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Mohamed HABE, Agus HH, Palabiyik B. A novel method for telomere length detection in fission yeast. FEMS Yeast Res 2025; 25:foae040. [PMID: 39719362 PMCID: PMC11781191 DOI: 10.1093/femsyr/foae040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2024] [Revised: 11/25/2024] [Accepted: 12/23/2024] [Indexed: 12/26/2024] Open
Abstract
Fission yeast is the ideal model organism for studying telomere maintenance in higher eukaryotes. Telomere length has been directly correlated with life expectancy and the onset of aging-related diseases in mammals. In this study, we developed a novel simple, and reproducible method to measure the telomere length, by investigating the effect of caffeine and cisplatin on the telomere length in fission yeast. Hydroxyurea-synchronized fission yeast cells were exposed to 62 µM cisplatin and 8.67 mM caffeine treatments for 2 h, then their telomere lengths were evaluated with two different methods. First, the quantitative polymerase chain reaction (qPCR) assay was used as a confirmative method, where telomere length was determined relative to a single-copy gene in the genome. Second, the newly developed method standard polymerase chain reaction (PCR)/ImageJ assay assessed the telomere length based on the amplified PCR band intensity using a set of telomere primers, reflecting telomeric sequence availability in the genome. Both methods show a significant decrease and a notable telomere lengthening in response to cisplatin and caffeine treatments, respectively. The finding supports the accuracy and productivity of the standard PCR/ImageJ assay as it can serve as a quick screening tool to study the effect of suspected chemotherapeutic and antiaging drugs on telomere length in fission yeast.
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Affiliation(s)
- Hadeel A B Elnaim Mohamed
- Institute of Graduate Studies in Science, Department of Molecular Biology and Genetics, Istanbul University, 34116, Istanbul, Turkey
| | - Hizlan Hincal Agus
- Faculty of Science and Literature, Department of Molecular Biology and Genetics, Istanbul Yeni Yuzyil University, 34010, Istanbul, Turkey
| | - Bedia Palabiyik
- Faculty of Science, Department of Molecular Biology and Genetics, Istanbul University, 34134, Istanbul, Turkey
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2
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Burren OS, Dhindsa RS, Deevi SVV, Wen S, Nag A, Mitchell J, Hu F, Loesch DP, Smith KR, Razdan N, Olsson H, Platt A, Vitsios D, Wu Q, Codd V, Nelson CP, Samani NJ, March RE, Wasilewski S, Carss K, Fabre M, Wang Q, Pangalos MN, Petrovski S. Genetic architecture of telomere length in 462,666 UK Biobank whole-genome sequences. Nat Genet 2024; 56:1832-1840. [PMID: 39192095 PMCID: PMC11387196 DOI: 10.1038/s41588-024-01884-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 07/25/2024] [Indexed: 08/29/2024]
Abstract
Telomeres protect chromosome ends from damage and their length is linked with human disease and aging. We developed a joint telomere length metric, combining quantitative PCR and whole-genome sequencing measurements from 462,666 UK Biobank participants. This metric increased SNP heritability, suggesting that it better captures genetic regulation of telomere length. Exome-wide rare-variant and gene-level collapsing association studies identified 64 variants and 30 genes significantly associated with telomere length, including allelic series in ACD and RTEL1. Notably, 16% of these genes are known drivers of clonal hematopoiesis-an age-related somatic mosaicism associated with myeloid cancers and several nonmalignant diseases. Somatic variant analyses revealed gene-specific associations with telomere length, including lengthened telomeres in individuals with large SRSF2-mutant clones, compared with shortened telomeres in individuals with clonal expansions driven by other genes. Collectively, our findings demonstrate the impact of rare variants on telomere length, with larger effects observed among genes also associated with clonal hematopoiesis.
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Affiliation(s)
- Oliver S Burren
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Ryan S Dhindsa
- Center for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA, USA
| | - Sri V V Deevi
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Sean Wen
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Abhishek Nag
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Jonathan Mitchell
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Fengyuan Hu
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Douglas P Loesch
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Katherine R Smith
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Neetu Razdan
- Biosciences COPD & IPF, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA
| | - Henric Olsson
- Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Adam Platt
- Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Dimitrios Vitsios
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Qiang Wu
- Center for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA, USA
- Department of Mathematical Sciences, Middle Tennessee State University, Murfreesboro, TN, USA
| | - Veryan Codd
- Department of Cardiovascular Sciences, University of Leicester and Leicester NIHR Biomedical Research Centre, Leicester, UK
| | - Christopher P Nelson
- Department of Cardiovascular Sciences, University of Leicester and Leicester NIHR Biomedical Research Centre, Leicester, UK
| | - Nilesh J Samani
- Department of Cardiovascular Sciences, University of Leicester and Leicester NIHR Biomedical Research Centre, Leicester, UK
| | - Ruth E March
- Precision Medicine & Biosamples, Oncology R&D, AstraZeneca, Dublin, Ireland
| | - Sebastian Wasilewski
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Keren Carss
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - Margarete Fabre
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
- Department of Haematology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
- Department of Haematology, University of Cambridge, Cambridge, UK
| | - Quanli Wang
- Center for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Waltham, MA, USA
| | | | - Slavé Petrovski
- Centre for Genomics Research, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.
- Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, Australia.
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3
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Ma TZ, Liu LY, Zeng YL, Ding K, Zhang H, Liu W, Cao Q, Xia W, Xiong X, Wu C, Mao ZW. G-quadruplex-guided cisplatin triggers multiple pathways in targeted chemotherapy and immunotherapy. Chem Sci 2024; 15:9756-9774. [PMID: 38939132 PMCID: PMC11206235 DOI: 10.1039/d4sc00643g] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2024] [Accepted: 05/09/2024] [Indexed: 06/29/2024] Open
Abstract
G-quadruplexes (G4s) are atypical nucleic acid structures involved in basic human biological processes and are regulated by small molecules. To date, pyridostatin and its derivatives [e.g., PyPDS (4-(2-aminoethoxy)-N 2,N 6-bis(4-(2-(pyrrolidin-1-yl) ethoxy) quinolin-2-yl) pyridine-2,6-dicarboxamide)] are the most widely used G4-binding small molecules and considered to have the best G4 specificity, which provides a new option for the development of cisplatin-binding DNA. By combining PyPDS with cisplatin and its analogs, we synthesize three platinum complexes, named PyPDSplatins. We found that cisplatin with PyPDS (CP) exhibits stronger specificity for covalent binding to G4 domains even in the presence of large amounts of dsDNA compared with PyPDS either extracellularly or intracellularly. Multiomics analysis reveals that CP can effectively regulate G4 functions, directly damage G4 structures, activate multiple antitumor signaling pathways, including the typical cGAS-STING pathway and AIM2-ASC pathway, trigger a strong immune response and lead to potent antitumor effects. These findings reflect that cisplatin-conjugated specific G4 targeting groups have antitumor mechanisms different from those of classic cisplatin and provide new strategies for the antitumor immunity of metals.
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Affiliation(s)
- Tian-Zhu Ma
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, IGCME, GBRCE for Functional Molecular Engineering, Sun Yat-Sen University Guangzhou 510275 P. R. China
| | - Liu-Yi Liu
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, IGCME, GBRCE for Functional Molecular Engineering, Sun Yat-Sen University Guangzhou 510275 P. R. China
| | - You-Liang Zeng
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, IGCME, GBRCE for Functional Molecular Engineering, Sun Yat-Sen University Guangzhou 510275 P. R. China
| | - Ke Ding
- The Second Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine Hangzhou 311121 P. R. China
| | - Hang Zhang
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, IGCME, GBRCE for Functional Molecular Engineering, Sun Yat-Sen University Guangzhou 510275 P. R. China
| | - Wenting Liu
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, IGCME, GBRCE for Functional Molecular Engineering, Sun Yat-Sen University Guangzhou 510275 P. R. China
| | - Qian Cao
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, IGCME, GBRCE for Functional Molecular Engineering, Sun Yat-Sen University Guangzhou 510275 P. R. China
| | - Wei Xia
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, IGCME, GBRCE for Functional Molecular Engineering, Sun Yat-Sen University Guangzhou 510275 P. R. China
| | - Xushen Xiong
- The Second Affiliated Hospital & Liangzhu Laboratory, Zhejiang University School of Medicine Hangzhou 311121 P. R. China
| | - Chao Wu
- Department of Neurology, The First Affiliated Hospital, Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Sun Yat-sen University Guangzhou 510080 P. R. China
| | - Zong-Wan Mao
- MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, School of Chemistry, IGCME, GBRCE for Functional Molecular Engineering, Sun Yat-Sen University Guangzhou 510275 P. R. China
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Kasyanenko N, Qiushi Z, Bakulev V, Sokolov P, Yakovlev K. DNA Conformational Changes Induced by Its Interaction with Binuclear Platinum Complexes in Solution Indicate the Molecular Mechanism of Platinum Binding. Polymers (Basel) 2022; 14:polym14102044. [PMID: 35631926 PMCID: PMC9143540 DOI: 10.3390/polym14102044] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/10/2022] [Accepted: 05/10/2022] [Indexed: 02/06/2023] Open
Abstract
Platinum anticancer drugs inhibit the division of cancer cells through a DNA binding mechanism. The bimetallic platinum compounds have a possibility for blocking DNA replication via the cross-linking of DNA functional groups at different distances. Many compounds with metals of the platinum group have been tested for possible antitumor activity. The main target of their biological action is a DNA molecule. A combined approach to the study of the interaction of DNA with biologically active compounds of this type is proposed. The capabilities of various methods (hydrodynamic, spectral, microscopy) in obtaining information on the type of binding of coordination compounds to DNA are compared. The analysis of DNA binding with platinum binuclear compounds containing pyrazine, tetrazole, 5- methyltetrazole, 3-propanediamine as bridging ligands in a solution was carried out with the methods of circular dichroism (CD), luminescent spectroscopy (LS), low gradient viscometry (LGV), flow birefringence (FB) and atomic force microscopy (AFM). The competitive binding of different platinum compounds to DNA and the analysis of platinum attachment to DNA after protonation of its nitrogen bases simply indicates the involvement of N7 guanine in binding. Fluorescent dye DAPI was also used to recognize the location of platinum compounds in DNA grooves. DNA conformational changes recorded by variations in persistent length, polyelectrolyte swelling, DNA secondary structure, and its stability clarify the molecular mechanism of the biological activity of platinum compounds.
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Affiliation(s)
- Nina Kasyanenko
- Department of Molecular Biophysics and Polymer Physics, Saint Petersburg State University, 7/9 Universitetskaya emb., 199034 St. Petersburg, Russia; (Z.Q.); (V.B.); (P.S.)
