Abstract
Background: Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photodamage and carcinogenesis, and inflammatory dysregulation is a key mechanism underlying detrimental effects of acute and chronic UV exposure. The health and economic burden of skin cancer treatment is substantial, creating an increasingly urgent need for the development of improved molecular strategies for photoprotection and photochemoprevention.
Methods: A structured search of bibliographic databases for peer-reviewed research literature revealed 139 articles including our own that are presented and critically evaluated in this TLR4-directed review.
Objective: To understand the molecular role of Toll-like receptor 4 (TLR4) as a key regulator of skin anti-microbial defense, wound healing, and cutaneous tumorigenic inflammation. The specific focus of this review is on recent published evidence suggesting that TLR4 represents a novel molecular target for skin photoprotection and cancer photochemoprevention.
Results: Cumulative experimental evidence indicates that pharmacological and genetic antagonism of TLR4 suppresses UV-induced inflammatory signaling involving the attenuation of cutaneous NF-κB and AP-1 stress signaling observable in vitro and in vivo. TLR4-directed small molecule pharmacological antagonists [including eritoran, (+)-naloxone, ST2825, and resatorvid] have now been identified as a novel class of molecular therapeutics. TLR4 antagonists are in various stages of preclinical and clinical development for the modulation of dysregulated TLR4-dependent inflammatory signaling that may also contribute to skin photodamage and photocarcinogenesis in human populations.
Conclusion: Future research should explore the skin photoprotective and photochemopreventive efficacy of topical TLR4 antagonism if employed in conjunction with other molecular strategies including sunscreens.
Keywords: TLR4, skin photodamage, UV exposure, photocarcinogenesis, pharmacological TLR4 modulation, resatorvid.
Current Medicinal Chemistry
Title:TLR4-directed Molecular Strategies Targeting Skin Photodamage and Carcinogenesis
Volume: 25 Issue: 40
Author(s): Sally E. Dickinson*Georg T. Wondrak*
Affiliation:
- Department of Pharmacology, College of Medicine and The University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724,United States
- Department of Pharmacology and Toxicology, College of Pharmacy and The University of Arizona Cancer Center, University of Arizona, Tucson, AZ 85724,United States
Keywords: TLR4, skin photodamage, UV exposure, photocarcinogenesis, pharmacological TLR4 modulation, resatorvid.
Abstract: Background: Exposure to solar ultraviolet (UV) radiation is a causative factor in skin photodamage and carcinogenesis, and inflammatory dysregulation is a key mechanism underlying detrimental effects of acute and chronic UV exposure. The health and economic burden of skin cancer treatment is substantial, creating an increasingly urgent need for the development of improved molecular strategies for photoprotection and photochemoprevention.
Methods: A structured search of bibliographic databases for peer-reviewed research literature revealed 139 articles including our own that are presented and critically evaluated in this TLR4-directed review.
Objective: To understand the molecular role of Toll-like receptor 4 (TLR4) as a key regulator of skin anti-microbial defense, wound healing, and cutaneous tumorigenic inflammation. The specific focus of this review is on recent published evidence suggesting that TLR4 represents a novel molecular target for skin photoprotection and cancer photochemoprevention.
Results: Cumulative experimental evidence indicates that pharmacological and genetic antagonism of TLR4 suppresses UV-induced inflammatory signaling involving the attenuation of cutaneous NF-κB and AP-1 stress signaling observable in vitro and in vivo. TLR4-directed small molecule pharmacological antagonists [including eritoran, (+)-naloxone, ST2825, and resatorvid] have now been identified as a novel class of molecular therapeutics. TLR4 antagonists are in various stages of preclinical and clinical development for the modulation of dysregulated TLR4-dependent inflammatory signaling that may also contribute to skin photodamage and photocarcinogenesis in human populations.
Conclusion: Future research should explore the skin photoprotective and photochemopreventive efficacy of topical TLR4 antagonism if employed in conjunction with other molecular strategies including sunscreens.
Export Options
About this article
Cite this article as:
Dickinson E. Sally*, Wondrak T. Georg *, TLR4-directed Molecular Strategies Targeting Skin Photodamage and Carcinogenesis, Current Medicinal Chemistry 2018; 25 (40) . https://dx.doi.org/10.2174/0929867324666170828125328
DOI https://dx.doi.org/10.2174/0929867324666170828125328 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
Call for Papers in Thematic Issues
Advances in Medicinal Chemistry: From Cancer to Chronic Diseases.
