Exposure to Pesticides and Cancer Development Introduction Environmental and Occupational Exposure to Pesticides Herbicides Organochlorine Pesticides Organophosphate Pesticides Conclusion References 29 Benzo(a)Pyrene-Induced ROS-Mediated Lung Cancer Introduction Benzo(a)Pyrene and Lung Cancer Source and Route of B(a)P B(a)P Metabolism B(a)P and Oxidative Stress Radical Cations and B(a)P Redox-Active Quinone Radical DNA Adducts Oxygen Free Radicals and DNA Adducts Role of Free Radicals in Cigarette Smoking Role of Oxygen Radicals in Initiating Tumors Oxygen Radicals as Tumor Promoters Conclusion References 30 Essential Role of Occupational Hazards in Cancer Among Women Introduction Breast Cancer Colon Cancer Gastrointestinal Cancers Ovarian and Uterine Cancers Lung Cancer Skin Cancer Conclusion References 31 Arsenic: An Environmental Toxicant-Induced Oxidative Stress and Carcinogenesis Introduction Skin Cancer Lung Cancer Bladder Cancer Liver Cancer Kidney Cancer Cellular Metabolism of Arsenic Role of ROS in Arsenic Carcinogenicity Conclusion Cross-References References 32 ROS in Apoptosis of Cancer Cells Introduction Definitions for Cancer Cells, ROS, and Apoptosis Relationship Between Apoptosis and ROS ROS in Regulation of the Mitochondrial or Intrinsic Apoptotic Pathway ROS in Regulation of the Death Receptor or Extrinsic Apoptotic Pathway Apoptosis of Cancer Cells Triggered by ROS Conclusion References 33 Role of ROS in Triggering Death Receptor-Mediated Apoptosis Introduction to Apoptosis Apoptosis Signaling Pathways General Features of Apoptosis Caspase Main Mechanisms of Apoptosis Regulation and Execution The Mitochondrial or Intrinsic Pathway The Death Receptor or Extrinsic Pathway Endoplasmic Reticulum Pathway ROS and Apoptosis The Intrinsic Pathway and ROS ROS and the Extrinsic Pathway The ER Pathway and ROS ROS in Apoptosis and Cell Survival in Cancer Cells ROS Mediator and Executor of Apoptosis Conclusions References 34 Advanced Glycation End Products-Mediated Oxidative Stress and Regulated Cell Death Signaling in Cancer Introduction Receptor for Advanced Glycation End Products (RAGE) AGES and RAGE in Cancer Oxidative Stress and AGE/RAGE Signaling in Cancer AGE/RAGE and Regulated Cell Death Signaling in Cancer Conclusion References 35 Helping Leukemia Cells to Die with Natural or Chemical Compounds Through H2O2 Signaling Introduction An Enemy Within Myself Making Fun of Death Oxidative Distress: The Dose Makes Life or Death Signals H2O2: ``A match that starts bush fires ́ ́ Quo Vadis? Conclusion References 36 Microtubule-Targeting Agents Induce ROS-Mediated Apoptosis in Cancer Introduction Importance of Microtubules in Anticancer Therapy ROS: A Friend or Foe ROS in Cancer Development and Metastasis Cytotoxic Role of ROS in Cancer Cells Mitochondria: The Missing Link Between MTAs and ROS Generation in Cancer Cells Modulation of ROS-Mediated Apoptotic Signaling by MTAs Microtubule Targeting Agent Kills Cancer Cells by Modulating ROS Induced Autophagy Conclusion References 37 ROS Induced by Chemo- and Targeted Therapy Promote Apoptosis in Cancer Cells Introduction ROS: A Double-Edged Sword ROS as an Oncogene ROS as a Tumor Suppressor ROS-Mediated Apoptosis in Malignant Cells by Targeted Therapy Tyrosine Kinase Inhibitors PIM Kinase Inhibitors ROS-Mediated Apoptosis in Malignant Cells by Chemotherapy Strategies and Drugs Targeted to Increases ROS-Mediated Apoptosis in Malignant Cells Conclusion Cross-References References 38 ROS-Mediated Apoptosis in Cancer Introduction ROS in the Mitochondria-Mediated Intrinsic Apoptotic Pathway ROS in the Death Receptor-Mediated Apoptotic Pathway ROS in p53-Mediated Apoptosis ROS in ER Stress-Induced Apoptosis ROS in Calcium-Mediated Apoptosis Prooxidant-Based Cancer Therapy Conclusion Cross-References References 39 Genomic Instability in Carcinogenesis Introduction Genomic Instability - An Overview Genomic Instability and Cancer The Role of Oxidative Stress in Genomic Instability in Cancer Oxidative Stress Induced Genomic Instability in Carcinogenesis: Mechanism and Evidences The Role of Oxidative Stress-Induced Lipid Peroxidation in Genomic Instability