Abstract
The ends of chromosomes in mammals are composed of telomeric DNA containing TTAGGG repeats, which bind specific proteins called shelterins. This telomeric DNA together with shelterins form a cap that protects the ends of chromosomes from being recognized as sites of DNA damage and from chromosomal fusions. Many very successful antitumor drugs used in the treatment of cancer patients bind to DNA, some of them with a prominent sequence specificity leads to changes in DNA structure and integrity. We propose a new target for antitumor drugs where small molecule ligands can bind to telomeric DNA and induce specific structural changes. These changes would lead to a selective interference with the formation of telomeric DNA-shelterin complexes, especially involving TRF1 and TRF2 proteins, as these proteins bind double-stranded telomeric DNA in a sequence- and structure-dependent manner. The rationale of the proposed therapeutic strategy is further justified by the fact that tumor cells have relatively short telomeres and frequently de-regulated shelterin expression and/or functionality. Thus uncapping of chromosome ends by DNA binding compounds which disrupt DNA-shelterin complexes can ultimately induce selective cytotoxic effect in tumor cells. Possible implications for rational design of new antitumor drugs which interfere with telomeric DNA structure and formation of DNA-shelterin complexes are discussed.
Keywords: Anticancer agent, DNA binding, shelterin, telomere, TRF1, TRF2, telomeric DNA.
Current Cancer Drug Targets
Title:Novel Anticancer Strategy Aimed at Targeting Shelterin Complexes by the Induction of Structural Changes in Telomeric DNA: Hitting two Birds with one Stone
Volume: 14 Issue: 2
Author(s): Joanna Bidzinska, Maciej Baginski and Andrzej Skladanowski
Affiliation:
Keywords: Anticancer agent, DNA binding, shelterin, telomere, TRF1, TRF2, telomeric DNA.
Abstract: The ends of chromosomes in mammals are composed of telomeric DNA containing TTAGGG repeats, which bind specific proteins called shelterins. This telomeric DNA together with shelterins form a cap that protects the ends of chromosomes from being recognized as sites of DNA damage and from chromosomal fusions. Many very successful antitumor drugs used in the treatment of cancer patients bind to DNA, some of them with a prominent sequence specificity leads to changes in DNA structure and integrity. We propose a new target for antitumor drugs where small molecule ligands can bind to telomeric DNA and induce specific structural changes. These changes would lead to a selective interference with the formation of telomeric DNA-shelterin complexes, especially involving TRF1 and TRF2 proteins, as these proteins bind double-stranded telomeric DNA in a sequence- and structure-dependent manner. The rationale of the proposed therapeutic strategy is further justified by the fact that tumor cells have relatively short telomeres and frequently de-regulated shelterin expression and/or functionality. Thus uncapping of chromosome ends by DNA binding compounds which disrupt DNA-shelterin complexes can ultimately induce selective cytotoxic effect in tumor cells. Possible implications for rational design of new antitumor drugs which interfere with telomeric DNA structure and formation of DNA-shelterin complexes are discussed.
