Abstract
DNA-damaging drugs in cancer present two main problems: therapeutic resistance and side effects and both can associate with DNA repair, which can be targeted in cancer therapy. Bleomycin (BLM) induces complex DNA damages, including strand breaks, base loss and 3’-phosphoglycolate (3’PG) residues repaired by several pathways, but 3’PGs must be processed to the 3’-OH ends, usually by tyrosyl-DNA phosphodiesterase 1 (Tdp1). Therefore, targeting Tdp1 can improve anticancer therapy with BLM. Mitomycin C (MMC) produces a variety of adducts with DNA, including inter-strand cross-links (ICLs) and Xeroderma pigmentosum (XP) proteins, including XPG, XPE and XPF can be crucial for the initial stage of ICL repair, so they can be targeted by inhibitors to increase toxicity of MMC in cancer cells. Although these proteins are essential for nucleotide excision repair (NER), their decreased activity may not be fatal in normal cells as almost all NER substrates can be repaired by other pathways. Four-stranded DNA, resulted mainly from guanine quadruplexes (G-4s), are highly overexpressed at the end of telomeres, where they can inhibit telomerase, hence stabilization G-4s at the telomeres ends can hamper proliferation of cancer cells. Quadruplexes are also found in the promoters of genes important for cancer and are resolved by DNA helicases, which can be targeted in cancer along with stabilization of quadruplexes. As cancer cells often have defects in DNA repair pathway(s), they can be subjected by synthetic lethality, with the most promising results with poly(ADP-ribose) polymerase 1 (PARP-1) and DNA-dependent protein kinase, catalytic subunit (DNA-PKCS).
Keywords: DNA-damaging drugs, DNA repair, bleomycin, mitomycin C, DNA topoisomerase 1 and 2 inhibitors, DNA quadruplex, synthetic lethality
Current Medicinal Chemistry
Title:DNA-Damaging Anticancer Drugs – A Perspective for DNA Repair- Oriented Therapy
Volume: 24 Issue: 15
Author(s): Janusz Blasiak*
Affiliation:
- Department of Molecular Genetics, University of Lodz, Lodz,Poland
Keywords: DNA-damaging drugs, DNA repair, bleomycin, mitomycin C, DNA topoisomerase 1 and 2 inhibitors, DNA quadruplex, synthetic lethality
Abstract: DNA-damaging drugs in cancer present two main problems: therapeutic resistance and side effects and both can associate with DNA repair, which can be targeted in cancer therapy. Bleomycin (BLM) induces complex DNA damages, including strand breaks, base loss and 3’-phosphoglycolate (3’PG) residues repaired by several pathways, but 3’PGs must be processed to the 3’-OH ends, usually by tyrosyl-DNA phosphodiesterase 1 (Tdp1). Therefore, targeting Tdp1 can improve anticancer therapy with BLM. Mitomycin C (MMC) produces a variety of adducts with DNA, including inter-strand cross-links (ICLs) and Xeroderma pigmentosum (XP) proteins, including XPG, XPE and XPF can be crucial for the initial stage of ICL repair, so they can be targeted by inhibitors to increase toxicity of MMC in cancer cells. Although these proteins are essential for nucleotide excision repair (NER), their decreased activity may not be fatal in normal cells as almost all NER substrates can be repaired by other pathways. Four-stranded DNA, resulted mainly from guanine quadruplexes (G-4s), are highly overexpressed at the end of telomeres, where they can inhibit telomerase, hence stabilization G-4s at the telomeres ends can hamper proliferation of cancer cells. Quadruplexes are also found in the promoters of genes important for cancer and are resolved by DNA helicases, which can be targeted in cancer along with stabilization of quadruplexes. As cancer cells often have defects in DNA repair pathway(s), they can be subjected by synthetic lethality, with the most promising results with poly(ADP-ribose) polymerase 1 (PARP-1) and DNA-dependent protein kinase, catalytic subunit (DNA-PKCS).
Export Options
About this article
Cite this article as:
Blasiak Janusz*, DNA-Damaging Anticancer Drugs – A Perspective for DNA Repair- Oriented Therapy, Current Medicinal Chemistry 2017; 24 (15) . https://dx.doi.org/10.2174/0929867324666170124145557
DOI https://dx.doi.org/10.2174/0929867324666170124145557 |
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
-
Relaxin-Like Peptides in Neoplastic Lesions
Current Medicinal Chemistry - Immunology, Endocrine & Metabolic Agents Invasive Pulmonary Aspergillosis in Acute Leukemia: Current Issues for Pathogenesis, Diagnosis and Treatment
Current Respiratory Medicine Reviews Dietary Phytochemicals in Chemoprevention of Cancer: An Update
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Maximizing Baculovirus-Mediated Foreign Proteins Expression in Mammalian Cells
Current Gene Therapy Modulation of Energy Intake and Expenditure Due to Habitual Physical Exercise
Current Pharmaceutical Design Electrocatalytic Determination of 6-Mercaptopurine Using Multiwall Carbon Nanotubes Paste Electrode in the Presence of Methyldopa
Current Nanoscience Emerging Roles for Modulation of microRNA Signatures in Cancer Chemoprevention
Current Cancer Drug Targets BSA Au Clusters as a Probe for Enhanced Fluorescence Detection Using Multipulse Excitation Scheme
Current Pharmaceutical Biotechnology MiR-125b Inhibits Cell Proliferation and Induces Apoptosis in Human Colon Cancer SW480 Cells <i>via</i> Targeting STAT3
Recent Patents on Anti-Cancer Drug Discovery Status of Flavonols as P-Glycoprotein Inhibitors in Cancer Chemotherapy
Current Cancer Therapy Reviews Protein-protein Interactions: Network Analysis and Applications in Drug Discovery
Current Pharmaceutical Design Tackling COVID-19 Through Ayurveda: A Review on the Herbs of Recommended Indian Remedies
Current Traditional Medicine Synthesis of Nitroaromatic Compounds as Potential Anticancer Agents
Anti-Cancer Agents in Medicinal Chemistry Development and Assessment of Conventional and Targeted Drug Combinations for Use in the Treatment of Aggressive Breast Cancers
Current Cancer Drug Targets Small Molecule Aurora Kinases Inhibitors
Current Medicinal Chemistry Plant Cells as Pharmaceutical Factories
Current Pharmaceutical Design Reduced-Intensity Transplantation in the Treatment of Haematological Malignancies: Current Status and Future-Prospects
Current Stem Cell Research & Therapy N-Heterocyclic Dronic Acids: Applications and Synthesis
Mini-Reviews in Medicinal Chemistry Strategies for Retargeted Gene Delivery Using Vectors Derived from Lentiviruses
Current Gene Therapy Membrane Tyrosine Kinase Receptors are an Important Target for the Therapy of Acute Myeloid Leukemia
Current Cancer Therapy Reviews