Cellular Defense Mechanism against Oxidative Stress-Induced Genomic Instability Conclusion and Future Perspectives References 40 Impact of Environmental and Occupational Exposures in Reactive Oxygen Species-Induced Pancreatic Cancer Introduction Epidemiology of Pancreatic Cancer with Incidence and Prevalence Prevalence/Geographic Distribution of Pancreatic Cancer Environmental, Occupational, Lifestyle, and Genetic Risk Factors for Pancreatic Cancer Age, Gender, and Race Smoking and Tobacco Alcohol Dietary Factors Vitamin D and UVB Irradiation Obesity Occupational Exposures of Heavy Metals Chronic Pancreatitis Infections Genetic Risk Factors Current Treatment of Pancreatic Cancer Reactive Oxygen Species (ROS)/Oxidative Stress Promotes Cancer Development Reactive Oxygen Species (ROS) in Relation to Pancreatic Adenocarcinoma Environmental Risk Factor of Pancreatic Cancer: Tobacco Smoking in Relation to Reactive Oxygen Species Occupational Risk Factor of Pancreatic Cancer: Cadmium Heavy Metal in Pesticide in Relation to Reactive Oxygen Species (ROS) Cadmium Conclusions References 41 Reactive Oxygen Species: Central Regulators of the Tumor Microenvironment Introduction The Origin of ROS: Mitochondrial and Nonmitochondrial Sources Major Producers of ROS in the TME Molecular Events Triggered by ROS: Impact on Tumorigenesis Modulation of Immune Cells by Tumor Microenvironment-Associated Oxidative Stress Natural Killer Cells Dendritic Cells T-Cells Treg Cells ROS Involvement on Immunomodulation by Antitumor Therapeutics Immunotherapy Conclusion References 42 Biomarkers of Oxidative Stress-Induced Cancer Introduction Oxidative Stress and Cancer Biomarkers of Oxidative Stress and Role in Cancer Diagnosis and Treatment Oxidative Stress Biomarker Research in Breast Cancer Oxidative Stress Biomarker Research in Gastro-Intestinal and Colorectal Cancer Oxidative Stress Biomarker Research in Prostate Cancer Biomarkers of Oxidative Stress Research in Lung Cancer Biomarkers of Oxidative Stress Research in Ovarian Cancer Biomarker of Oxidative Stress in Cervical Cancer Conclusion References 43 Reactive Oxygen Species in Male Reproductive Cancers Introduction ROS in Prostate Cancer Development Imbalance in ROS Generation and Antioxidant Protection in Prostate Leads to mtDNA Mutations Mutations in Mitochondrial Genome and Correlation with Prostate Cancer NADPH Oxidase Is a Source of ROS for Prostatic Cancer Cells Androgens in Regulation of ROS Generation in Prostate Cancer Ageing and ROS in Incidence of Prostate Cancer Cancer Prevention by Dietary Antioxidants? Testicular Cancer Regulation of ROS and Aerobic Glycolysis in Testicular Cancer Heat Stress and Testicular Cancers Penile Cancer SOD2 as a Marker for Penile Cancer Metastasis Targeting ROS for Cancer Therapy Conclusions and Future Directions Cross-References References 44 Biomarkers of Oxidative Stress in Cancer and Their Clinical Implications Introduction Reactive Oxygen Species and Oxidative Stress Cellular Sources of ROS Cellular Signaling Mediated by ROS The Antioxidant System ROS Influences Signaling Pathways in Cancer Inflammation and Oxidative Stress in Cancer Biomarkers of Oxidative Stress End Products of Lipid Oxidation By-products of DNA Oxidation By-products of Protein Oxidation Other Biomarkers of Oxidative Stress in Cancer ROS Markers: Methods of Measurement Direct Measurement of ROS Superoxide Hydrogen Peroxide Nitric Oxide Peroxy-Nitrite Assessing the Damage to Macromolecules Such as DNA, Proteins, and Lipids Protein Damage Lipid Damage DNA Damage Measurement of Antioxidant Levels Enzymatic Antioxidants Superoxide Dismutase Catalase Glutathione Peroxidase Nonenzymatic Antioxidants Glutathione Vitamin-C Vitamin-E Clinical Implications of Oxidative Stress Markers in Cancer ROS-Induced Apoptosis ROS-Induced Autophagy and Necrosis ROS-Induced Necrosis ROS-Mediated Resistance to Cancer Therapy ROS as a Marker of Risk Prediction and Prognosis in Cancer Conclusion References 45 The Role of Reactive Oxygen Species on Cellular Fate and Function of Tumor-Infiltrating Lymphocytes Introduction Role of ROS as Signaling Molecules in Cancer ROS and the