- Correspondence:
| | - Zhang Qiushi
- Department of Molecular Biophysics and Polymer Physics, Saint Petersburg State University, 7/9 Universitetskaya emb., 199034 St. Petersburg, Russia; (Z.Q.); (V.B.); (P.S.)
| | - Vladimir Bakulev
- Department of Molecular Biophysics and Polymer Physics, Saint Petersburg State University, 7/9 Universitetskaya emb., 199034 St. Petersburg, Russia; (Z.Q.); (V.B.); (P.S.)
| | - Petr Sokolov
- Department of Molecular Biophysics and Polymer Physics, Saint Petersburg State University, 7/9 Universitetskaya emb., 199034 St. Petersburg, Russia; (Z.Q.); (V.B.); (P.S.)
| | - Konstantin Yakovlev
- Department of Analytical Chemistry, Saint Petersburg State Chemical-Pharmaceutical Academy, 14, Prof. Popov str., 197376 St. Petersburg, Russia;
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Bolzán AD. Mutagen-induced telomere instability in human cells. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2021; 868-869:503387. [PMID: 34454696 DOI: 10.1016/j.mrgentox.2021.503387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/13/2021] [Accepted: 07/18/2021] [Indexed: 11/27/2022]
Abstract
Telomere instability is one of the main sources of genome instability and may result from chromosome end loss (due to chromosome breakage at one or both ends) or, more frequently, telomere dysfunction. Dysfunctional telomeres arise when they lose their end-capping function or become critically short, which causes chromosomal termini to behave like a DNA double-strand break. Telomere instability may occur at the chromosomal or at the molecular level, giving rise, respectively, to telomere-related chromosomal aberrations or the loss or modification of any of the components of the telomere (telomere DNA, telomere-associated proteins, or telomere RNA). Since telomeres play a fundamental role in maintaining genome stability, the study of telomere instability in cells exposed to mutagens is of great importance to understand the telomere-driven genomic instability present in those cells. In the present review, we will focus on the current knowledge about telomere instability induced by physical, chemical, and biological mutagens in human cells.
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Affiliation(s)
- Alejandro D Bolzán
- Laboratorio de Citogenética y Mutagénesis, Instituto Multidisciplinario de Biología Celular (IMBICE, CONICET-CICPBA-UNLP), calle 526 y Camino General Belgrano, B1906APO La Plata, Buenos Aires, Argentina; Universidad Nacional de La Plata, Facultad de Ciencias Naturales y Museo, calle 60 y 122, La Plata, Buenos Aires, Argentina.
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6
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DE Souza Dutra C, Martello CL, Cadore NA, Ferreira HB, Zaha A, Monteiro KM. Proteomic Analysis of the Non-genetic Response to Cisplatin in Lung Cancer Cells. CANCER DIAGNOSIS & PROGNOSIS 2021; 1:235-243. [PMID: 35399307 PMCID: PMC8962784 DOI: 10.21873/cdp.10032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 04/27/2021] [Indexed: 06/14/2023]
Abstract
BACKGROUND Drug resistance is the main cause of therapy failure in advanced lung cancer. Although non-genetic mechanisms play important roles in tumor chemoresistance, drug-induced epigenetic reprogramming is still poorly understood. MATERIALS AND METHODS The A549 cell line was used to generate cells with non-genetic resistance to cisplatin (CDDP), namely A549/CDDP cells. Bioorthogonal non-canonical amino acid tagging (BONCAT) and mass spectrometry were used to identify proteins modulated by CDDP in A549 and A549/CDDP cells. RESULTS Proteins related to proteostasis, telomere maintenance, cell adhesion, cytoskeletal remodeling, and cell redox homeostasis were found enriched in both cell lines upon CDDP exposure. On the other hand, proteins involved in drug response, metabolic pathways and mRNA processing and splicing were up-regulated by CDDP only in A549/CDDP cells. CONCLUSION Our study revealed proteome dynamics involved in the non-genetic response to CDDP, pointing out potential targets to monitor and overcome epigenetic resistance in lung cancer.
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Affiliation(s)
- Cristine DE Souza Dutra
- Laboratório de Genômica Estrutural e Funcional, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Carolina Lumertz Martello
- Laboratório de Genômica Estrutural e Funcional, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Nathan Araujo Cadore
- Laboratório de Genômica Estrutural e Funcional, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Henrique Bunselmeyer Ferreira
- Laboratório de Genômica Estrutural e Funcional, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Departamento de Biologia Molecular e Biotecnologia, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Arnaldo Zaha
- Laboratório de Genômica Estrutural e Funcional, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Departamento de Biologia Molecular e Biotecnologia, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Karina Mariante Monteiro
- Laboratório de Genômica Estrutural e Funcional, Centro de Biotecnologia, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Departamento de Biologia Molecular e Biotecnologia, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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Nejad MA, Urbassek HM. Adsorption and Diffusion of Cisplatin Molecules in Nanoporous Materials: A Molecular Dynamics Study. Biomolecules 2019; 9:biom9050204. [PMID: 31137858 PMCID: PMC6572581 DOI: 10.3390/biom9050204] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Accepted: 05/22/2019] [Indexed: 11/16/2022] Open
Abstract
Using molecular dynamics simulations, the adsorption and diffusion of cisplatin drug molecules in nanopores is investigated for several inorganic materials. Three different materials are studied with widely-varying properties: metallic gold, covalent silicon, and silica. We found a strong influence of both the van der Waals and the electrostatic interaction on the adsorption behavior on the pore walls, which in turn influence the diffusion coefficients. While van der Waals forces generally lead to a reduction of the diffusion coefficient, the fluctuations in the electrostatic energy induced by orientation changes of the cisplatin molecule were found to help desorb the molecule from the wall.
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Affiliation(s)
- Marjan A Nejad
- Physics Department and Research Center OPTIMAS, University Kaiserslautern, Erwin-Schrödinger-Straße, D-67663 Kaiserslautern, Germany.
| | - Herbert M Urbassek
- Physics Department and Research Center OPTIMAS, University Kaiserslautern, Erwin-Schrödinger-Straße, D-67663 Kaiserslautern, Germany.
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8
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Sommers JA, Kulikowicz T, Croteau DL, Dexheimer T, Dorjsuren D, Jadhav A, Maloney DJ, Simeonov A, Bohr VA, Brosh RM. A high-throughput screen to identify novel small molecule inhibitors of the Werner Syndrome Helicase-Nuclease (WRN). PLoS One 2019; 14:e0210525. [PMID: 30625228 PMCID: PMC6326523 DOI: 10.1371/journal.pone.0210525] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Accepted: 12/26/2018] [Indexed: 01/26/2023] Open
Abstract
Werner syndrome (WS), an autosomal recessive genetic disorder, displays accelerated clinical symptoms of aging leading to a mean lifespan less than 50 years. The WS helicase-nuclease (WRN) is involved in many important pathways including DNA replication, recombination and repair. Replicating cells are dependent on helicase activity, leading to the pursuit of human helicases as potential therapeutic targets for cancer treatment. Small molecule inhibitors of DNA helicases can be used to induce synthetic lethality, which attempts to target helicase-dependent compensatory DNA repair pathways in tumor cells that are already genetically deficient in a specific pathway of DNA repair. Alternatively, helicase inhibitors may be useful as tools to study the specialized roles of helicases in replication and DNA repair. In this study, approximately 350,000 small molecules were screened based on their ability to inhibit duplex DNA unwinding by a catalytically active WRN helicase domain fragment in a high-throughput fluorometric assay to discover new non-covalent small molecule inhibitors of the WRN helicase. Select compounds were screened to exclude ones that inhibited DNA unwinding by other helicases in the screen, bound non-specifically to DNA, acted as irreversible inhibitors, or possessed unfavorable chemical properties. Several compounds were tested for their ability to impair proliferation of cultured tumor cells. We observed that two of the newly identified WRN helicase inhibitors inhibited proliferation of cancer cells in a lineage-dependent manner. These studies represent the first high-throughput screen for WRN helicase inhibitors and the results have implications for anti-cancer strategies targeting WRN in different cancer cells and genetic backgrounds.
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Affiliation(s)
- Joshua A. Sommers
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
| | - Tomasz Kulikowicz
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
| | - Deborah L. Croteau
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
| | - Thomas Dexheimer
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, United States of America
| | - Dorjbal Dorjsuren
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, United States of America
| | - Ajit Jadhav
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, United States of America
| | - David J. Maloney
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, United States of America
| | - Anton Simeonov
- National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, United States of America
| | - Vilhelm A. Bohr
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
| | - Robert M. Brosh
- Laboratory of Molecular Gerontology, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America
- * E-mail:
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9
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Nejad MA, Urbassek HM. Diffusion of cisplatin molecules in silica nanopores: Molecular dynamics study of a targeted drug delivery system. J Mol Graph Model 2019; 86:228-234. [PMID: 30390543 DOI: 10.1016/j.jmgm.2018.10.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Revised: 10/22/2018] [Accepted: 10/22/2018] [Indexed: 11/24/2022]
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10
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Cheng Y, Zeng W, Cheng Y, Zhang J, Zou T, Wu K, Wang F. Selective binding of an organoruthenium complex to G-rich human telomeric sequence by tandem mass spectrometry. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2018; 32:2152-2158. [PMID: 30252980 DOI: 10.1002/rcm.8292] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/01/2018] [Revised: 09/20/2018] [Accepted: 09/21/2018] [Indexed: 06/08/2023]
Abstract
RATIONALE Human telomeric DNA is reported to be a potential target for anticancer organometallic ruthenium(II) complexes, however, the interaction sites were not clearly discriminated and identified. METHODS In the current study, tandem mass spectrometry (MS/MS) using collision-induced dissociation (CID) was firstly introduced to identify the interaction sites of an organometallic ruthenium(II) complex [(η6 -biphenyl)Ru(en)Cl][PF6 ] (1; en = ethylenediamine) with 5'-T1 T2 A3 G4 G5 G6 -3' (I), the repeating unit of human telomeric DNA, in both positive- and negative-ion mode at a low reaction molar ratio (1/I = 0.2) which was applied to preserve the site selectivity. RESULTS Mass spectrometric results showed that mono-ruthenated I was the main product under the conditions. In positive-ion mode, MS/MS results indicated that ruthenium complex 1 binds to T2 or G6 in strand I. However, in negative-ion mode, no efficient information was obtained for exact identification of ruthenation sites which may be attributed to losses of fragment ions due to charge neutralization by the coordination of the positively charged ruthenium complex to the short MS/MS fragments. CONCLUSIONS This is the first report of using top-down MS to characterize the interactions of organometallic ruthenium(II) complexes and human telomeric DNA. Thymine can be thermodynamically competitive with guanine for binding to ruthenium complexes even at low reaction molar ratio, which inspired us to explore in greater depth the significance of thymine binding.
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Affiliation(s)
- Yiyu Cheng
- School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, 430081, PR China
| | - Wenjuan Zeng
- Beijing National Laboratory for Molecular Sciences; National Centre for Mass Spectrometry in Beijing; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, CAS Research/Education Centre for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, PR China
- University of Chinese Academy Sciences, Beijing, 100049, PR China
| | - Yang Cheng
- School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, 430081, PR China
| | - Jishuai Zhang
- School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, 430081, PR China
| | - Tao Zou
- School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, 430081, PR China
| | - Kui Wu
- School of Chemistry and Chemical Engineering, Wuhan University of Science and Technology, Wuhan, 430081, PR China
| | - Fuyi Wang
- Beijing National Laboratory for Molecular Sciences; National Centre for Mass Spectrometry in Beijing; CAS Key Laboratory of Analytical Chemistry for Living Biosystems, CAS Research/Education Centre for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, PR China
- University of Chinese Academy Sciences, Beijing, 100049, PR China
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11
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Saker L, Ali S, Masserot C, Kellermann G, Poupon J, Teulade-Fichou MP, Ségal-Bendirdjian E, Bombard S. Platinum Complexes Can Bind to Telomeres by Coordination. Int J Mol Sci 2018; 19:E1951. [PMID: 29970863 PMCID: PMC6073198 DOI: 10.3390/ijms19071951] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 06/27/2018] [Accepted: 06/29/2018] [Indexed: 01/07/2023] Open
Abstract
It is suggested that several compounds, including G-quadruplex ligands, can target telomeres, inducing their uncapping and, ultimately, cell death. However, it has never been demonstrated whether such ligands can bind directly and quantitatively to telomeres. Here, we employed the property of platinum and platinum-G-quadruplex complexes to target G-rich sequences to investigate and quantify their covalent binding to telomeres. Using inductively coupled plasma mass spectrometry, surprisingly, we found that, in cellulo, in the presence of cisplatin, a di-functional platinum complex, telomeric DNA was platinated 13-times less than genomic DNA in cellulo, as compared to in vitro data. On the contrary, the amount of mono-functional platinum complexes (Pt-ttpy and Pt-tpy) bound either to telomeric or to genomic DNA was similar and occurred in a G-quadruplex independent-manner. Importantly, the quantification revealed that the low level of cisplatin bound to telomeric DNA could not be the direct physical cause of TRF2 displacement from telomeres. Altogether, our data suggest that platinum complexes can affect telomeres both directly and indirectly.