Export Options
About this article
Cite this article as:
Bidzinska Joanna, Baginski Maciej and Skladanowski Andrzej, Novel Anticancer Strategy Aimed at Targeting Shelterin Complexes by the Induction of Structural Changes in Telomeric DNA: Hitting two Birds with one Stone, Current Cancer Drug Targets 2014; 14 (2) . https://dx.doi.org/10.2174/1568009614666140120122535
DOI https://dx.doi.org/10.2174/1568009614666140120122535 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
Call for Papers in Thematic Issues
Advances in Cancer Biomarkers and Potential Drug Targets: From Diagnosis to Therapy
Cancer biomarkers play a crucial role in the diagnosis, prognosis, and treatment of cancer. They provide valuable information for cancer detection, risk assessment, treatment selection, and monitoring response to therapy. With advancements in molecular biology and high-throughput technologies, there has been an increasing interest in identifying and characterizing cancer biomarkers ...read more
Novel Therapeutic Approaches to Target Drug Resistant Tumors
With the development of disciplines such as chemical biology and molecular biology, the genes or proteins closely related to tumor occurrence and development have gradually become clear. Targeted therapies targeting these genes or proteins provide more effective methods for tumor treatment. Tumor targeted drugs generally only act on specific targets ...read more
ROLE OF IMMUNE AND GENOTOXIC RESPONSE BIOMARKERS IN TUMOR MICROENVIRONMENT IN CANCER DIAGNOSIS AND TREATMENT
Biological biomarkers have been used in medical research as an indicator of a normal or abnormal process inside the body, or of a disease. Nowadays, various researchers are in process to explore and investigate the biological markers for the early assessment of cancer. DNA Damage response (DDR) pathways and immune ...read more
Targeting the battlefield between host and tumor: basic research and clinical practice on reshaping tumor immune microenvironment
Immune system protects host against malignant tumors through effector cells and molecules. Cancer development and its response to therapy are regulated by inflammation, which either promotes or suppresses cancer progression. Chronic inflammation facilitates cancer progression and treatment resistance, whereas induction of acute inflammatory reactions often lead to anti-cancer immune responses. ...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
Related Articles
-
Hypoxia Inducible Factor-1 in Cancer Immune Suppression
Current Immunology Reviews (Discontinued) T11TS/SLFA-3 Differentially Regulate the Population of Microglia and Brain Infiltrating Lymphocytes to Reduce Glioma by Modulating Intrinsic Bcl-2 Expression rather than p53
Central Nervous System Agents in Medicinal Chemistry Prospective Function of Different Antioxidant Containing Natural Products in the Treatment of Neurodegenerative Diseases
CNS & Neurological Disorders - Drug Targets Editorial (BIOQUEST India: A Global Biotechnology Forum for Knowledge-Based Innovation and Sustainable Development)
Current Pharmacogenomics and Personalized Medicine Virtual Screening of Acetylcholinesterase Inhibitors Based on Machine Learning Combined with Molecule Docking Methods
Current Bioinformatics The Hippocampal Autophagic Machinery is Depressed in the Absence of the Circadian Clock Protein PER1 that may Lead to Vulnerability During Cerebral Ischemia
Current Neurovascular Research Recent Progress in the Syntheses and Biological Evaluation of Boronated Porphyrins for Boron Neutron-Capture Therapy
Anti-Cancer Agents in Medicinal Chemistry RGD Peptide–mediated Molecular Imaging for Targeting Integrin Alpha(v) Beta(3) in Tumors: A Review
Current Medical Imaging Meet Our Editorial Board Member
CNS & Neurological Disorders - Drug Targets TGF Beta Inhibition for Cancer Therapy
Current Cancer Drug Targets Oncomirs: From Tumor Biology to Molecularly Targeted Anticancer Strategies
Mini-Reviews in Medicinal Chemistry Therapeutic Window, a Critical Developmental Stage for Stem Cell Therapies
Current Stem Cell Research & Therapy MicroRNA-21: From Cancer to Cardiovascular Disease
Current Drug Targets Gap Junctions as Therapeutic Targets in Brain Injury Following Hypoxia- Ischemia
Recent Patents on CNS Drug Discovery (Discontinued) Antibody Engineering, Virus Retargeting and Cellular Immunotherapy: One Ring to Rule Them All?
Current Gene Therapy Antineoplastic Chemotherapy Induced QTc Prolongation
Current Drug Safety Genomic Context Vectors and Artificial Chromosomes for Cystic Fibrosis Gene Therapy
Current Gene Therapy An Update on Overcoming MDR1-Mediated Multidrug Resistance in Cancer Chemotherapy
Current Pharmaceutical Design Functional Selectivity in Cannabinoid Signaling
Current Molecular Pharmacology Tankyrases: Structure, Function and Therapeutic Implications in Cancer
Current Pharmaceutical Design