Immune System ROS and Innate Immunity ROS in Adaptive Immunity ROS Production in the Tumor Microenvironment MDSCs Tumor-Associated Macrophages Tumor Cells ROS and Tumor-Infiltrating Lymphocytes Mechanisms of Action of ROS on Tumor-Infiltrating T Lymphocytes T Cell Hyporesponsiveness Altered T Cell Activation T Cell Death Therapeutic Strategies that Affect ROS and Influence Anti-tumor Immunity Conclusions References 46 ROS-Mediated Inflammatory Response in Cancer Introduction Production of ROS ROS from Mitochondria ROS from Oxidase Activity ROS from Peroxisomes Chronic Inflammation and Cancer Oxidative-Stress-Induced Inflammation Molecular Mechanisms of ROS-Induced Carcinogenesis DNA Damage Role of ROS in DNA Damage Induced by Replication Stress/Other Factors Cell Signaling Cascades in ROS-Mediated Inflammation and Cancer Transcription Factors - NF-κB, STAT, AP-1, HIF-1 Apoptosis and Survival Inflammatory Markers and ROS Tumor Microenvironment Components and Characteristics of TME Hypoxia, Angiogenesis, and Metastasis ROS in Cancer Metastasis Angiogenesis and ROS Regulation of ROS Conclusion References 47 Food Colors and Associated Oxidative Stress in Chemical Carcinogenesis Introduction Use of Synthetic Dyes International Legislations Regulation in the European Union Regulation in the USA, Japan, and China Regulatory Measures in India Carcinogenicity of Food Dyes Oxidative Stress Genotoxicity Neurotoxicity Biotransformation Oxidative Effects and Associated Health Risks of Synthetic Dyes Health Concerns of Approved Dyes Health Concerns of Illegal Dyes Conclusions Cross-References References 48 Benzo(a)Pyrene-Induced Oxidative Stress During Lung Cancer and Treatment with Baicalein Introduction Lung Cancer Epidemiology and Incidence Statistics Known Risk Factors Polycyclic Aromatic Hydrocarbons (PAHs) Benzo(a)pyrene [B(a)P] B(a)P: A Potent Inducer of Oxidative Stress B(a)P-Induced Inflammatory Responses Mechanisms of B(a)P-Induced Lung Cancer Lung Cancer Progression Stages Traditional Treatment for Oxidative Damage and Lung Cancer Free Radical Scavenging and Antioxidant Activity of Baicalein Anti-Inflammatory Activity of Baicalein Conclusion References 49 Assessing the Contributions of Lipid Profile and Oxidative Lipid Damage to Carcinogenesis Introduction Lipids: Key Macromolecules with Structural and Functional Diversities Body Carcinogenesis Through Inflammation Redox Homeostasis: Oxidative Stress and Antioxidant Defense ROS and Lipid Peroxidation in Physiological and Pathophysiological Conditions Dietary, Blood, and Biomembrane Lipid Composition and LPO Products Mechanism of Carcinogenesis Through LPO and Inflammation Organelle Dysfunction Caused by LPO Products Lipid Peroxidation and Its Products: Structure, Signalling, and Cellular Biochemical Effects Conclusion References 50 Oxidative Stress in Hepatocarcinogenesis and Role of Antioxidant Therapy Introduction Liver Cells and Inflammatory Cytokines Mitochondrial Roles in ROS-Induced Hepatocarcinogenesis Viral Hepatitis Increases Free Radicals: Toward HCC Induction Alcohol and Oxidants Cause HCC Warburg Effect Increases Oxidative Stress in HCC Cells Current Preventive and Treatment Modalities of HCC and Related Limitations Antioxidant Therapy for HCC Natural Honey Nigella sativa Ajwa Date Fruit Costus Fennel (Foeniculum vulgare Mill) Conclusion References Part II: ROS- Induced Cancer Progression and Metastasis 51 Oxidative Stress in Orchestrating Genomic Instability-Associated Cancer Progression Introduction Oxidative Stress: Its Generation and Implication in Cancer Oxidative Stress-Mediated DNA Damage Leads to Genomic Instability Chromosomal Instability Telomere Shortening Centrosome Amplification, Multipolarity, and Centrosome Clustering Microsatellite Instability Epigenetic Modifications Oncogenic Replication Stress Oxidative Stress Manipulates DNA Damage Response to Facilitate Genomic Instability Therapeutic Strategies to Mitigate Genomic Instability in Cancer Progression Amelioration of Oxidative Stress to Prohibit Establishment of Genomic Instability Increasing Oxidative Stress to Kill Cancer Cells Via Comprehensive Genomic Degradation