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Affiliation(s)
- Lina Saker
- INSERM UMR-S 1007, Cellular Homeostasis and Cancer, 75006 Paris, France.
- Paris Descartes University, Paris Sorbonne Cité, 75006 Paris, France.
| | - Samar Ali
- INSERM UMR-S 1007, Cellular Homeostasis and Cancer, 75006 Paris, France.
- Paris Sud University, Paris-Saclay University, 91405 Orsay, France.
| | - Caroline Masserot
- INSERM UMR-S 1007, Cellular Homeostasis and Cancer, 75006 Paris, France.
- Paris Sud University, Paris-Saclay University, 91405 Orsay, France.
| | - Guillaume Kellermann
- INSERM UMR-S 1007, Cellular Homeostasis and Cancer, 75006 Paris, France.
- Paris Descartes University, Paris Sorbonne Cité, 75006 Paris, France.
| | - Joel Poupon
- Laboratoire de Toxicologie-Biologique, Hôpital Lariboisière, 2 rue Ambroise Paré, 75475 Paris, France.
| | - Marie-Paule Teulade-Fichou
- Paris Sud University, Paris-Saclay University, 91405 Orsay, France.
- Institut Curie-Recherche, Bât. 112, Centre Universitaire, 91405 Orsay, France.
- CNRS UMR918, Centre Universitaire, 91405 Orsay, France.
- INSERM U1196, Centre Universitaire, 91405 Orsay, France.
| | - Evelyne Ségal-Bendirdjian
- INSERM UMR-S 1007, Cellular Homeostasis and Cancer, 75006 Paris, France.
- Paris Descartes University, Paris Sorbonne Cité, 75006 Paris, France.
- Paris Sud University, Paris-Saclay University, 91405 Orsay, France.
| | - Sophie Bombard
- INSERM UMR-S 1007, Cellular Homeostasis and Cancer, 75006 Paris, France.
- Paris Descartes University, Paris Sorbonne Cité, 75006 Paris, France.
- Paris Sud University, Paris-Saclay University, 91405 Orsay, France.
- Institut Curie-Recherche, Bât. 112, Centre Universitaire, 91405 Orsay, France.
- CNRS UMR918, Centre Universitaire, 91405 Orsay, France.
- INSERM U1196, Centre Universitaire, 91405 Orsay, France.
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12
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Dual functional dinuclear platinum complex with selective reactivity towards c-myc G-quadruplex. Sci Rep 2018; 8:767. [PMID: 29335501 PMCID: PMC5768759 DOI: 10.1038/s41598-017-19095-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Accepted: 12/20/2017] [Indexed: 01/24/2023] Open
Abstract
G-quadruplexes (GQ) folded by the oncogenic G-rich sequences are the promising targets for developing anticancer therapeutic molecules. However, the current drug development mainly focused on non-covalent dynamic binders to stabilize GQ structures, while the covalent targeting from inorganic complexes via chelating principles, as a potent therapeutic strategy was surprisingly lack of exploration. Herein, a series of dinuclear platinum complexes, [(Pt(Dip)Cl)2(μ-diamine)](NO3)2 (Dip: 4,7-diphenyl-1,10-phenanthroline), were designed to contain two dual-functional Pt cores connected by an alkyl linkage. Pt3 with nonanediamine linkage optimized the specific binding towards c-myc G-quadruplex via dual functional clamp on GQ as 1) non-covalently π-stacking of aromatic ligands, and 2) two Pt(II) cores covalently chelated to guanines at both 3'- and 5'-ends.
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13
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Charif R, Granotier-Beckers C, Bertrand HC, Poupon J, Ségal-Bendirdjian E, Teulade-Fichou MP, Boussin FD, Bombard S. Association of a Platinum Complex to a G-Quadruplex Ligand Enhances Telomere Disruption. Chem Res Toxicol 2017; 30:1629-1640. [DOI: 10.1021/acs.chemrestox.7b00131] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Affiliation(s)
- Razan Charif
- Université
Paris Descartes, INSERM UMR-S-1007, 45 rue des Saints-Pères, 75006 Paris, France
| | - Christine Granotier-Beckers
- CEA/DRF/IRCM,
Laboratoire de RadioPathologie, INSERM U967, Université Paris
VII, Université Paris XI, 18
route du Panorama, 92265 Fontenay-aux-Roses Cedex, France
| | - Hélène Charlotte Bertrand
- Institut
Curie,
Centre Universitaire Paris Saclay, CNRS UMR9187/INSERM U1196, Bâtiments 110-112, 91405 Orsay, France
- Département
de Chimie, Ecole Normale Supérieure, PSL Research University,
UPMC Univ Paris 06, CNRS, Laboratoire des Biomolécules (LBM), 24 rue Lhomond, 75005 Paris, France
- Sorbonne Universités,
UPMC Univ Paris 06, Ecole Normale Supérieure, CNRS, Laboratoire
des Biomolécules (LBM), 24 rue
Lhomond, 75005 Paris, France
| | - Joël Poupon
- Laboratoire
de Toxicologie-Biologique, Hôpital Lariboisière, 2 rue Ambroise Paré, 75475 Paris, France
| | | | - Marie-Paule Teulade-Fichou
- Institut
Curie,
Centre Universitaire Paris Saclay, CNRS UMR9187/INSERM U1196, Bâtiments 110-112, 91405 Orsay, France
| | - François D. Boussin
- CEA/DRF/IRCM,
Laboratoire de RadioPathologie, INSERM U967, Université Paris
VII, Université Paris XI, 18
route du Panorama, 92265 Fontenay-aux-Roses Cedex, France
| | - Sophie Bombard
- Université
Paris Descartes, INSERM UMR-S-1007, 45 rue des Saints-Pères, 75006 Paris, France
- Institut
Curie,
Centre Universitaire Paris Saclay, CNRS UMR9187/INSERM U1196, Bâtiments 110-112, 91405 Orsay, France
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14
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Common Chemical Inductors of Replication Stress: Focus on Cell-Based Studies. Biomolecules 2017; 7:biom7010019. [PMID: 28230817 PMCID: PMC5372731 DOI: 10.3390/biom7010019] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2016] [Accepted: 02/10/2017] [Indexed: 01/01/2023] Open
Abstract
DNA replication is a highly demanding process regarding the energy and material supply and must be precisely regulated, involving multiple cellular feedbacks. The slowing down or stalling of DNA synthesis and/or replication forks is referred to as replication stress (RS). Owing to the complexity and requirements of replication, a plethora of factors may interfere and challenge the genome stability, cell survival or affect the whole organism. This review outlines chemical compounds that are known inducers of RS and commonly used in laboratory research. These compounds act on replication by direct interaction with DNA causing DNA crosslinks and bulky lesions (cisplatin), chemical interference with the metabolism of deoxyribonucleotide triphosphates (hydroxyurea), direct inhibition of the activity of replicative DNA polymerases (aphidicolin) and interference with enzymes dealing with topological DNA stress (camptothecin, etoposide). As a variety of mechanisms can induce RS, the responses of mammalian cells also vary. Here, we review the activity and mechanism of action of these compounds based on recent knowledge, accompanied by examples of induced phenotypes, cellular readouts and commonly used doses.
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15
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Huang L, Chen Y, Weng LT, Leung M, Xing X, Fan Z, Wu H. Fast Single-Cell Patterning for Study of Drug-Induced Phenotypic Alterations of HeLa Cells Using Time-of-Flight Secondary Ion Mass Spectrometry. Anal Chem 2016; 88:12196-12203. [DOI: 10.1021/acs.analchem.6b03170] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Lu Huang
- Department
of Chemistry, ‡Division of Biomedical Engineering, §Materials Characterization and Preparation
Facility, Department of Chemical and Biomolecular Engineering, and ∥Department of
Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Yin Chen
- Department
of Chemistry, ‡Division of Biomedical Engineering, §Materials Characterization and Preparation
Facility, Department of Chemical and Biomolecular Engineering, and ∥Department of
Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Lu-Tao Weng
- Department
of Chemistry, ‡Division of Biomedical Engineering, §Materials Characterization and Preparation
Facility, Department of Chemical and Biomolecular Engineering, and ∥Department of
Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Mark Leung
- Department
of Chemistry, ‡Division of Biomedical Engineering, §Materials Characterization and Preparation
Facility, Department of Chemical and Biomolecular Engineering, and ∥Department of
Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Xiaoxing Xing
- Department
of Chemistry, ‡Division of Biomedical Engineering, §Materials Characterization and Preparation
Facility, Department of Chemical and Biomolecular Engineering, and ∥Department of
Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Zhiyong Fan
- Department
of Chemistry, ‡Division of Biomedical Engineering, §Materials Characterization and Preparation
Facility, Department of Chemical and Biomolecular Engineering, and ∥Department of
Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong, China
| | - Hongkai Wu
- Department
of Chemistry, ‡Division of Biomedical Engineering, §Materials Characterization and Preparation
Facility, Department of Chemical and Biomolecular Engineering, and ∥Department of
Electronic and Computer Engineering, The Hong Kong University of Science and Technology, Hong Kong, China
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16
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Menendez JA, Rubio MA, Campisi J, Lupu R. Heregulin, a new regulator of telomere length in human cells. Oncotarget 2016; 6:39422-36. [PMID: 26318724 PMCID: PMC4741836 DOI: 10.18632/oncotarget.4964] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2015] [Accepted: 07/12/2015] [Indexed: 01/12/2023] Open
Abstract
The growth factor heregulin (HRG) promotes breast cancer (BC) tumorigenesis and metastasis and differentially modulates BC cell responses to DNA-damaging agents via its dual extracellular and nuclear localization. Given the central role of telomere dysfunction to drive carcinogenesis and to alter the chemotherapeutic profile of transformed cells, we hypothesized that an unanticipated nuclear function of HRG might be to regulate telomere length. Engineered overexpression of the HRGβ2 isoform in non-aggressive, HRG-negative MCF-7 BC cells resulted in a significant shortening of telomeres (up to 1.3 kb) as measured by Southern blotting of telomere terminal restriction fragments. Conversely, antisense-mediated suppression of HRGβ2 in highly aggressive, HRG-overexpressing MDA-MB-231 and Hs578T cells increased telomere length up to 3.0 kb. HRGβ2 overexpression promoted a marked upregulation of telomere-binding protein 2 (TRF2) protein expression, whereas its knockdown profoundly decreased TRF2 expression. Double staining of endogenous HRGβ2 with telomere-specific peptide nucleic acid probe/fluorescence in situ hybridization (PNA/FISH) revealed the partial localization of HRG at the chromosome ends. Moreover, a predominantly nucleoplasmic staining pattern of endogenous HRGβ2 appeared to co-localize with TRF2 and, concomitantly with RAP1, a telomere regulator that specifically interacts with TRF2. Small interfering RNA-mediated knockdown of HRG decreased the expression of TRF2 and RAP1, decreased their presence at chromosome ends, and coincidentally resulted in the formation of longer telomeres. This study uncovers a new function for HRGβ2 in controlling telomere length, in part due to its ability to regulate and interact with the telomere-associated proteins TRF2 and RAP1.
