Abstract
DNA topoisomerase II enzymes regulate essential cellular processes by altering the topology of chromosomal DNA. These enzymes function by creating transient double-stranded breaks in the DNA molecule that allow the DNA strands to pass through each other and unwind or unknot tangled DNA. Because of the integral role of topoisomerases in regulating DNA metabolism, these enzymes are vital for cell survival. Several clinically active antitumor agents target these enzymes. Mammalian cells contain two topoisomerase II isozymes that are encoded by different genes: topoisomerase IIα and IIβ. Although, both isozymes are homologous and exhibit similar catalytic activity, they are differentially regulated and are involved in distinct biological functions. The topoisomerase IIα and topoisomerase IIβ enzymes are regulated by post-translational modifications, including sumoylation, ubiquitination and phosphorylation. These posttranslational modifications influence the biologic and catalytic activity of the enzyme and affect sensitivity of cells to topoisomerase II-targeted drugs. In this review, we describe how the catalytic and biologic activity of the topoisomerase II enzyme is regulated and discuss the mechanisms by which chemotherapeutic agents that target these enzymes function. Given the potential importance of site-specific modifications, in particular phosphorylation, in regulating sensitivity to topoisomerase II-targeted drugs, we discuss the potential role of altered topoisomerase II phosphorylation in development of drug resistance, which is often a limiting factor in the treatment of cancer.
Keywords: DNA topoisomerases, topoisomerase inhibitors, cancer chemotherapy, drug resistance, phosphorylation.
Current Cancer Drug Targets
Title:DNA Topoisomerase II Enzymes as Molecular Targets for Cancer Chemotherapy
Volume: 10 Issue: 7
Author(s): K. Chikamori, A. G. Grozav, T. Kozuki, D. Grabowski, R. Ganapathi and M. K. Ganapathi
Affiliation:
Keywords: DNA topoisomerases, topoisomerase inhibitors, cancer chemotherapy, drug resistance, phosphorylation.
Abstract: DNA topoisomerase II enzymes regulate essential cellular processes by altering the topology of chromosomal DNA. These enzymes function by creating transient double-stranded breaks in the DNA molecule that allow the DNA strands to pass through each other and unwind or unknot tangled DNA. Because of the integral role of topoisomerases in regulating DNA metabolism, these enzymes are vital for cell survival. Several clinically active antitumor agents target these enzymes. Mammalian cells contain two topoisomerase II isozymes that are encoded by different genes: topoisomerase IIα and IIβ. Although, both isozymes are homologous and exhibit similar catalytic activity, they are differentially regulated and are involved in distinct biological functions. The topoisomerase IIα and topoisomerase IIβ enzymes are regulated by post-translational modifications, including sumoylation, ubiquitination and phosphorylation. These posttranslational modifications influence the biologic and catalytic activity of the enzyme and affect sensitivity of cells to topoisomerase II-targeted drugs. In this review, we describe how the catalytic and biologic activity of the topoisomerase II enzyme is regulated and discuss the mechanisms by which chemotherapeutic agents that target these enzymes function. Given the potential importance of site-specific modifications, in particular phosphorylation, in regulating sensitivity to topoisomerase II-targeted drugs, we discuss the potential role of altered topoisomerase II phosphorylation in development of drug resistance, which is often a limiting factor in the treatment of cancer.
Export Options
About this article
Cite this article as:
Chikamori K., G. Grozav A., Kozuki T., Grabowski D., Ganapathi R. and K. Ganapathi M., DNA Topoisomerase II Enzymes as Molecular Targets for Cancer Chemotherapy, Current Cancer Drug Targets 2010; 10 (7) . https://dx.doi.org/10.2174/156800910793605785
DOI https://dx.doi.org/10.2174/156800910793605785 |
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
-
Pegylated Liposomal Doxorubicin in Salvage Chemotherapy for Multiple Myeloma Patients
Current Cancer Therapy Reviews Molecular Determinants of the Cardiometabolic Phenotype
Endocrine, Metabolic & Immune Disorders - Drug Targets Ultrasound Techniques for Drug Delivery in Cardiovascular Medicine
Current Drug Discovery Technologies Update on the Evaluation and Management of Brief Resolved Unexplained Events (Previously Apparent Life-Threatening Events)
Reviews on Recent Clinical Trials Editorial: Perioperative Pharmacological Management: From Prescription Medications to Dietary Supplements
Current Clinical Pharmacology Is the Vascular System a Main Target for Thyroid Hormones? From Molecular and Biochemical Findings to Clinical Perspectives
Current Vascular Pharmacology MicroRNA-208a Potentiates Angiotensin II-triggered Cardiac Myoblasts Apoptosis via Inhibiting Nemo-like Kinase (NLK)
Current Pharmaceutical Design Anti-inflammatory Treatment of Acute Coronary Syndromes
Current Pharmaceutical Design Emerging Potential of Natural Products as an Alternative Strategy to Pharmacological Agents Used Against Metabolic Disorders
Current Drug Metabolism Mitochondrial Dysfunction and Its Relationship with mTOR Signaling and Oxidative Damage in Autism Spectrum Disorders
Mini-Reviews in Medicinal Chemistry Remediation of Cellular Hypoxic Damage by Pharmacological Agents
Current Pharmaceutical Design The GH/IGF-1 Axis and Heart Failure
Current Cardiology Reviews Cathinone Neurotoxicity (“The “3Ms”)
Current Neuropharmacology Genetics of Congenital Heart Disease
Current Cardiology Reviews Targeting the Chemokines in Cardiac Repair
Current Pharmaceutical Design Bidirectional Nature of Cardiovascular and Kidney Disease
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Crosstalk between Oxidative and Nitrosative Stress and Arterial Stiffness
Current Vascular Pharmacology Repurposed Drugs in Metabolic Disorders
Current Topics in Medicinal Chemistry Population Pharmacogenomics and Personalized Medicine Research in Hungary: Achievements and Lessons Learned
Current Pharmacogenomics and Personalized Medicine Long-circulating Targeted Nanoparticles for Cancer Therapy
Current Nanoscience