Clickable Cisplatin Derivatives as Versatile Tools to Probe the DNA Damage Response to Chemotherapy

Lade...
Vorschaubild
Dateien
Moretton_2-thibq31o8vaa3.pdf
Moretton_2-thibq31o8vaa3.pdfGröße: 5.67 MBDownloads: 33
Datum
2022
Autor:innen
Moretton, Amandine
Slyskova, Jana
Simaan, Marwan E.
Arasa-Verge, Emili A.
Meyenberg, Mathilde
Loizou, Joanna I.
Herausgeber:innen
Kontakt
ISSN der Zeitschrift
Electronic ISSN
ISBN
Bibliografische Daten
Verlag
Schriftenreihe
Auflagebezeichnung
ArXiv-ID
Internationale Patentnummer
Link zur Lizenz
Angaben zur Forschungsförderung
Projekt
Open Access-Veröffentlichung
Open Access Gold
Sammlungen
Core Facility der Universität Konstanz
Gesperrt bis
Titel in einer weiteren Sprache
Forschungsvorhaben
Organisationseinheiten
Zeitschriftenheft
Publikationstyp
Zeitschriftenartikel
Publikationsstatus
Published
Erschienen in
Zusammenfassung

Cisplatin induces DNA crosslinks that are highly cytotoxic. Hence, platinum complexes are frequently used in the treatment of a broad range of cancers. Efficiency of cisplatin treatment is limited by the tumor-specific DNA damage response to the generated lesions. We reasoned that better tools to investigate the repair of DNA crosslinks induced by cisplatin would therefore be highly useful in addressing drug limitations. Here, we synthesized a series of cisplatin derivatives that are compatible with click chemistry, thus allowing visualization and isolation of DNA-platinum crosslinks from cells to study cellular responses. We prioritized one alkyne and one azide Pt(II) derivative, Pt-alkyne-53 and Pt-azide-64, for further biological characterization. We demonstrate that both compounds bind DNA and generate DNA lesions and that the viability of treated cells depends on the active DNA repair machinery. We also show that the compounds are clickable with both a fluorescent probe as well as biotin, thus they can be visualized in cells, and their ability to induce crosslinks in genomic DNA can be quantified. Finally, we show that Pt-alkyne-53 can be used to identify DNA repair proteins that bind within its proximity to facilitate its removal from DNA. The compounds we report here can be used as valuable experimental tools to investigate the DNA damage response to platinum complexes and hence might shed light on mechanisms of chemoresistance.