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Affiliation(s)
- Javier A Menendez
- ProCURE (Program Against Cancer Therapeutic Resistance), Metabolism & Cancer Group, Catalan Institute of Oncology (ICO), Girona, Spain.,Girona Biomedical Research Institute (IDIBGI), Girona, Spain
| | - Miguel A Rubio
- Laboratory of Hematology Service, Institut d'Investigació Biomèdica Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Judith Campisi
- Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, CA, USA.,Buck Institute for Research on Aging, Novato, CA, USA
| | - Ruth Lupu
- Mayo Clinic, Department of Laboratory Medicine and Pathology, Division of Experimental Pathology, Rochester, MN, USA.,Mayo Clinic Cancer Center, Rochester, MN, USA
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17
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Johnson BW, Murray V, Temple MD. Characterisation of the DNA sequence specificity, cellular toxicity and cross-linking properties of novel bispyridine-based dinuclear platinum complexes. BMC Cancer 2016; 16:333. [PMID: 27225032 PMCID: PMC4880875 DOI: 10.1186/s12885-016-2368-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 05/18/2016] [Indexed: 12/21/2022] Open
Abstract
Background The anti-tumour activity of cisplatin is thought to be a result of its capacity to form DNA adducts which prevent cellular processes such as DNA replication and transcription. These DNA adducts can effectively induce cancer cell death, however, there are a range of clinical side effects and drug resistance issues associated with its use. In this study, the biological properties of three novel dinuclear platinum-based compounds (that contain alkane bridging linkers of eight, ten and twelve carbon atoms in length) were characterised to assess their potential as anticancer agents. Methods The properties of these compounds were determined using a DNA template containing seven tandem telomeric repeat sequences. A linear amplification reaction was used in combination with capillary electrophoresis to quantify the sequence specificity of DNA adducts formed by these compounds at base pair resolution. The DNA cross-linking ability of these compounds was assessed using denaturing agarose gel electrophoresis and cytotoxicity was determined in HeLa cells using a colorimetric cell viability assay. Results The dinuclear compounds were found to preferentially form DNA adducts at guanine bases and they exhibited different damage intensity profiles at the telomeric repeat sequences compared to that of cisplatin. The dinuclear compounds were found to exhibit a low level of cytotoxicity relative to cisplatin and their cytotoxicity increased as the linker length increased. Conversely, the interstrand cross-linking efficiency of the dinuclear compounds increased as the linker length decreased and the compound with the shortest alkane linker was six-fold more effective than cisplatin. Conclusions Since the bifunctional compounds exhibit variation in sequence specificity of adduct formation and a greater ability to cross-link DNA relative to cisplatin they warrant further investigation towards the goal of developing new cancer chemotherapeutic agents.
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Affiliation(s)
- Ben W Johnson
- School of Science and Health, Western Sydney University, Campbelltown, NSW, 2560, Australia
| | - Vincent Murray
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Mark D Temple
- School of Science and Health, Western Sydney University, Campbelltown, NSW, 2560, Australia.
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18
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Langie SA, Koppen G, Desaulniers D, Al-Mulla F, Al-Temaimi R, Amedei A, Azqueta A, Bisson WH, Brown D, Brunborg G, Charles AK, Chen T, Colacci A, Darroudi F, Forte S, Gonzalez L, Hamid RA, Knudsen LE, Leyns L, Lopez de Cerain Salsamendi A, Memeo L, Mondello C, Mothersill C, Olsen AK, Pavanello S, Raju J, Rojas E, Roy R, Ryan E, Ostrosky-Wegman P, Salem HK, Scovassi I, Singh N, Vaccari M, Van Schooten FJ, Valverde M, Woodrick J, Zhang L, van Larebeke N, Kirsch-Volders M, Collins AR. Causes of genome instability: the effect of low dose chemical exposures in modern society. Carcinogenesis 2015; 36 Suppl 1:S61-S88. [PMID: 26106144 PMCID: PMC4565613 DOI: 10.1093/carcin/bgv031] [Citation(s) in RCA: 138] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 12/08/2014] [Accepted: 12/11/2014] [Indexed: 12/17/2022] Open
Abstract
Genome instability is a prerequisite for the development of cancer. It occurs when genome maintenance systems fail to safeguard the genome's integrity, whether as a consequence of inherited defects or induced via exposure to environmental agents (chemicals, biological agents and radiation). Thus, genome instability can be defined as an enhanced tendency for the genome to acquire mutations; ranging from changes to the nucleotide sequence to chromosomal gain, rearrangements or loss. This review raises the hypothesis that in addition to known human carcinogens, exposure to low dose of other chemicals present in our modern society could contribute to carcinogenesis by indirectly affecting genome stability. The selected chemicals with their mechanisms of action proposed to indirectly contribute to genome instability are: heavy metals (DNA repair, epigenetic modification, DNA damage signaling, telomere length), acrylamide (DNA repair, chromosome segregation), bisphenol A (epigenetic modification, DNA damage signaling, mitochondrial function, chromosome segregation), benomyl (chromosome segregation), quinones (epigenetic modification) and nano-sized particles (epigenetic pathways, mitochondrial function, chromosome segregation, telomere length). The purpose of this review is to describe the crucial aspects of genome instability, to outline the ways in which environmental chemicals can affect this cancer hallmark and to identify candidate chemicals for further study. The overall aim is to make scientists aware of the increasing need to unravel the underlying mechanisms via which chemicals at low doses can induce genome instability and thus promote carcinogenesis.
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Affiliation(s)
- Sabine A.S. Langie
- Environmental Risk and Health Unit, Flemish Institute for Technological Research (VITO), Boeretang 200, 2400 Mol, Belgium
- Health Canada, Environmental Health Sciences and Research Bureau, Environmental Health Centre, Ottawa, Ontario K1A0K9, Canada
- Department of Pathology, Kuwait University, Safat 13110, Kuwait
- Department of Experimental and Clinical Medicine, University of Firenze, Florence 50134, Italy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Navarra, Pamplona 31009, Spain
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
- Department of Chemicals and Radiation, Division of Environmental Medicine, Norwegian Institute of Public Health, PO Box 4404, N-0403 Oslo, Norway
- Hopkins Building, School of Biological Sciences, University of Reading, Reading, Berkshire RG6 6UB, UK
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
- Human and Environmental Safety Research, Department of Health Sciences, College of North Atlantic, Doha, State of Qatar
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy
- Laboratory for Cell Genetics, Vrije Universiteit Brussel, Brussels 1050, Belgium
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, University Putra, Serdang 43400, Selangor, Malaysia
- University of Copenhagen, Department of Public Health, Copenhagen 1353, Denmark
- Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy
- Medical Physics & Applied Radiation Sciences, McMaster University, Hamilton, Ontario L8S4L8, Canada
- Department of Cardiac, Thoracic and Vascular Sciences, Unit of Occupational Medicine, University of Padova, Padova 35128, Italy
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
- Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de México, México CP 04510, México
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
- Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow 226003, Uttar Pradesh, India
- Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, 6200MD, PO Box 61, Maastricht, The Netherlands
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720-7360, USA
- Laboratory for Analytical and Environmental Chemistry, Vrije Universiteit Brussel, Brussels 1050, Belgium
- Study Centre for Carcinogenesis and Primary Prevention of Cancer, Ghent University, Ghent 9000, Belgium
- Department of Nutrition, University of Oslo, Oslo 0316, Norway
| | - Gudrun Koppen
- *To whom correspondence should be addressed. Tel: +32 14335165; Fax: +32 14580523
| | - Daniel Desaulniers
- Health Canada, Environmental Health Sciences and Research Bureau, Environmental Health Centre, Ottawa, Ontario K1A0K9, Canada
| | - Fahd Al-Mulla
- Department of Pathology, Kuwait University, Safat 13110, Kuwait
| | | | - Amedeo Amedei
- Department of Experimental and Clinical Medicine, University of Firenze, Florence 50134, Italy
| | - Amaya Azqueta
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, University of Navarra, Pamplona 31009, Spain
| | - William H. Bisson
- Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331, USA
| | - Dustin Brown
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - Gunnar Brunborg
- Department of Chemicals and Radiation, Division of Environmental Medicine, Norwegian Institute of Public Health, PO Box 4404, N-0403 Oslo, Norway
| | - Amelia K. Charles
- Hopkins Building, School of Biological Sciences, University of Reading, Reading, Berkshire RG6 6UB, UK
| | - Tao Chen
- Division of Genetic and Molecular Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR 72079, USA
| | - Annamaria Colacci
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
| | - Firouz Darroudi
- Human and Environmental Safety Research, Department of Health Sciences, College of North Atlantic, Doha, State of Qatar
| | - Stefano Forte
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy
| | - Laetitia Gonzalez
- Laboratory for Cell Genetics, Vrije Universiteit Brussel, Brussels 1050, Belgium
| | - Roslida A. Hamid
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, University Putra, Serdang 43400, Selangor, Malaysia
| | - Lisbeth E. Knudsen
- University of Copenhagen, Department of Public Health, Copenhagen 1353, Denmark
| | - Luc Leyns
- Laboratory for Cell Genetics, Vrije Universiteit Brussel, Brussels 1050, Belgium
| | | | - Lorenzo Memeo
- Mediterranean Institute of Oncology, 95029 Viagrande, Italy
| | - Chiara Mondello
- Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy
| | - Carmel Mothersill
- Medical Physics & Applied Radiation Sciences, McMaster University, Hamilton, Ontario L8S4L8, Canada
| | - Ann-Karin Olsen
- Department of Chemicals and Radiation, Division of Environmental Medicine, Norwegian Institute of Public Health, PO Box 4404, N-0403 Oslo, Norway
| | - Sofia Pavanello
- Department of Cardiac, Thoracic and Vascular Sciences, Unit of Occupational Medicine, University of Padova, Padova 35128, Italy
| | - Jayadev Raju
- Toxicology Research Division, Bureau of Chemical Safety Food Directorate, Health Products and Food Branch Health Canada, Ottawa, Ontario K1A0K9, Canada
| | - Emilio Rojas
- Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de México, México CP 04510, México
| | - Rabindra Roy
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Elizabeth Ryan
- Department of Environmental and Radiological Health Sciences/Food Science and Human Nutrition, College of Veterinary Medicine and Biomedical Sciences, Colorado State University/Colorado School of Public Health, Fort Collins, CO 80523-1680, USA
| | - Patricia Ostrosky-Wegman
- Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de México, México CP 04510, México
| | - Hosni K. Salem
- Urology Department, kasr Al-Ainy School of Medicine, Cairo University, El Manial, Cairo 12515, Egypt
| | - Ivana Scovassi
- Institute of Molecular Genetics, National Research Council, Pavia 27100, Italy
| | - Neetu Singh
- Centre for Advanced Research, King George’s Medical University, Chowk, Lucknow 226003, Uttar Pradesh, India
| | - Monica Vaccari
- Center for Environmental Carcinogenesis and Risk Assessment, Environmental Protection and Health Prevention Agency, Bologna 40126, Italy
| | - Frederik J. Van Schooten
- Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University, 6200MD, PO Box 61, Maastricht, The Netherlands
| | - Mahara Valverde
- Departamento de Medicina Genomica y Toxicologia Ambiental, Instituto de Investigaciones Biomedicas, Universidad Nacional Autonoma de México, México CP 04510, México
| | - Jordan Woodrick
- Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20057, USA
| | - Luoping Zhang
- Division of Environmental Health Sciences, School of Public Health, University of California, Berkeley, CA 94720-7360, USA
| | - Nik van Larebeke
- Laboratory for Analytical and Environmental Chemistry, Vrije Universiteit Brussel, Brussels 1050, Belgium
- Study Centre for Carcinogenesis and Primary Prevention of Cancer, Ghent University, Ghent 9000, Belgium
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19
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Dasgupta P, Sengupta SB. Role of diallyl disulfide-mediated cleavage of c-Myc and Sp-1 in the regulation of telomerase activity in human lymphoma cell line U937. Nutrition 2015; 31:1031-7. [PMID: 26059379 DOI: 10.1016/j.nut.2015.02.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 02/22/2015] [Accepted: 02/25/2015] [Indexed: 02/01/2023]
Abstract
OBJECTIVE Garlic (Allium sativum) has been considered a wonder herb for years with a reputation of disease prevention. Telomerase, a ribonucleoprotein enzyme responsible for telomere integrity, is strongly up-regulated in different types of cancers. The aim of this study was to reveal the role of diallyl disulfide (DADS), an organosulfur component of garlic, on telomerase activity in human lymphoma with an emphasis on key transcription factors c-Myc and Sp-1. METHODS Human lymphoma cell line U937 was used as model cell line. Telomerase activity was measured by telomerase repeat amplification protocol assay, levels of related proteins and mRNAs were measured by Western blot and reverse transcriptase polymerase chain reaction, respectively. Moreover, in vitro binding assay was performed using radiolabeled double-stranded DNA having specific sequences to detect involvement of transcription factors in DADS-dependent modulation of telomerase activity. RESULTS The present study demonstrated DADS-mediated decrease in telomerase activity in U937 cells with concomitant transcriptional down-regulation of human telomerase reverse transcriptase (hTERT) that is caused by reduced binding of c-Myc and Sp-1 to their respective binding sites on hTERT promoter. Lowering of DNA-binding activity of c-Myc and Sp-1 due to DADS treatment is caused by the deactivation of these transcription factors due to cleavage. Additionally, Mad1-the repressor protein of hTERT expression-is also overexpressed in DADS-treated U937 cells. CONCLUSIONS These findings strongly suggest that DADS down-regulate telomerase activity through c-Myc-, Sp-1-, and Mad1-dependent transcriptional down-regulation of hTERT.