The broad spectrum of the issue will provide a comprehensive overview of emerging trends, novel therapeutic interventions, and translational insights that impact modern medicine. The primary focus will be diseases of global concern, including cancer, chronic pain, metabolic disorders, and autoimmune conditions, providing a broad overview of the advancements in ...read more
Approaches to the treatment of chronic inflammation
Chronic inflammation is a hallmark of numerous diseases, significantly impacting global health. Although chronic inflammation is a hot topic, not much has been written about approaches to its treatment. This thematic issue aims to showcase the latest advancements in chronic inflammation treatment and foster discussion on future directions in this ...read more
Cellular and Molecular Mechanisms of Non-Infectious Inflammatory Diseases: Focus on Clinical Implications
The Special Issue covers the results of the studies on cellular and molecular mechanisms of non-infectious inflammatory diseases, in particular, autoimmune rheumatic diseases, atherosclerotic cardiovascular disease and other age-related disorders such as type II diabetes, cancer, neurodegenerative disorders, etc. Review and research articles as well as methodology papers that summarize ...read more
Chalcogen-modified nucleic acid analogues
Chalcogen-modified nucleosides, nucleotides and oligonucleotides have been of great interest to scientific research for many years. The replacement of oxygen in the nucleobase, sugar or phosphate backbone by chalcogen atoms (sulfur, selenium, tellurium) gives these biomolecules unique properties resulting from their altered physical and chemical properties. The continuing interest in ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Folate-Linked Lipid-Based Nanoparticle for Targeted Gene Delivery
Current Drug Delivery Thrombospondin and Apoptosis: Molecular Mechanisms and Use for Design of Complementation Treatments
Current Drug Targets Development of Anticancer Agents from Plant-Derived Sesquiterpene Lactones
Current Medicinal Chemistry Shared Signaling Pathways Between Endocrine and Immune System Receptors: The Model of Gamma Chain
Current Signal Transduction Therapy Targeted Ultrasound Imaging of Cancer: An Emerging Technology on its Way to Clinics
Current Pharmaceutical Design The Potential of Modulating Small RNA Activity In Vivo
Mini-Reviews in Medicinal Chemistry Potential Disease Targets for Drugs that Disrupt Protein - Protein Interactions of Grb2 and Crk Family Adaptors
Current Pharmaceutical Design Synthesis and <i>In Silico</i> Studies of C-4 Substituted Coumarin Analogues as Anticancer Agents
Current Computer-Aided Drug Design Integrin αvβ3 Antagonists for Anti-Angiogenic Cancer Treatment
Recent Patents on Anti-Cancer Drug Discovery Arylurea Derivatives: A Class of Potential Cancer Targeting Agents
Current Topics in Medicinal Chemistry Tubulin-Targeting Agents in Hybrid Drugs
Current Medicinal Chemistry Iontophoresis: Drug Delivery System by Applying an Electrical Potential Across the Skin
Drug Delivery Letters Nongenomic Actions of Retinoids: Role of Nur77 and RXR in the Regulation of Apoptosis and Inflammation
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Paclitaxel Resistance: Molecular Mechanisms and Pharmacologic Manipulation
Current Cancer Drug Targets Fibroblast Growth Factors, Fibroblast Growth Factor Receptors, Diseases, and Drugs
Recent Patents on Cardiovascular Drug Discovery A Novel Information Theoretic Approach to Gene Selection for Cancer Classification Using Microarray Data
Current Bioinformatics Nuclear Magnetic Resonance Spectroscopy of Lipids in Cancer
Current Organic Chemistry Suppression of Cancer Invasiveness by Dietary Compounds
Mini-Reviews in Medicinal Chemistry Chrysin Induces Apoptosis in Peripheral Blood Lymphocytes Isolated from Human Chronic Lymphocytic Leukemia
Anti-Cancer Agents in Medicinal Chemistry Brain MR Image Classification for Glioma Tumor detection using Deep Convolutional Neural Network Features
Current Medical Imaging