Chapter
Generation of ROS during Cancer Therapy
Antioxidants that Act as Metal Chelators
Antioxidants and DNA Damage
Endogenous Enzymatic Antioxidants
Oxidative Stress and Carcinogenesis
Role of Antioxidants in Cancer
Oncology Therapy and Antioxidants
Conclusion and Perspectives
Chapter III: Vitamin E Isoforms: Multiple Mechanisms of Action against Carcinogenesis
Diet Plays a Role in Cancer Risk
Vitamin E Compounds Other than Alpha Tocopherol are Physiologically Relevant
Vitamin E has Antioxidant Properites BUT Also Plays a Role in Signal Transduction Modulation
Vitamin E is at Least Eight Structurally Related Compounds
Synthetic Vitamin E is Not Identical to Natural Vitamin E
Vitamin E Transport and Metabolism Occur in the Liver with Different Reaction Kinetics Depending Upon Various Conditions
The Role of Vitamin E Isoforms on Apoptosis
Natural Vitamin E Isoforms are Effective Apoptotic Modulators in Cancer Cell Lines
Apoptotic Induction by Natural Tocopherols and Tocotrienols Occurs in Animal Models
Natural Tocotrienols Need not be Purified to Demonstrate Apoptotic Activity
Synthetic Forms of Vitamin E Result in Apoptosis of Cancer Cells
Anticancer Effects of Synthetic Vitamin E Analogues Using Apoptosis as an Endpoint
The Influence of Vitamin E Isoforms on Cell Cycle, Cell Proliferation, and Tumor Burden
a-VES Modulates the Cell Cycle
Cell Cycle Modulation is Also Regulated by Tocotrienols
Cell Cycle Intervention by Vitamin E Isoforms in Animal Models
Non-Alpha-Tocopherol Forms of Vitamin E Reduce Tumor Burden in Animal Models
Vitamin E Inhibits Radiation-Induced Genotoxicity
Epidemiological Evidence that Multiple Forms of Vitamin E, Rather than Alpha Tocopherol Alone May be Chemopreventive
Vitamin E’s Role in Oxidative Stress and Cancer
Vitamin E and Aberrant Crypt Foci
Some Vitamin E Isoforms May Exert Anticancer Effects by Non-Redox Mechanisms
The Potential for Vitamin E Isoforms to be Used as Adjuvant Chemotherapy
Some Vitamin E Isoforms Demonstrate an Ability to Enhance the Antiproliferative Effects of Chemotherapy in Cancer Cell Lines
Some Vitamin E Isoforms Reduce the Harmful Side Effects of Chemotherapeutic Agents
Vitamin E Isoforms Modulate Major Regulatory Elements Involved in Inflammation
Vitamin E Isoforms Modulate Pathways Involved in Metastasis
Vitamin E Isoforms Modulate Ras Levels Resulting in Cell Cycle Arrest and Apoptosis
Vitamin E Modulates the Master Fat Regulatory Element, Peroxisome Proliferator Activator Receptor, (PPAR)
Receptor Tyrosine Kinase Activity is Modulated by Redox Silent Forms of Vitamin E as Well as Naturally occuring Vitamin E forms
Vitamin E Compounds Modulate Proteins Involved in the Sphingolipid and Cholesterol Metabolism
Chapter IV: Glutaredoxin in Cancer Development, Progression, Chemo-Resistance and Clinical Applications
1. The Glutaredoxin System
2. Grxs in Cancer Development
2.1. Expression of Grxs in Human Cancers
2.2. Cancer Specific Isoforms and Subcellular Localizations
2.3 The Role of Grxs in Cancer Cell Proliferation and Survival
2.4. Reversible Glutathionylation of Cancer-Associated Proteins by Grxs
2.5. The Role of Grxs in the Cancer Microenvironment
3. Grxs in Cancer Metastasis and Therapy Resistance
3.1. Grxs in Cancer Metastasis
3.2. The Role of Grxs in Therapy Resistance
3.3. Grx Levels and Drug Sensitivity
3.4. The Involment of Grxs in Drug Metabolism
4. Grxs as Potential Targets in Cancer Treatment
4.1. Killing Cancer Cells by Targeting Grxs
4.2. Detection of Grxs in Serum as Biomarkers
4.3. Detection of Mutations and Post-Translational Modifications
Chapter V: Pharmacological Ascorbate: Oxidative Stress and the Treatment of Pancreatic Cancer
Introduction and Background
Ascorbate (Ascorbic Acid, Vitamin C)
Ascorbate as a Cancer Therapeutic Agent
Ascorbate Induced Cytotoxicity in Pancreatic Cancer
Mechanism of Ascorbate Induced Cytotoxicity in Pancreatic Cancer
Enhancement of Ascorbate-Induced Cytotoxicity in Pancreatic Cancer
Phase I Clinical Trials of Ascorbate in Pancreatic Cancer
Intravenous Ascorbate in Patients with Advanced Cancers to Investigate Dose Tolerance, Pharmacokinetics, Plasma Concentrations and Safety