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Affiliation(s)
- Pritha Dasgupta
- Department of Biophysics, Molecular Biology and Bioinformatics, University of Calcutta, Kolkata, India
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Komosa M, Root H, Meyn MS. Visualization and quantitative analysis of extrachromosomal telomere-repeat DNA in individual human cells by Halo-FISH. Nucleic Acids Res 2015; 43:2152-63. [PMID: 25662602 PMCID: PMC4344523 DOI: 10.1093/nar/gkv091] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Current methods for characterizing extrachromosomal nuclear DNA in mammalian cells do not permit single-cell analysis, are often semi-quantitative and frequently biased toward the detection of circular species. To overcome these limitations, we developed Halo-FISH to visualize and quantitatively analyze extrachromosomal DNA in single cells. We demonstrate Halo-FISH by using it to analyze extrachromosomal telomere-repeat (ECTR) in human cells that use the Alternative Lengthening of Telomeres (ALT) pathway(s) to maintain telomere lengths. We find that GM847 and VA13 ALT cells average ∼80 detectable G/C-strand ECTR DNA molecules/nucleus, while U2OS ALT cells average ∼18 molecules/nucleus. In comparison, human primary and telomerase-positive cells contain <5 ECTR DNA molecules/nucleus. ECTR DNA in ALT cells exhibit striking cell-to-cell variations in number (<20 to >300), range widely in length (<1 to >200 kb) and are composed of primarily G- or C-strand telomere-repeat DNA. Halo-FISH enables, for the first time, the simultaneous analysis of ECTR DNA and chromosomal telomeres in a single cell. We find that ECTR DNA comprises ∼15% of telomere-repeat DNA in GM847 and VA13 cells, but <4% in U2OS cells. In addition to its use in ALT cell analysis, Halo-FISH can facilitate the study of a wide variety of extrachromosomal DNA in mammalian cells.
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Affiliation(s)
- Martin Komosa
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada
| | - Heather Root
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada
| | - M Stephen Meyn
- Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, M5G 0A4, Canada Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, M5G 1X8, Canada Department of Paediatrics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada Department of Molecular Genetics, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
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21
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DNA interstrand cross-link repair requires replication-fork convergence. Nat Struct Mol Biol 2015; 22:242-7. [PMID: 25643322 PMCID: PMC4351167 DOI: 10.1038/nsmb.2956] [Citation(s) in RCA: 111] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 12/17/2014] [Indexed: 12/14/2022]
Abstract
DNA interstrand cross-links (ICLs) prevent strand separation during DNA replication and transcription and therefore are extremely cytotoxic. In metazoans, a major pathway of ICL repair is coupled to DNA replication, and it requires the Fanconi anemia pathway. In most current models, collision of a single DNA replication fork with an ICL is sufficient to initiate repair. In contrast, we show here that in Xenopus egg extracts two DNA replication forks must converge on an ICL to trigger repair. When only one fork reaches the ICL, the replicative CMG helicase fails to unload from the stalled fork, and repair is blocked. Arrival of a second fork, even when substantially delayed, rescues repair. We conclude that ICL repair requires a replication-induced X-shaped DNA structure surrounding the lesion, and we speculate on how this requirement helps maintain genomic stability in S phase.
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22
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Margiotta N, Petruzzella E, Platts JA, Mutter ST, Deeth RJ, Ranaldo R, Papadia P, Marzilli PA, Marzilli LG, Hoeschele JD, Natile G. DNA fragment conformations in adducts with Kiteplatin. Dalton Trans 2015; 44:3544-56. [DOI: 10.1039/c4dt01796j] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The anticancer-active platinum complex with cis-1,4-diaminocyclohexane has proved to be very valuable in detecting multiple conformers in adducts with oligonucleotides.
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Affiliation(s)
- Nicola Margiotta
- Dipartimento di Chimica
- Università degli Studi di Bari A. Moro
- 70125 Bari
- Italy
| | | | | | | | | | - Rosa Ranaldo
- Dipartimento di Chimica
- Università degli Studi di Bari A. Moro
- 70125 Bari
- Italy
- Department of Chemistry
| | - Paride Papadia
- Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali
- Università del Salento
- 73100 Lecce
- Italy
| | | | | | | | - Giovanni Natile
- Dipartimento di Chimica
- Università degli Studi di Bari A. Moro
- 70125 Bari
- Italy
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23
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Liu M, Hales BF, Robaire B. Effects of four chemotherapeutic agents, bleomycin, etoposide, cisplatin, and cyclophosphamide, on DNA damage and telomeres in a mouse spermatogonial cell line. Biol Reprod 2014; 90:72. [PMID: 24571982 DOI: 10.1095/biolreprod.114.117754] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Treatment with chemotherapeutics agents may induce persistent DNA damage in male germ cells with the possibility of long-term consequences on fertility and progeny outcome. Telomeres, specialized structures at the physical ends of chromosomes, play an important role in the maintenance of genetic stability and in the response of somatic cells to anticancer drugs. Our objective was to test the hypothesis that exposure to bleomycin, etoposide, or cisplatin (the drugs used to treat testicular cancer) or cyclophosphamide (an anticancer agent and immunosuppressant) targets telomeres in the male germ line. C18-4 spermatogonial cells were exposed to bleomycin, etoposide, cisplatin, or 4-hydroperoxycyclophosphamide (4OOH-CPA, a preactivated analog of cyclophosphamide). All four anticancer drugs induced a significant increase in DNA damage in C18-4 cells, as assessed by gamma-H2AX immunofluorescence. Interestingly, the gamma-H2AX signal was localized to telomeres after treatment with bleomycin, cisplatin, and 4OOH-CPA, but not etoposide. Mean telomere lengths, the intensity of the telomere fluorescence in situ hybridization signal, telomerase activity, and the expression of the telomerase enzyme mRNA components, Tert and Terc, were reduced by exposure to cisplatin and 4OOH-CPA, but not by bleomycin or etoposide. Thus, although all four anticancer drugs induced DNA damage in this spermatogonial cell line, telomeres were not specifically affected by etoposide and only the two alkylating agents, cisplatin and 4OOH-CPA, induced telomere dysfunction. This telomere dysfunction may contribute to infertility and developmental defects in the offspring.
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Affiliation(s)
- Mingxi Liu
- Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada
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24
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Wu K, Liu S, Luo Q, Hu W, Li X, Wang F, Zheng R, Cui J, Sadler PJ, Xiang J, Shi Q, Xiong S. Thymines in Single-Stranded Oligonucleotides and G-Quadruplex DNA Are Competitive with Guanines for Binding to an Organoruthenium Anticancer Complex. Inorg Chem 2013; 52:11332-42. [DOI: 10.1021/ic401606v] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Kui Wu
- Beijing National
Laboratory
for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
- CAS Key Laboratory of Analytical
Chemistry for Living Biosystems, Beijing Centre for Mass Spectrometry, Beijing 100190, P. R. China
| | - Suyan Liu
- Beijing National
Laboratory
for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
- CAS Key Laboratory of Analytical
Chemistry for Living Biosystems, Beijing Centre for Mass Spectrometry, Beijing 100190, P. R. China
| | - Qun Luo
- Beijing National
Laboratory
for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
- CAS Key Laboratory of Analytical
Chemistry for Living Biosystems, Beijing Centre for Mass Spectrometry, Beijing 100190, P. R. China
| | - Wenbing Hu
- Beijing National
Laboratory
for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
- CAS Key Laboratory of Analytical
Chemistry for Living Biosystems, Beijing Centre for Mass Spectrometry, Beijing 100190, P. R. China
| | - Xianchan Li
- Beijing National
Laboratory
for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
- CAS Key Laboratory of Analytical
Chemistry for Living Biosystems, Beijing Centre for Mass Spectrometry, Beijing 100190, P. R. China
| | - Fuyi Wang
- Beijing National
Laboratory
for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
- CAS Key Laboratory of Analytical
Chemistry for Living Biosystems, Beijing Centre for Mass Spectrometry, Beijing 100190, P. R. China
| | - Renhui Zheng
- Beijing National
Laboratory
for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
- State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Beijing 100190, P. R. China
| | - Jie Cui
- Beijing National
Laboratory
for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
| | - Peter J. Sadler
- Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4
7AL, United Kingdom
| | - Junfeng Xiang
- Beijing National
Laboratory
for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
| | - Qiang Shi
- Beijing National
Laboratory
for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
- State Key Laboratory for Structural Chemistry of Unstable and Stable Species, Beijing 100190, P. R. China
| | - Shaoxiang Xiong
- Beijing National
Laboratory
for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. China
- CAS Key Laboratory of Analytical
Chemistry for Living Biosystems, Beijing Centre for Mass Spectrometry, Beijing 100190, P. R. China
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Chung CYS, Yam VWW. Selective label-free detection of G-quadruplex structure of human telomere by emission spectral changes in visible-and-NIR region under physiological condition through the FRET of a two-component PPE-SO3−–Pt(ii) complex ensemble with Pt⋯Pt, electrostatic and π–π interactions. Chem Sci 2013. [DOI: 10.1039/c2sc20897k] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
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Nguyen HTQ, Galea AM, Murray V. The interaction of cisplatin with a human telomeric DNA sequence containing seventeen tandem repeats. Bioorg Med Chem Lett 2012; 23:1041-5. [PMID: 23302441 DOI: 10.1016/j.bmcl.2012.12.021] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2012] [Revised: 11/27/2012] [Accepted: 12/10/2012] [Indexed: 01/01/2023]
Abstract
The anti-tumour drug, cisplatin, preferentially forms adducts at G-rich DNA sequences. Telomeres are found at the ends of chromosomes and, in humans, contain the repeated DNA sequence (GGGTTA)(n) that is expected to be targeted by cisplatin. Using a plasmid clone with 17 tandem telomeric repeats, (GGGTTA)(17), the DNA sequence specificity of cisplatin was investigated utilising the linear amplification procedure that pin-pointed the precise sites of cisplatin adduct formation. This procedure used a fluorescently labelled primer and capillary electrophoresis with laser-induced fluorescence detection to determine the DNA sequence specificity of cisplatin. This technique provided a very accurate analysis of cisplatin-DNA adduct formation in a long telomeric repeat DNA sequence. The DNA sequence specificity of cisplatin in a long telomeric tandem repeat has not been previously reported. The results indicated that the 3'-end of the G-rich strand of the telomeric repeat was preferentially damaged by cisplatin and this suggests that the telomeric DNA repeat has an unusual conformation.