Zusammenfassung in einer weiteren Sprache
Fachgebiet (DDC)
540 Chemie
Schlagwörter
cisplatin, chemotherapy, chemoresistance, DNA Damage, DNA crosslinks, DNA repair, click chemistry
Konferenz
Rezension
undefined / . - undefined, undefined
Zitieren
ISO 690MORETTON, Amandine, Jana SLYSKOVA, Marwan E. SIMAAN, Emili A. ARASA-VERGE, Mathilde MEYENBERG, Daniel Alonso CERRÓN INFANTES, Miriam M. UNTERLASS, Joanna I. LOIZOU, 2022. Clickable Cisplatin Derivatives as Versatile Tools to Probe the DNA Damage Response to Chemotherapy. In: Frontiers in Oncology. Frontiers Media. 2022, 12, 874201. eISSN 2234-943X. Available under: doi: 10.3389/fonc.2022.874201
BibTex
@article{Moretton2022Click-57892,
  year={2022},
  doi={10.3389/fonc.2022.874201},
  title={Clickable Cisplatin Derivatives as Versatile Tools to Probe the DNA Damage Response to Chemotherapy},
  volume={12},
  journal={Frontiers in Oncology},
  author={Moretton, Amandine and Slyskova, Jana and Simaan, Marwan E. and Arasa-Verge, Emili A. and Meyenberg, Mathilde and Cerrón Infantes, Daniel Alonso and Unterlass, Miriam M. and Loizou, Joanna I.},
  note={Article Number: 874201}
}
RDF
<rdf:RDF
    xmlns:dcterms="http://purl.org/dc/terms/"
    xmlns:dc="http://purl.org/dc/elements/1.1/"
    xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#"
    xmlns:bibo="http://purl.org/ontology/bibo/"
    xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#"
    xmlns:foaf="http://xmlns.com/foaf/0.1/"
    xmlns:void="http://rdfs.org/ns/void#"
    xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > 
  <rdf:Description rdf:about="https://kops.uni-konstanz.de/server/rdf/resource/123456789/57892">
    <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/29"/>
    <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/57892"/>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2022-06-30T09:56:40Z</dc:date>
    <dc:creator>Meyenberg, Mathilde</dc:creator>
    <dc:contributor>Loizou, Joanna I.</dc:contributor>
    <dc:contributor>Meyenberg, Mathilde</dc:contributor>
    <dc:contributor>Slyskova, Jana</dc:contributor>
    <dc:creator>Loizou, Joanna I.</dc:creator>
    <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/57892/1/Moretton_2-thibq31o8vaa3.pdf"/>
    <dc:creator>Arasa-Verge, Emili A.</dc:creator>
    <foaf:homepage rdf:resource="http://localhost:8080/"/>
    <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/29"/>
    <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2022-06-30T09:56:40Z</dcterms:available>
    <dc:creator>Slyskova, Jana</dc:creator>
    <dc:creator>Moretton, Amandine</dc:creator>
    <dc:language>eng</dc:language>
    <dcterms:title>Clickable Cisplatin Derivatives as Versatile Tools to Probe the DNA Damage Response to Chemotherapy</dcterms:title>
    <dc:rights>Attribution 4.0 International</dc:rights>
    <dcterms:rights rdf:resource="http://creativecommons.org/licenses/by/4.0/"/>
    <dc:contributor>Moretton, Amandine</dc:contributor>
    <dcterms:abstract xml:lang="eng">Cisplatin induces DNA crosslinks that are highly cytotoxic. Hence, platinum complexes are frequently used in the treatment of a broad range of cancers. Efficiency of cisplatin treatment is limited by the tumor-specific DNA damage response to the generated lesions. We reasoned that better tools to investigate the repair of DNA crosslinks induced by cisplatin would therefore be highly useful in addressing drug limitations. Here, we synthesized a series of cisplatin derivatives that are compatible with click chemistry, thus allowing visualization and isolation of DNA-platinum crosslinks from cells to study cellular responses. We prioritized one alkyne and one azide Pt(II) derivative, Pt-alkyne-53 and Pt-azide-64, for further biological characterization. We demonstrate that both compounds bind DNA and generate DNA lesions and that the viability of treated cells depends on the active DNA repair machinery. We also show that the compounds are clickable with both a fluorescent probe as well as biotin, thus they can be visualized in cells, and their ability to induce crosslinks in genomic DNA can be quantified. Finally, we show that Pt-alkyne-53 can be used to identify DNA repair proteins that bind within its proximity to facilitate its removal from DNA. The compounds we report here can be used as valuable experimental tools to investigate the DNA damage response to platinum complexes and hence might shed light on mechanisms of chemoresistance.</dcterms:abstract>
    <dc:contributor>Simaan, Marwan E.</dc:contributor>
    <dc:creator>Cerrón Infantes, Daniel Alonso</dc:creator>
    <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/57892/1/Moretton_2-thibq31o8vaa3.pdf"/>
    <dc:creator>Unterlass, Miriam M.</dc:creator>
    <dc:contributor>Cerrón Infantes, Daniel Alonso</dc:contributor>
    <dc:contributor>Unterlass, Miriam M.</dc:contributor>
    <dc:creator>Simaan, Marwan E.</dc:creator>
    <dc:contributor>Arasa-Verge, Emili A.</dc:contributor>
    <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/>
    <dcterms:issued>2022</dcterms:issued>
  </rdf:Description>
</rdf:RDF>
Interner Vermerk
xmlui.Submission.submit.DescribeStep.inputForms.label.kops_note_fromSubmitter
Kontakt
URL der Originalveröffentl.
Prüfdatum der URL
Prüfungsdatum der Dissertation
Finanzierungsart
Kommentar zur Publikation
Allianzlizenz
Corresponding Authors der Uni Konstanz vorhanden
Internationale Co-Autor:innen
Universitätsbibliographie
Ja
Begutachtet
Ja
Diese Publikation teilen