Pharmacological Ascorbate in the Treatment of Pancreatic Cancer:
Pharmacological Ascorbate as an Adjuvant to Radiotherapy
Chapter VI: The Design, Synthesis and In Vitro Evaluation of a Novel Pro-Oxidant Anticancer Prodrug Substrate Targeted to Acylamino-Acid-Releasing Enzyme
Oxidative Stress and Cancer
Akt Activation, Glutathione (GSH) and Oxidative Stress in Cancer Cells
Acylamino-acid-releasing Enzyme (AARE) as an Anticancer Drug Target
The Known Functions of AARE
Nitric oxide Generating Prodrugs and Oxidative Stress Induced Apoptosis in Cancer Cells
The Rational Design and In Vitro Evaluation of a Novel Prodrug Ester, (4-[(nitrooxy) Phenyl-N-acetyl-L-alaninate or NPAA) Activated by Acylamino-acid-releasing Enzyme
There Are No Reported Structures for Any Mammalian AARE
Protein-Structure Modeling
Energy Minimization and Refinement of Initial AARE Models
Structural Quality of AARE Models before and after Energy Minimization
Protein-ligand Docking and Drug Binding Sites in AARE
Organic Synthesis of the Novel 4-[(nitrooxy)phenyl-N-acetyl-L-alaninate (NPAA) Prodrug
In Vitro Glutathione (GSH) Depletion Assay
Predicted Protein Structures, Refinement and Structural Evaluation Analyses
The Active Site of AARE as Compared to other Serine Proteases: An Additional Measure of AARE Structural Quality
Ramachandran Plot Quality, YASARA Energy Minimization and the Spatial Distribution of Conserved Amino Acid Residues in AARE Models
I-TASSER Results in More Detail and with MolProbity Scores Suggesting Reasonable Models
Structural Features of the Optimal AARE Models
Blind Docking Calculations Show that Both N-acetyl-L-alanine-4-nitroanilide (AANA) and the Prototype QM Donating Analogue of AANA (NPAA) Bind at the Active Site of Human and Rat ITY-AARE Models with Reasonable Affinities
The Binding Site for AANA and NPAA in ITY-hAARE and ITY-rAARE Is in a Pocket with a High Druggability Score
Proof of Concept for the Glutathione (GSH) Depleting Ability of NPAA in the Presence of rAARE
Exploiting the Esterase Activity of AARE for Pro-oxidant Anticancer Prodrug Activation
The Potential Utility of Having 3D AARE Models for the Design of Anticancer Drugs
Chapter VII: The Role of the Antioxidant Defense System in the Pathogenesis of Colorectal Cancer
Institute of Pathology, Medical Experimental Centre,
Faculty of Medicine, University of Ljubljana, Slovenia
Antioxidative Protective Mechanisms
Mechanisms Directed towards the Prevention of Production of Free Radicals
Mechanisms Directed towards Reduction/Neutralization of Increased Production of Free Radicals
Mechanisms Directed towards Repair or Elimination of Damage Caused by Free Radicals
The Role and Failure of Antioxidative Protective Mechanisms in the Pathogenesis of Cancer
The Role and/or Failure of Antioxidative Protective Mechanisms in the Pathogenesis of Colorectal Cancer
Homeostatic Mechanisms and the Antioxidant Paradox
Protective Mechanisms of the Gut
Colorectal Carcinogenesis
Chapter VIII: Oxidative Stress Imbalance in the Development of Prostate Cancer
Prostate Structure and Function
Pro-Oxidants Lead to Oxidative Damage
Prostate Cancer Development
Benign Prostatic Hyperplasia
Prostatic Intraepithelial Neoplasia
Hypoxia in Prostate Cancer
Hormones in Prostate Cancer
Molecular Aspects of Prostate Cancer
Prevention of Prostate Cancer
Detection of Prostate Cancer
Chapter IX: Registering Superoxide Production in Live Neuronal Cultures by EPR
1. Preparation of Culture Media and Cell Cultures
2. Preparation of Coverslips
3. Seeding Cells onto Coverslips
4. Treating Cells for Experimentation
5. EPR Measurement of Superoxide Production from Living Cells
Chapter X: Role of Antioxidants in Cancer Onset and Development
TAC and Oxidative Stress-Related Diseases
Cancer Generation, Progression and Promotion
Oxidative Stress and Inflammation Plays an Important Role in Cancer Development
Antioxidants Can Be Effective in Treating Prostate Cancer in the TRAMP Mouse Model
Importance of 5-Hydroxymethylcytosine (5hmC)
Free Radicals: The Role of Antioxidants and Pro-oxidants in Cancer Development
( Cancer Etiology, Diagnosis and Treatments )
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