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Affiliation(s)
- Hanh T Q Nguyen
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney NSW 2052, Australia
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27
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Zhang B, Suer S, Livak F, Adediran S, Vemula A, Khan MA, Ning Y, Hussain A. Telomere and microtubule targeting in treatment-sensitive and treatment-resistant human prostate cancer cells. Mol Pharmacol 2012; 82:310-21. [PMID: 22584221 DOI: 10.1124/mol.111.076752] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Modulating telomere dynamics may be a useful strategy for targeting prostate cancer cells, because they generally have short telomeres. Because a plateau has been reached in the development of taxane-based treatments for prostate cancer, this study was undertaken to evaluate the relative efficacy of targeting telomeres and microtubules in taxane-sensitive, taxane-resistant, androgen-sensitive, and androgen-insensitive prostate cancer cells. Paclitaxel- and docetaxel-resistant DU145 cells were developed and their underlying adaptive responses were evaluated. Telomere dynamics and the effects of targeting telomeres with sodium meta-arsenite (KML001) (an agent undergoing early clinical trials), including combinations with paclitaxel and docetaxel, were evaluated in parental and drug-resistant cells. The studies were extended to androgen-sensitive LNCaP cells and androgen-insensitive LNCaP/C81 cells. Both P-glycoprotein (Pgp)-dependent and non-Pgp-dependent mechanisms of resistance were recruited within the same population of DU145 cells with selection for drug resistance. Wild-type DU145 cells have a small side population (SP) (0.4-1.2%). The SP fraction increased with increasing drug resistance, which was correlated with enhanced expression of Pgp but not breast cancer resistance protein. Telomere dynamics remained unchanged in taxane-resistant cells, which retained sensitivity to KML001. Furthermore, KML001 targeted SP and non-SP fractions, inducing DNA damage signaling in both fractions. KML001 induced telomere erosion, decreased telomerase gene expression, and was highly synergistic with the taxanes in wild-type and drug-resistant DU145 cells. This synergism extended to androgen-sensitive and androgen-insensitive LNCaP cells under basal and androgen-deprived conditions. These studies demonstrate that KML001 plus docetaxel and KML001 plus paclitaxel represent highly synergistic drug combinations that should be explored further in the different disease states of prostate cancer.
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Affiliation(s)
- Bin Zhang
- University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, USA
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28
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Terry KL, Tworoger SS, Vitonis AF, Wong J, Titus-Ernstoff L, De Vivo I, Cramer DW. Telomere length and genetic variation in telomere maintenance genes in relation to ovarian cancer risk. Cancer Epidemiol Biomarkers Prev 2012; 21:504-12. [PMID: 22267287 DOI: 10.1158/1055-9965.epi-11-0867] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Telomeres protect chromosomal ends, shorten with cellular division, and signal cellular senescence, but unchecked telomere attrition can lead to telomere dysfunction, upregulation of telomerase, and carcinogenesis. Shorter telomeres in peripheral blood leukocytes (PBL) have been associated with elevated cancer risk. Furthermore, genetic variants in and around the TERT gene have been implicated in carcinogenesis. METHODS We measured relative telomere length (RTL) in PBLs of 911 cases and 948 controls from the New England case-control (NECC) study, a population-based study of ovarian cancer. In addition, we assessed germ line genetic variation in five telomere maintenance genes among 2,112 cases and 2,456 controls from the NECC study and the Nurses' Health Study, a prospective cohort study. ORs and 95% CIs were estimated by logistic regression. RESULTS Overall, we observed no differences in telomere length between cases and controls. Compared with women with RTL in the longest tertile, women with RTL in the shortest tertile had no increase in risk (OR = 1.01, 95% CI: 0.80-1.28). However, several SNPs in the TERT gene, including rs2736122, rs4246742, rs4975605, rs10069690, rs2736100, rs2853676, and rs7726159, were significantly associated with ovarian cancer risk. We observed a significant gene-level association between TERT and ovarian cancer risk (P = 0.00008). CONCLUSION Our observations suggest that genetic variation in the TERT gene may influence ovarian cancer risk, but the association between average telomere length in PBLs and ovarian cancer remains unclear. IMPACT The role of telomeres in ovarian carcinogenesis remains unsettled and warrants further investigation.
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Affiliation(s)
- Kathryn L Terry
- Obstetrics and Gynecology Epidemiology Center, Department of Obstetrics and Gynecology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
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Stucki SR, Nyakas A, Schürch S. Tandem mass spectrometry of platinated quadruplex DNA. JOURNAL OF MASS SPECTROMETRY : JMS 2011; 46:1288-1297. [PMID: 22223421 DOI: 10.1002/jms.2019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Quadruplexes are higher-order structures formed by G-rich DNA strands that are involved in various processes of cell cycle regulation, such as control of telomere length and participation in gene regulation. Because of these central biological functions, quadruplex DNA represents a promising target for cancer therapy, e.g. by applying organometallic drugs, such as cisplatin. High-resolution electrospray tandem mass spectrometry is evaluated as a technique for exploring structural features of unplatinated and platinated quadruplexes. Results of experiments on tetramolecular, bimolecular and monomolecular quadruplexes provide information about the extent of platination and the binding sites of the drug. The dissociation behavior of the different types of quadruplexes is compared. Tetramolecular quadruplexes were found to weave out a strand end in order to provide a platination site, and their fragmentation is characterized by the release of an unplatinated strand and the formation of a platinated triplex. Partial opening of the structure in combination with the loss of small fragments leads to truncated quadruplex ions. For the bimolecular quadruplexes studied, strand separation is the predominant dissociation pathway. Depending on the loop sequence, cross-linking of the loops by cisplatin is demonstrated. Distinct differences in the product ion spectra of unannealed and annealed monomolecular sequences provide proof of quadruplex formation and show that platination preferentially occurs at the terminal regions.
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Affiliation(s)
- Silvan R Stucki
- Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, CH-3012, Bern, Switzerland
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Guittat L, Alberti P, Gomez D, De Cian A, Pennarun G, Lemarteleur T, Belmokhtar C, Paterski R, Morjani H, Trentesaux C, Mandine E, Boussin F, Mailliet P, Lacroix L, Riou JF, Mergny JL. Targeting human telomerase for cancer therapeutics. Cytotechnology 2011; 45:75-90. [PMID: 19003245 DOI: 10.1007/s10616-004-5127-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2004] [Accepted: 09/21/2004] [Indexed: 01/28/2023] Open
Abstract
The enzyme telomerase is involved in the replication of telomeres, specialized structures that cap and protect the ends of chromosomes. Its activity is required for maintenance of telomeres and for unlimited lifespan, a hallmark of cancer cells. Telomerase is overexpressed in the vast majority of human cancer cells and therefore represents an attractive target for therapy. Several approaches have been developed to inhibit this enzyme through the targeting of its RNA or catalytic components as well as its DNA substrate, the single-stranded 3'-telomeric overhang. Telomerase inhibitors are chemically diverse and include modified oligonucleotides as well as small diffusable molecules, both natural and synthetic. This review presents an update of recent investigations pertaining to these agents and discusses their biological properties in the context of the initial paradigm that the exposure of cancer cells to these agents should lead to progressive telomere shortening followed by a delayed growth arrest response.
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Affiliation(s)
- Lionel Guittat
- Laboratoire de Biophysique, Muséum National d'Histoire Naturelle USM503, INSERM U 565, CNRS UMR 5153, 43, rue Cuvier, 75231, Paris cedex 05, France
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Paul M, Murray V. Use of an automated capillary DNA sequencer to investigate the interaction of cisplatin with telomeric DNA sequences. Biomed Chromatogr 2011; 26:350-4. [PMID: 21678458 DOI: 10.1002/bmc.1664] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The determination of the sequence selectivity of DNA-damaging agents is very important in elucidating the mechanism of action of anti-tumour drugs. The development of automated capillary DNA sequencers with fluorescent labelling has enabled a more precise method for DNA sequence specificity analysis. In this work we utilized the ABI 3730 capillary sequencer with laser-induced fluorescence to examine the sequence selectivity of cisplatin with purified DNA sequences. The use of this automated machine enabled a higher degree of precision of both position and intensity of cisplatin-DNA adducts than previously possible with manual and automated slab gel procedures. A problem with artefact bands was overcome by ethanol precipitation. It was found that cisplatin strongly formed adducts with telomeric DNA sequences.
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Affiliation(s)
- Moumita Paul
- School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, NSW, 2052, Australia
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Rocca CJ, Poindessous V, Soares DG, Ouadrani KE, Sarasin A, Guérin E, de Gramont A, Henriques JA, Escargueil AE, Larsen AK. The NER proteins XPC and CSB, but not ERCC1, regulate the sensitivity to the novel DNA binder S23906: Implications for recognition and repair of antitumor alkylators. Biochem Pharmacol 2010; 80:335-43. [DOI: 10.1016/j.bcp.2010.04.012] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2010] [Revised: 04/07/2010] [Accepted: 04/09/2010] [Indexed: 11/16/2022]
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Koprinarova M, Markovska P, Iliev I, Anachkova B, Russev G. Sodium butyrate enhances the cytotoxic effect of cisplatin by abrogating the cisplatin imposed cell cycle arrest. BMC Mol Biol 2010; 11:49. [PMID: 20576112 PMCID: PMC2906439 DOI: 10.1186/1471-2199-11-49] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2009] [Accepted: 06/24/2010] [Indexed: 01/29/2023] Open
Abstract
Background Histone deacetylase inhibitors have been proposed as potential enhancers of the cytotoxic effect of cisplatin and other anticancer drugs. Their application would permit the use of lower therapeutic doses and reduction of the adverse side effects of the drugs. However, the molecular mechanisms by which they sensitize the cells towards anticancer drugs are not known in details, which is an obstacle in developing effective therapeutic protocols. Results In the present work, we studied the molecular mechanisms by which sodium butyrate sensitizes cancer cells towards cisplatin. HeLa cells were treated with 5 mM butyrate, with 8 μM cis-diaminedichloroplatinum II (cisplatin), or with both. Cells treated with both agents showed approximately two-fold increase of the mortality rate in comparison with cells treated with cisplatin only. Accordingly, the life span of albino mice transfected with Ehrlich ascites tumor was prolonged almost two-fold by treatment with cisplatin and butyrate in comparison with cisplatin alone. This showed that the observed synergism of cisplatin and butyrate was not limited to specific cell lines or in vitro protocols, but was also expressed in vivo during the process of tumor development. DNA labeling and fluorescence activated cell sorting experiments showed that cisplatin treatment inhibited DNA synthesis and arrested HeLa cells at the G1/S transition and early S phase of the cell cycle. Western blotting and chromatin immunoprecipitation revealed that this effect was accompanied with a decrease of histone H4 acetylation levels. Butyrate treatment initially reversed the effect of cisplatin by increasing the levels of histone H4 acetylation in euchromatin regions responsible for the G1/S phase transition and initiation of DNA synthesis. This abrogated the cisplatin imposed cell cycle arrest and the cells traversed S phase with damaged DNA. However, this effect was transient and continued only a few hours. The long-term effect of butyrate was a massive histone acetylation in both eu- and heterochromatin, inhibition of DNA replication and apoptosis. Conclusion The study presents evidence that cell sensitization towards cisplatin by sodium butyrate is due to hyperacetylation of histone H4 in specific chromatin regions, which temporarily abrogates the cisplatin imposed cell cycle arrest.
