Abstract
To assure their growth advantage cancer cells require the appropriation of key pathways, such as those controlled by G-protein coupled receptor (GPCR), that influence cell growth, migration, and death, as well as the expansion of vascular networks. Accumulating molecular and in vivo evidences demonstrate that the activation of the endothelin-1 (ET-1) axis elicites pleiotropic effects on tumour cells and on the tumour microenvironment as well, modulating epithelial to mesenchymal transition, chemoresistance, and other tumourassociated processes. As ET-1 axis blockade has been shown to reduce tumor growth in preclinical models, several small molecule antagonists of ET-1 receptors are currently undergoing clinical trial as novel agents in cancer therapy. To fully appreciate the potential hegemony of the ET-1 axis in cancer, here we review emerging preclinical and clinical data outlining the spectrum of cellular activities triggered by ET-1 signaling and the challenges facing molecular targeted therapy. Because scaffold proteins, such as β-arrestin, create signalling platforms that drive cellular transformation upon GPCR activation, mechanisms mediated by β-arrestin in ET-1 signalling are discussed. Deeper understanding of molecular mechanisms activated by ET-1 receptor, as well as of how pathway crosstalk can influence ET-1 signalling outcome in cancer, is of paramount translational relevance in the study of ET-1 receptor-targeted therapy. The improved knowledge of the interconnected molecular mechanism promoted by ET-1 axis in cancer will certainly result in more effective and durable mechanism-guided combinations of ET-1 receptor antagonists with cytotoxic drugs or other targeted agents in the clinical management of ET-1 axis-dependent malignancies.
Keywords: Endothelin, endothelin receptor, epithelial-mesenchymal transition, β-arrestin, cancer therapy, chemoresistance, G-protein coupled receptor (GPCR), pleiotropic effects, cytotoxic drugs, malignancies
Current Pharmaceutical Design
Title:The Endothelin Axis as Therapeutic Target in Human Malignancies: Present and Future
Volume: 18 Issue: 19
Author(s): Anna Bagnato
Affiliation:
Keywords: Endothelin, endothelin receptor, epithelial-mesenchymal transition, β-arrestin, cancer therapy, chemoresistance, G-protein coupled receptor (GPCR), pleiotropic effects, cytotoxic drugs, malignancies
Abstract: To assure their growth advantage cancer cells require the appropriation of key pathways, such as those controlled by G-protein coupled receptor (GPCR), that influence cell growth, migration, and death, as well as the expansion of vascular networks. Accumulating molecular and in vivo evidences demonstrate that the activation of the endothelin-1 (ET-1) axis elicites pleiotropic effects on tumour cells and on the tumour microenvironment as well, modulating epithelial to mesenchymal transition, chemoresistance, and other tumourassociated processes. As ET-1 axis blockade has been shown to reduce tumor growth in preclinical models, several small molecule antagonists of ET-1 receptors are currently undergoing clinical trial as novel agents in cancer therapy. To fully appreciate the potential hegemony of the ET-1 axis in cancer, here we review emerging preclinical and clinical data outlining the spectrum of cellular activities triggered by ET-1 signaling and the challenges facing molecular targeted therapy. Because scaffold proteins, such as β-arrestin, create signalling platforms that drive cellular transformation upon GPCR activation, mechanisms mediated by β-arrestin in ET-1 signalling are discussed. Deeper understanding of molecular mechanisms activated by ET-1 receptor, as well as of how pathway crosstalk can influence ET-1 signalling outcome in cancer, is of paramount translational relevance in the study of ET-1 receptor-targeted therapy. The improved knowledge of the interconnected molecular mechanism promoted by ET-1 axis in cancer will certainly result in more effective and durable mechanism-guided combinations of ET-1 receptor antagonists with cytotoxic drugs or other targeted agents in the clinical management of ET-1 axis-dependent malignancies.
Export Options
About this article
Cite this article as:
Bagnato Anna, The Endothelin Axis as Therapeutic Target in Human Malignancies: Present and Future, Current Pharmaceutical Design 2012; 18 (19) . https://dx.doi.org/10.2174/138161212800626157
DOI https://dx.doi.org/10.2174/138161212800626157 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...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
-
New Targets, New Agents, and the Evolving Phenomena of Drug Resistance in Cancer
Current Cancer Therapy Reviews Positron Emitting Tracers in Pre-Clinical Drug Development
Current Radiopharmaceuticals Potential of Plant-Derived Natural Products in the Treatment of Leukemia and Lymphoma
Current Drug Targets Biological Properties of Citrus Flavonoids Pertaining to Cancer and Inflammation
Current Medicinal Chemistry Multi-Modal Imaging and Cancer Therapy Using Lanthanide Oxide Nanoparticles: Current Status and Perspectives
Current Medicinal Chemistry Oncotarget Strategies For Herpes Simplex Virus-1
Current Gene Therapy Interactions of Cisplatin with non-DNA Targets and their Influence on Anticancer Activity and Drug Toxicity: The Complex World of the Platinum Complex
Current Cancer Drug Targets Targeting Sphingosine-1-Phosphate Receptors in Cancer
Anti-Cancer Agents in Medicinal Chemistry MicroRNAs and the Warburg Effect: New Players in an Old Arena
Current Gene Therapy Synthesis and in vitro Evaluation of the Anticancer Potential of New Aminoalkanol Derivatives of Xanthone
Anti-Cancer Agents in Medicinal Chemistry Pharmacological Perspectives of Wasp Venom
Protein & Peptide Letters Towards Understanding the Roles of Prohibitins, Multi-Functional Regulator Proteins
Current Chemical Biology Application of Nanotechnology in the Diagnosis and Therapy of Hepatocellular Carcinoma
Recent Patents on Anti-Cancer Drug Discovery Automated PET Radiotracer Manufacture on the BG75 System and Imaging Validation Studies of [18F]fluoromisonidazole ([18F]FMISO)
Current Radiopharmaceuticals New Features in the Treatment of Androgen-Independent Prostate Cancer
Current Pharmaceutical Design Statins and Alkylphospholipids as New Anticancer Agents Targeting Lipid Metabolism
Anti-Cancer Agents in Medicinal Chemistry Hepatic Steatosis and Peroxisomal Fatty Acid Beta-oxidation
Current Drug Metabolism Insulin Resistance the Link between T2DM and CVD: Basic Mechanisms and Clinical Implications
Current Vascular Pharmacology Looking out for Cancer Stem Cells’ Properties: The Value-Driving Role of CD44 for Personalized Medicines
Current Cancer Drug Targets Evaluation of Polygonum bistorta for Anticancer Potential Using Selected Cancer Cell Lines
Medicinal Chemistry