Abstract
Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a pro-apoptotic ligand that has shown the exquisite ability to trigger extrinsic apoptosis in various types of cancer cells without significant toxicity toward normal cells, when compared to other pro-apoptotic ligands such as tumor necrosis factor (TNF)α or Fas ligand. Consequently, TRAIL-based therapies aim to trigger apoptosis in cancer cells by providing the soluble TRAIL or monoclonal antibodies targeting the death receptors TRAIL-R1 or TRAIL-R2. In this review, we start by highlighting the relevance of the tumor microenvironment in tumor development and elimination. We then address conventional and targeted therapeutic approaches for cancer treatment, highlighting the mechanisms involved or targeted. We describe the extrinsic and intrinsic pro-apoptotic pathways of TRAIL, together with the evidences for its pro-survival signaling, and with the relevance of these pathways in therapy. Possible mechanisms of resistance to TRAIL-induced apoptosis are highlighted (i.e. c-FLIP, Bcl-2, IAPs, p53, NF-κ B) and the rationale for the combined administration of TRAIL with drugs targeting these mechanisms is provided. Preclinical data are reported and show encouraging evidences for TRAIL consideration in pediatric malignancies (i.e., leukemia, lymphomas, neuroblastoma, osteosarcoma, medulloblastoma). Clinical trials of TRAIL-based therapies on the overall population are in phase I or II, and we put particular focus on the pediatric population, on which only few trials have been conducted or are ongoing. Finally, we consider emerging cellular therapies based on TRAIL, such as TRAIL-engineered mesenchymal stem cells or ‘inflammatory’ dendritic cells.
Keywords: Cancer, pediatric malignancies, PARAs, targeted therapies, TRAIL, TRAIL resistance.
Current Medicinal Chemistry
Title:TRAIL-Based Therapeutic Approaches for the Treatment of Pediatric Malignancies
Volume: 20 Issue: 17
Author(s): C. Gasparini, L. Vecchi Brumatti, L. Monasta and G. Zauli
Affiliation:
Keywords: Cancer, pediatric malignancies, PARAs, targeted therapies, TRAIL, TRAIL resistance.
Abstract: Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a pro-apoptotic ligand that has shown the exquisite ability to trigger extrinsic apoptosis in various types of cancer cells without significant toxicity toward normal cells, when compared to other pro-apoptotic ligands such as tumor necrosis factor (TNF)α or Fas ligand. Consequently, TRAIL-based therapies aim to trigger apoptosis in cancer cells by providing the soluble TRAIL or monoclonal antibodies targeting the death receptors TRAIL-R1 or TRAIL-R2. In this review, we start by highlighting the relevance of the tumor microenvironment in tumor development and elimination. We then address conventional and targeted therapeutic approaches for cancer treatment, highlighting the mechanisms involved or targeted. We describe the extrinsic and intrinsic pro-apoptotic pathways of TRAIL, together with the evidences for its pro-survival signaling, and with the relevance of these pathways in therapy. Possible mechanisms of resistance to TRAIL-induced apoptosis are highlighted (i.e. c-FLIP, Bcl-2, IAPs, p53, NF-κ B) and the rationale for the combined administration of TRAIL with drugs targeting these mechanisms is provided. Preclinical data are reported and show encouraging evidences for TRAIL consideration in pediatric malignancies (i.e., leukemia, lymphomas, neuroblastoma, osteosarcoma, medulloblastoma). Clinical trials of TRAIL-based therapies on the overall population are in phase I or II, and we put particular focus on the pediatric population, on which only few trials have been conducted or are ongoing. Finally, we consider emerging cellular therapies based on TRAIL, such as TRAIL-engineered mesenchymal stem cells or ‘inflammatory’ dendritic cells.
Export Options
About this article
Cite this article as:
Gasparini C., Vecchi Brumatti L., Monasta L. and Zauli G., TRAIL-Based Therapeutic Approaches for the Treatment of Pediatric Malignancies, Current Medicinal Chemistry 2013; 20 (17) . https://dx.doi.org/10.2174/0929867311320170009
DOI https://dx.doi.org/10.2174/0929867311320170009 |
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
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
Current advances in inherited cardiomyopathy
Describe in detail all novel advances in multimodality imaging related to inherited cardiomyopathy diagnosis and prognosis. Shed light to deeper phenotypic characterization. Acknowledge recent advances in genetics, genomics and precision medicineread 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
-
Amyloid-Degrading Enzymes as Therapeutic Targets in Alzheimers Disease
Current Alzheimer Research Radiolabeled RGD Peptides as Integrin alpha(v)beta3–targeted PET Tracers
Current Medicinal Chemistry Protein Arginine Methyltransferase 1 and its Dynamic Regulation Associated with Cellular Processes and Diseases
Protein & Peptide Letters Signal Transduction Therapy Targeting Apoptosis Pathways in Cancers
Current Signal Transduction Therapy Vasoactive Intestinal Peptide Receptors: A Molecular Target in Breast and Lung Cancer
Current Pharmaceutical Design CDC25A: A Rebel Within the CDC25 Phosphatases Family?
Anti-Cancer Agents in Medicinal Chemistry Orange Pulp Increases Antioxidant Status and Improves Bone Quality in Orchidectomized Rats
Current Nutrition & Food Science The Tachykinergic System as Avenues for Drug Intervention
Recent Patents on CNS Drug Discovery (Discontinued) Functional Interplay between RNA-Binding Protein HuR and microRNAs
Current Protein & Peptide Science NK-1 Receptor Antagonists: A New Generation of Anticancer Drugs
Mini-Reviews in Medicinal Chemistry Naphthoflavones as Antiproliferative Agents: Design, Synthesis and Biological Evaluation
Anti-Cancer Agents in Medicinal Chemistry Pathophysiological Roles of Transglutaminase - Catalyzed Reactions in the Pathogenesis of Human Diseases
Inflammation & Allergy - Drug Targets (Discontinued) Target Driven Preclinical Screening for New Antimitotic Chemotherapy Agents
Current Topics in Medicinal Chemistry Peptide Therapeutics in Neurodegenerative Disorders
Current Medicinal Chemistry Induction of Synthetic Lethality by Natural Compounds Targeting Cancer Signaling
Current Pharmaceutical Design Will it Ever Become Possible to Prevent Dopaminergic Neuronal Degeneration?
CNS & Neurological Disorders - Drug Targets Amyloid β-Peptide: The Inside Story
Current Alzheimer Research A Novel Technology for Hematopoietic Stem Cell Expansion Using Combination of Nanofiber and Growth Factors
Recent Patents on Nanotechnology B7-H3 Immune Checkpoint Protein in Human Cancer
Current Medicinal Chemistry Functions of S100 Proteins
Current Molecular Medicine