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Affiliation(s)
- Miglena Koprinarova
- Institute of Molecular Biology, Bulgarian Academy of Sciences, Acad. G. Bonchev Street, block 21, 1113 Sofia, Bulgaria
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Biological activity of enantiomeric complexes [PtCl(2)L (2)] (L (2) is aromatic bisphosphanes and aromatic diamines). J Biol Inorg Chem 2010; 15:841-50. [PMID: 20333420 DOI: 10.1007/s00775-010-0648-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2010] [Accepted: 03/09/2010] [Indexed: 12/25/2022]
Abstract
Enantiomeric complexes of formula [PtCl(2)L(2)] [L(2) is (R)-(+)-BINAP and (S)-(-)-BINAP, where BINAP is 2,2'-bis(diphenylphosphane)-1,1'-binaphthyl, and (R)-(+)-DABN and (S)-(-)-DABN, where DABN is 1,1'-binaphthyl-2,2'-diamine], were tested for their cytotoxic activity against three cancer cell lines and for their ability to bind to the human telomeric sequence folded in the G-quadruplex structure. Similar experiments were carried out on prototypal complexes cisplatin and cis-[PtCl(2)(PPh(3))(2)] for comparison. Platinum complexes containing phosphanes proved less cytotoxic to cancer cell lines and less likely to interact with the nucleobases of the G-quadruplex than those containing amines; in both cases the S-(-) isomer was more active than the R-(+) counterpart. More specifically, whereas all the platinum complexes were able to platinate the G-quadruplex structure from the human telomeric repeat, the extent and sites of platination depended on the nature of the ligands. Complexes containing (bulky) phosphanes interacted only with the adenines of the loops, whereas those containing the less sterically demanding amines interacted with adenines and some guanines of the G-quartet.
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Platination of telomeric DNA by cisplatin disrupts recognition by TRF2 and TRF1. J Biol Inorg Chem 2010; 15:641-54. [DOI: 10.1007/s00775-010-0631-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2009] [Accepted: 01/27/2010] [Indexed: 12/23/2022]
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Abstract
UV-induced melanogenesis (tanning) and "premature aging" or photoaging result in large part from DNA damage. This article reviews data tying both phenomena to telomere-based DNA damage signaling and develops a conceptual framework in which both responses may be understood as cancer-avoidance protective mechanisms.Journal of Investigative Dermatology Symposium Proceedings (2009) 14, 25-31; doi:10.1038/jidsymp.2009.9.
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Smith V, Dai F, Spitz M, Peters GJ, Fiebig HH, Hussain A, Burger AM. Telomerase activity and telomere length in human tumor cells with acquired resistance to anticancer agents. J Chemother 2009; 21:542-549. [PMID: 19933046 DOI: 10.1179/joc.2009.21.5.542] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Telomeres and telomerase are targets for anticancer drug development and specific inhibitors are currently under clinical investigation. However, it has been reported that standard cytotoxic agents can affect telomere length and telomerase activity suggesting that they also have of a role in drug resistance. in this study, telomere lengths and telomerase activity as well as drug efflux pump expression, glutathione (GSH) levels and polyadenosine-ribose polymerase (PARP) cleavage were assessed in a panel of human tumor cell lines made resistant to vindesine, gemcitabine and cisplatin. these included two lung cancer cell lines resistant to vindesine (LXFL 529L/Vind, LXFA 526L/Vind), a renal cancer cell line (RXF944L/Gem) and an ovarian cancer cell line (AG6000) resistant to gemcitabine, and one resistant to cisplatin (ADDP). The resistant clones were compared to their parental lines and evaluated for cross resistance to other cytotoxic agents. Several drug specific resistance patterns were found, and various complex patterns of cross resistance emerged from some cell lines, but these mechanisms of resistance could not be related to drug efflux pump expression, GSH levels or pARp cleavage. However, all displayed changes in telomerase activity and/or telomere length. Our studies present evidence that telomere maintenance should be taken into consideration in efforts not only to overcome drug resistance, but also to optimize the use of telomere-based therapeutics.
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Affiliation(s)
- V Smith
- Institute for Experimental Oncology, Oncotest GmbH, Freiburg, Germany
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Saad JS, Natile G, Marzilli LG. Origins of the Distortions in the Base Pair Step Adjacent to Platinum Anticancer Drug−DNA Adducts. Fundamental NMR Solution Studies Utilizing Right-Handed Cross-Link Models Having 5′- and 3′-Flanking Residues. J Am Chem Soc 2009; 131:12314-24. [DOI: 10.1021/ja903787m] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Affiliation(s)
- Jamil S. Saad
- Departments of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, and Emory University, Atlanta, Georgia 30322, and Dipartimento Farmaco-Chimico, Università di Bari, Via E. Orabona 4, 70125 Bari, Italy
| | - Giovanni Natile
- Departments of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, and Emory University, Atlanta, Georgia 30322, and Dipartimento Farmaco-Chimico, Università di Bari, Via E. Orabona 4, 70125 Bari, Italy
| | - Luigi G. Marzilli
- Departments of Chemistry, Louisiana State University, Baton Rouge, Louisiana 70803, and Emory University, Atlanta, Georgia 30322, and Dipartimento Farmaco-Chimico, Università di Bari, Via E. Orabona 4, 70125 Bari, Italy
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Yang Y, Sun H, Zhou Y, Ji S, Li M. Effects of three diterpenoids on tumour cell proliferation and telomerase activity. Nat Prod Res 2009; 23:1007-12. [DOI: 10.1080/14786410802295149] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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Abuzeid WM, Jiang X, Shi G, Wang H, Paulson D, Araki K, Jungreis D, Carney J, O’Malley BW, Li D. Molecular disruption of RAD50 sensitizes human tumor cells to cisplatin-based chemotherapy. J Clin Invest 2009; 119:1974-85. [PMID: 19487811 PMCID: PMC2701852 DOI: 10.1172/jci33816] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2007] [Accepted: 03/19/2009] [Indexed: 11/17/2022] Open
Abstract
Platinum-based drugs that induce DNA damage are commonly used first-line chemotherapy agents for testicular, bladder, head and neck, lung, esophageal, stomach, and ovarian cancers. The inherent resistance of tumors to DNA damage often limits the therapeutic efficacy of these agents, such as cisplatin. An enhanced DNA repair and telomere maintenance response by the Mre11/Rad50/Nbs1 (MRN) complex is critical in driving this chemoresistance. We hypothesized therefore that the targeted impairment of native cellular MRN function could sensitize tumor cells to cisplatin. To test this, we designed what we believe to be a novel dominant-negative adenoviral vector containing a mutant RAD50 gene that significantly downregulated MRN expression and markedly disrupted MRN function in human squamous cell carcinoma cells. A combination of cisplatin and mutant RAD50 therapy produced significant tumor cytotoxicity in vitro, with a corresponding increase in DNA damage and telomere shortening. In cisplatin-resistant human squamous cell cancer xenografts in nude mice, this combination therapy caused dramatic tumor regression with increased apoptosis. Our findings suggest the use of targeted RAD50 disruption as what we believe to be a novel chemosensitizing approach for cancer therapy in the context of chemoresistance. This strategy is potentially applicable to several types of malignant tumors that demonstrate chemoresistance and may positively impact the treatment of these patients.
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Affiliation(s)
- Waleed M. Abuzeid
- Department of Otorhinolaryngology — Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Otolaryngology — Head and Neck Surgery, and
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Xiaoling Jiang
- Department of Otorhinolaryngology — Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Otolaryngology — Head and Neck Surgery, and
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Guoli Shi
- Department of Otorhinolaryngology — Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Otolaryngology — Head and Neck Surgery, and
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Hui Wang
- Department of Otorhinolaryngology — Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Otolaryngology — Head and Neck Surgery, and
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - David Paulson
- Department of Otorhinolaryngology — Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Otolaryngology — Head and Neck Surgery, and
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Koji Araki
- Department of Otorhinolaryngology — Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Otolaryngology — Head and Neck Surgery, and
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - David Jungreis
- Department of Otorhinolaryngology — Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Otolaryngology — Head and Neck Surgery, and
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - James Carney
- Department of Otorhinolaryngology — Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Otolaryngology — Head and Neck Surgery, and
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Bert W. O’Malley
- Department of Otorhinolaryngology — Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Otolaryngology — Head and Neck Surgery, and
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA
| | - Daqing Li
- Department of Otorhinolaryngology — Head and Neck Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Department of Otolaryngology — Head and Neck Surgery, and
Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland, USA
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Guthrie OW. DNA repair proteins and telomerase reverse transcriptase in the cochlear lateral wall of cisplatin-treated rats. J Chemother 2009; 21:74-9. [PMID: 19297277 DOI: 10.1179/joc.2009.21.1.74] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
Abstract
Cochlear lateral wall damage is a side effect of cisplatin chemotherapy. Recent studies have shown that cisplatin treatment precipitates platinated DNA adducts in the cochlear lateral wall which suggest that DNA damage may contribute to ototoxicity. Platinated adducts are high-affinity substrates for the global genomic nucleotide excision repair (GG-NeR) pathway which is facilitated by xeroderma pigmentosum (Xp) complementing proteins, such as XpC, XpD and XpA. tumor biology has shown that in addition to stimulating GG-NeR, cisplatin may deplete telomerase reverse transcriptase (teRt). in the current study Fischer344 rats were treated with cisplatin (2 mg/kg/4 days, i.p.) and their cochleae harvested for immunohistochemistry. XpC, XpD and XpA expression increased while teRt expression decreased among cisplatin treated animals compared to vehicle control. these findings suggest that in addition to forming platinated adducts, cisplatin chemotherapy may up-regulate DNA repair proteins and modify teRt expression in the cochlear lateral wall.
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Affiliation(s)
- O W Guthrie
- Department of Biology, Developmental, Cell and Molecular Biology Group, Duke University, French Family Center, Durham, NC 27708, USA.
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42
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Arsenic induces telomerase expression and maintains telomere length in human cord blood cells. Toxicology 2009; 260:132-41. [DOI: 10.1016/j.tox.2009.03.019] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2009] [Revised: 03/30/2009] [Accepted: 03/31/2009] [Indexed: 12/22/2022]
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43
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Ma DL, Che CM, Yan SC. Platinum(II) complexes with dipyridophenazine ligands as human telomerase inhibitors and luminescent probes for G-quadruplex DNA. J Am Chem Soc 2009; 131:1835-46. [PMID: 18998644 DOI: 10.1021/ja806045x] [Citation(s) in RCA: 238] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
A series of platinum(II) complexes containing dipyridophenazine (dppz) and C-deprotonated 2-phenylpyridine (N-CH) ligands were prepared and assayed for G-quadruplex DNA binding activities. [PtII(dppz-COOH)(N-C)]CF3SO3 (1; dppz-COOH = 11-carboxydipyrido[3,2-a:2',3'-c]phenazine) binds G-quadruplex DNA through an external end-stacking mode with a binding affinity of approximately 10(7) dm3 mol-1. G-quadruplex DNA binding is accompanied by up to a 293-fold increase in the intensity of photoluminescence at lambdamax = 512 nm. Using a biotinylated-primer extension telomerase assay, 1 was shown to be an effective inhibitor of human telomerase in vitro, with a telIC50 value of 760 nM.