Conclusion References 52 Hypoxic Stress Perturb DNA Repair Mechanisms Leading to Genetic Instability Introduction: The Hypoxic Tumor Microenvironment Hypoxia and Reoxygenation Induces Oxidative Stress Through Reactive Oxygen Species (ROS) Hypoxia and the Activation of DNA Damage Response Downregulation of DNA Repair Pathways Under Hypoxia Base Excision Repair (BER) Nucleotide Excision Repair (NER) Mismatch Repair (MMR) Pathway Homology-Directed Repair (HDR) Non-Homologous End Joining (NHEJ) Fanconi Anemia (FA) Pathway Hypoxia Induced Replication Stress Hypoxia Induced Genetic Instability Conclusion References 53 DNA Lesions Induced by Lipid Peroxidation Products in Cancer Progression Introduction DNA Lesions Induced by Reactive Lipid Peroxidation Products Malondialdehyde α,β-Unsaturated Aldehydes Propano Adducts Etheno Adducts Ketoaldehydes DNA Lesions from Lipid Peroxidation in Cancer Development Conclusion Cross-References References 54 Understanding ROS-Induced DNA Damage for Therapeutics Introduction Relevance of ROS-Induced Oxidation in Pathogenesis of Cancer ROS Interaction with Lipids Generation Cytosolic ROS from Proteins Ras Signaling PI3-K/Akt Pathway IKK/NF-κB Pathway Regulation by ROS ROS and Nuclear Signaling Oxidative Stress Promotes Cancer ROS Serves Dual Purpose in Cancer Cancer Progression and Metastasis Are Promoted by CAFs ROS and Cellular Death Pathways Apoptosis Caspases Autophagy and ROS (Programmed Cell Death Type II) Necrosis and ROS Necroptosis (Programmed Cell Death: Type III) Ferroptosis and ROS Therapeutics and ROS ROS and Multidrug Resistance Nuclear ROS Induces DNA Damage ROS Targeted Nanotherapeutic Drugs Conclusion References 55 Mitochondrial Metabolism, Oxidative Stress, and the Microenvironment in Breast Cancer Development and Progression Introduction The Role of Mitochondrial Metabolism in Breast Cancer Development and Progression with Focus on Mitochondria and ROS Production The Importance of Mitochondria for Cancer Cell Metabolism Mitochondrial Functions in Non-cancer Cells and Changes in Cancer Cells The Breast Tumor Microenvironment, Metabolic Interactions and Crosstalk Between Stroma and Tumor Cells Oxidative Stress as an Essential Factor in the Pathogenesis and Progression of Breast Cancer ROS and Oxidative Stress Triggers for ROS Production and Oxidative Stress Oxidative Stress Affecting Sites Distal from Tumor Tissue Conclusions and Perspectives References 56 Role of Oxidative Stress and DNA Damage/Repair in Lung Cancer Introduction Inducers of Lung Cancer Genetic Factors Epigenetics and Lung Cancer Environmental Factors Link Between Inflammation, Oxidative Stress, and DNA Damage Vicious Cycle Between Inflammation and DNA Damage in Development of Lung Cancer (Fig. 1) Relation Between Various Chronic Inflammatory Lung Diseases and Lung Cancer Sources of Reactive Oxidative Species (ROS) in Lung Cancer DNA Repair Mechanisms in Lung Cancer Oxidative Stress/DNA Damage Markers in Lung Cancer Therapeutic Targets in Lung Cancer in Oxidative Stress, DNA Damage, and DNA Repair Controversial Role of Oxidative Stress in Lung Cancer Important Clinical Trials Targeting Redox Candidates in Lung Cancer Conclusions and Future Direction References 57 Oxidative Stress and Cancer: Role of the Nrf2-Antioxidant Response Element Signaling Pathway Introduction Oxidative Stress and Cancer Oxidative Stress Oxidative Stress and Carcinogenesis The Nrf2-Antioxidant Response Element (Nrf2-ARE) Signaling Pathway The Double Role of Nrf2 in Cancer Pro-Oncogenic Effects of Nrf2: Nrf2 as a Proto-Oncogene Nrf2 as Tumor Suppressor Mechanisms of Nrf2 Activation in Cancer Cells Somatic Mutations of Keap1, Nrf2, and Cul3 Epigenetic Modifications of Keap1 Disruption of Nrf2/Keap1 Interactions by Other Signaling Pathways Role of Nrf2 in Chemoresistance Conclusions Cross-References References 58 Role of Macrophages in Oxidative Stress-Induced Inflammatory Tumor Microenvironment Introduction Oxidative Stress and Chronic Inflammation: Important Regulators of Tumor Progression Source of Oxidative Stress Within the Tumor Microenvironment Cancer Cells Microenvironmental Factors Stromal Cells Re