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Affiliation(s)
- Dik-Lung Ma
- Department of Chemistry and Open Laboratory of Chemical Biology of the Institute of Molecular Technology for Drug Discovery and Synthesis, The University of Hong Kong, Pokfulam Road, Hong Kong
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DNA adducts of antitumor cisplatin preclude telomeric sequences from forming G quadruplexes. J Biol Inorg Chem 2009; 14:959-68. [PMID: 19390878 DOI: 10.1007/s00775-009-0508-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2009] [Accepted: 04/16/2009] [Indexed: 10/20/2022]
Abstract
We studied the effect of antitumor cisplatin and inefficient transplatin on the structure and stability of G quadruplexes formed by the model human telomere sequence 5'-GGG(TTAGGG)(3)-3' using circular dichroism, UV-monitored thermal denaturation, and gel electrophoresis. In addition, to investigate whether there is a connection between the ability of cisplatin or transplatin to affect telomerase activity and stability of G quadruplexes, we also used a modified telomere repeat amplification protocol assay that uses an oligonucleotide substrate for telomerase elongation susceptible to forming a G quadruplex. The results indicate that cisplatin is more efficient than transplatin in disturbing the quadruplex structure, thereby precluding telomeric sequences from forming quadruplexes. On the other hand, the results of this work also demonstrate that in absence of free platinum complex, DNA adducts of antitumor cisplatin inhibit telomerase catalysis, so the mechanism underlying this inhibition does not involve formation of the G quadruplexes which are not elongated by telomerase.
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45
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Telomerase and DNA repair in glioma. Biochim Biophys Acta Mol Basis Dis 2009; 1792:275-9. [DOI: 10.1016/j.bbadis.2009.02.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2008] [Revised: 02/06/2009] [Accepted: 02/06/2009] [Indexed: 02/07/2023]
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Gümüş F, Eren G, Açık L, Çelebi A, Öztürk F, Yılmaz Ş, Saǧkan RI, Gür S, Özkul A, Elmalı A, Elerman Y. Synthesis, Cytotoxicity, and DNA Interactions of New Cisplatin Analogues Containing Substituted Benzimidazole Ligands. J Med Chem 2009; 52:1345-57. [DOI: 10.1021/jm8000983] [Citation(s) in RCA: 84] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Affiliation(s)
- Fatma Gümüş
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Gazi University, 06500 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Kirikkale University, 71450 Kirikkale, Turkey, Cell and Virus Bank Department, Foot and Mouth Disease Institute, Ankara, Turkey, Department of Immunology, Gulhane Military Medicinal Academia, Ankara, Turkey, Department of Virology, Faculty of Veterinary Medicine,
| | - Gökçen Eren
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Gazi University, 06500 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Kirikkale University, 71450 Kirikkale, Turkey, Cell and Virus Bank Department, Foot and Mouth Disease Institute, Ankara, Turkey, Department of Immunology, Gulhane Military Medicinal Academia, Ankara, Turkey, Department of Virology, Faculty of Veterinary Medicine,
| | - Leyla Açık
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Gazi University, 06500 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Kirikkale University, 71450 Kirikkale, Turkey, Cell and Virus Bank Department, Foot and Mouth Disease Institute, Ankara, Turkey, Department of Immunology, Gulhane Military Medicinal Academia, Ankara, Turkey, Department of Virology, Faculty of Veterinary Medicine,
| | - Ayten Çelebi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Gazi University, 06500 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Kirikkale University, 71450 Kirikkale, Turkey, Cell and Virus Bank Department, Foot and Mouth Disease Institute, Ankara, Turkey, Department of Immunology, Gulhane Military Medicinal Academia, Ankara, Turkey, Department of Virology, Faculty of Veterinary Medicine,
| | - Fatma Öztürk
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Gazi University, 06500 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Kirikkale University, 71450 Kirikkale, Turkey, Cell and Virus Bank Department, Foot and Mouth Disease Institute, Ankara, Turkey, Department of Immunology, Gulhane Military Medicinal Academia, Ankara, Turkey, Department of Virology, Faculty of Veterinary Medicine,
| | - Şükran Yılmaz
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Gazi University, 06500 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Kirikkale University, 71450 Kirikkale, Turkey, Cell and Virus Bank Department, Foot and Mouth Disease Institute, Ankara, Turkey, Department of Immunology, Gulhane Military Medicinal Academia, Ankara, Turkey, Department of Virology, Faculty of Veterinary Medicine,
| | - Rahşan Ilıkçı Saǧkan
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Gazi University, 06500 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Kirikkale University, 71450 Kirikkale, Turkey, Cell and Virus Bank Department, Foot and Mouth Disease Institute, Ankara, Turkey, Department of Immunology, Gulhane Military Medicinal Academia, Ankara, Turkey, Department of Virology, Faculty of Veterinary Medicine,
| | - Sibel Gür
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Gazi University, 06500 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Kirikkale University, 71450 Kirikkale, Turkey, Cell and Virus Bank Department, Foot and Mouth Disease Institute, Ankara, Turkey, Department of Immunology, Gulhane Military Medicinal Academia, Ankara, Turkey, Department of Virology, Faculty of Veterinary Medicine,
| | - Aykut Özkul
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Gazi University, 06500 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Kirikkale University, 71450 Kirikkale, Turkey, Cell and Virus Bank Department, Foot and Mouth Disease Institute, Ankara, Turkey, Department of Immunology, Gulhane Military Medicinal Academia, Ankara, Turkey, Department of Virology, Faculty of Veterinary Medicine,
| | - Ayhan Elmalı
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Gazi University, 06500 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Kirikkale University, 71450 Kirikkale, Turkey, Cell and Virus Bank Department, Foot and Mouth Disease Institute, Ankara, Turkey, Department of Immunology, Gulhane Military Medicinal Academia, Ankara, Turkey, Department of Virology, Faculty of Veterinary Medicine,
| | - Yalçın Elerman
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Gazi University, 06500 Ankara, Turkey, Department of Biology, Faculty of Art and Science, Kirikkale University, 71450 Kirikkale, Turkey, Cell and Virus Bank Department, Foot and Mouth Disease Institute, Ankara, Turkey, Department of Immunology, Gulhane Military Medicinal Academia, Ankara, Turkey, Department of Virology, Faculty of Veterinary Medicine,
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Viglasky V. Platination of telomeric sequences and nuclease hypersensitive elements of human c-myc and PDGF-A promoters and their ability to form G-quadruplexes. FEBS J 2008; 276:401-9. [PMID: 19054066 DOI: 10.1111/j.1742-4658.2008.06782.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Naturally occurring G-rich DNA sequences that are able to form G-quadruplex structures appear as potential targets for anti-cancer chemotherapy, and therefore play an important role in cellular processes, such as cell aging, death and carcinogenesis. The telomeric regions of DNA and nuclease hypersensitive elements of human c-myc and PDGF-A promoters represent a very appealing target for cisplatin and may interfere with normal DNA function. Platinum complexes bind covalently to nucleobases, and especially to the N7 atom of guanines, and the four guanines of a G-quartet have their N7 atoms involved in hydrogen bonding. Therefore, within a G-quadruplex structure, only the guanines out of the stack of G-quartets should react with electrophilic species such as platinum (II) complexes. Platinum complexes have significant influence on the formation of G-quadruplexes. Results obtained by CD spectroscopy and temperature gradient-gel electrophoresis clearly demonstrate that DNA platination significantly affects G-quadruplex folding for telomeric sequences; the abundance of un/misfolded DNAs compared to the G-quadruplex is proportional to the platinum concentration.
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Affiliation(s)
- Viktor Viglasky
- Department of Biochemistry, Faculty of Sciences, Institute of Chemistry, P. J. Safarik University, Kosice, Slovakia.
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Wu H, Wang S, Weng D, Xing H, Song X, Zhu T, Xia X, Weng Y, Xu G, Meng L, Zhou J, Ma D. Reversal of the malignant phenotype of ovarian cancer A2780 cells through transfection with wild-type PTEN gene. Cancer Lett 2008; 271:205-14. [PMID: 18662848 DOI: 10.1016/j.canlet.2008.06.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2008] [Revised: 04/18/2008] [Accepted: 06/02/2008] [Indexed: 12/22/2022]
Abstract
OBJECTIVE PTEN (phosphatase and tensin homologue deleted on chromosome 10) is a tumor suppressor gene identified on human chromosome 10q23. Substantial studies have demonstrated that PTEN can inhibit cell proliferation, migration and invasion of many cancer cells. The purpose of this study was to determine whether upregulation of PTEN gene by transfection wild-type PTEN gene to ovarian cancer cells can inhibit growth and migration and to explore the potential for PTEN gene therapy of ovarian cancers. METHOD Wild-type and phosphatase-inactive (C124A) PTEN plasmids were transfected into ovarian epithelial cancer A2780 cells, and their effects on cell apoptosis, cell proliferation, cell migration and cell invasion were analyzed by flow cytometry analysis, TUNEL assay, MTT assay, wound-healing assay and transwell assay. RESULTS Both wild-type and mutant PTEN can upregulate the expression of PTEN gene dramatically; however, it is wild-type PTEN not phosphatase-inactive PTEN that can induce apoptosis and decrease cell migration, invasion and proliferation in ovarian cancer cells. CONCLUSION These results demonstrated that PTEN had played an important role in the cell proliferation, cell migration and invasion dependent on its phosphatase activity. Enhanced expression of PTEN by gene transfer is sufficient to reverse the malignant phenotype of ovarian cancer cells and transfection of ovarian cancer cells with wild-type PTEN gene might be another novel approach for therapeutic intervention in ovarian cancer.
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Affiliation(s)
- Huijuan Wu
- Cancer Biology Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, PR China
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Phatak P, Dai F, Butler M, Nandakumar M, Gutierrez PL, Edelman MJ, Hendriks H, Burger AM. KML001 Cytotoxic Activity Is Associated with Its Binding to Telomeric Sequences and Telomere Erosion in Prostate Cancer Cells. Clin Cancer Res 2008; 14:4593-602. [DOI: 10.1158/1078-0432.ccr-07-4572] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Parsch D, Brassat U, Brümmendorf TH, Fellenberg J. Consequences of telomerase inhibition by BIBR1532 on proliferation and chemosensitivity of chondrosarcoma cell lines. Cancer Invest 2008; 26:590-6. [PMID: 18584350 DOI: 10.1080/07357900802072905] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE Human chondrosarcomas are generally resistant to conventional treatments like chemotherapy and radiotherapy. We investigated the effects of BIBR1532, an inhibitor of telomerase on chondrosarcoma cells in vitro. METHODS Telomerase activity, telomere lengths, growth kinetics and chemosensitivity were analyzed in chondrosarcoma cell lines treated with BIBR1532. RESULTS BIBR1532 treatment resulted in telomerase inhibition, decrease of telomere length and reduction of growth capacity of telomerase positive chondrosarcoma cells. Although resistant to cisplatin, telomerase positive cells were sensitive to paclitaxel, which rapidly induced telomere erosion. CONCLUSION Targeting of telomeres might represent a valid strategy for the (re-)sensitization of chemoresistant chondrosarcomas.
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Affiliation(s)
- D Parsch
- Karl-Olga-Krankenhaus GmbH, Orthopedic Hospital, Stuttgart, Germany
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