Cell cycle-dependent cytotoxicity and mitotic spindle checkpoint dependency of investigational and approved antimitotic agents

Loading...
Thumbnail Image
Date
2012
Authors
Birk, Martina
Pekari, Klaus
Maier, Thomas
Schmidt, Mathias
Editors
Contact
Journal ISSN
Electronic ISSN
ISBN
Bibliographical data
Publisher
Series
URI (citable link)
DOI (citable link)
ArXiv-ID
International patent number
Link to the license
EU project number
Project
Open Access publication
Collections
Restricted until
Title in another language
Research Projects
Organizational Units
Journal Issue
Publication type
Journal article
Publication status
Published in
International Journal of Cancer ; 130 (2012), 4. - pp. 798-807. - ISSN 0020-7136. - eISSN 1097-0215
Abstract
The mitotic spindle checkpoint (SPC) is a highly regulated mechanism in eukaryotic cells that ensures the even distribution of the duplicated genome between daughter cells. Malfunction of the SPC or deregulated expression of SPC regulatory proteins is frequently associated with a poor response to chemotherapeutic agents. We investigated various approved and investigational mitosis-specific agents, including spindle poisons, an Eg5 kinesin inhibitor, inhibitors of polo-like kinase 1 (Plk1) or Aurora-B kinase, a benzamide class HDAC inhibitor and compounds identified in a chemical genetics screen for their cell cycle-dependent cytotoxicities and for their activities toward SPC deficient (HT29, Caco-2, T47D) and SPC proficient human cell lines (A2780, HCT116, SW480). Using the RKOp27 cell system that allows inducible cell cycle arrest by the tunable expression of the cdk inhibitor p27Kip1, we found an exquisite proliferation-dependent cytotoxicity for all compounds except the aurora kinase inhibitor VX-680. Cytotoxicity of the antimitotic compounds was in general higher on SPC proficient than on deficient cells. We found two exceptions, a benzamide HDAC inhibitor which was effective on SPC proficient and deficient cells and an investigational compound, BYK72767, with a yet unknown mode of action. The degree of increased mitotic index was no predictor of cytotoxicity of the compounds nor was the phosphorylation of BubR1. However, SPC deficient cell lines were able to
tolerate mitotic arrest for far longer times than SPC proficient cells. We conclude that targeting of SPC deficient cancers with novel antimitotic principles remains a challenge but certain drug classes may be equally efficacious regardless of SPC status.
Summary in another language
Subject (DDC)
570 Biosciences, Biology
Keywords
mitotic spindle checkpoint,mitotic arrest,Polo-like kinase,Aurora,Eg5,HDAC,mitotic targeting,investigational drugs
Conference
Review
undefined / . - undefined, undefined. - (undefined; undefined)
Cite This
ISO 690BIRK, Martina, Alexander BÜRKLE, Klaus PEKARI, Thomas MAIER, Mathias SCHMIDT, 2012. Cell cycle-dependent cytotoxicity and mitotic spindle checkpoint dependency of investigational and approved antimitotic agents. In: International Journal of Cancer. 130(4), pp. 798-807. ISSN 0020-7136. eISSN 1097-0215. Available under: doi: 10.1002/ijc.26036
BibTex
@article{Birk2012-02-15cycle-21534,
  year={2012},
  doi={10.1002/ijc.26036},
  title={Cell cycle-dependent cytotoxicity and mitotic spindle checkpoint dependency of investigational and approved antimitotic agents},
  number={4},
  volume={130},
  issn={0020-7136},
  journal={International Journal of Cancer},
  pages={798--807},
  author={Birk, Martina and Bürkle, Alexander and Pekari, Klaus and Maier, Thomas and Schmidt, Mathias}
}
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/123456789/21534">
    <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dcterms:abstract xml:lang="eng">The mitotic spindle checkpoint (SPC) is a highly regulated mechanism in eukaryotic cells that ensures the even distribution of the duplicated genome between daughter cells. Malfunction of the SPC or deregulated expression of SPC regulatory proteins is frequently associated with a poor response to chemotherapeutic agents. We investigated various approved and investigational mitosis-specific agents, including spindle poisons, an Eg5 kinesin inhibitor, inhibitors of polo-like kinase 1 (Plk1) or Aurora-B kinase, a benzamide class HDAC inhibitor and compounds identified in a chemical genetics screen for their cell cycle-dependent cytotoxicities and for their activities toward SPC deficient (HT29, Caco-2, T47D) and SPC proficient human cell lines (A2780, HCT116, SW480). Using the RKOp27 cell system that allows inducible cell cycle arrest by the tunable expression of the cdk inhibitor p27Kip1, we found an exquisite proliferation-dependent cytotoxicity for all compounds except the aurora kinase inhibitor VX-680. Cytotoxicity of the antimitotic compounds was in general higher on SPC proficient than on deficient cells. We found two exceptions, a benzamide HDAC inhibitor which was effective on SPC proficient and deficient cells and an investigational compound, BYK72767, with a yet unknown mode of action. The degree of increased mitotic index was no predictor of cytotoxicity of the compounds nor was the phosphorylation of BubR1. However, SPC deficient cell lines were able to&lt;br /&gt;tolerate mitotic arrest for far longer times than SPC proficient cells. We conclude that targeting of SPC deficient cancers with novel antimitotic principles remains a challenge but certain drug classes may be equally efficacious regardless of SPC status.</dcterms:abstract>
    <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/21534/2/Birk_215347.pdf"/>
    <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/server/rdf/resource/123456789/28"/>
    <dc:contributor>Bürkle, Alexander</dc:contributor>
    <dc:contributor>Maier, Thomas</dc:contributor>
    <dc:creator>Schmidt, Mathias</dc:creator>
    <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2013-02-07T08:37:32Z</dc:date>
    <dc:creator>Maier, Thomas</dc:creator>
    <dc:contributor>Pekari, Klaus</dc:contributor>
    <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/21534/2/Birk_215347.pdf"/>
    <dcterms:issued>2012-02-15</dcterms:issued>
    <dc:language>eng</dc:language>
    <dcterms:bibliographicCitation>International Journal of Cancer ; 130 (2012), 4. - S. 798-807</dcterms:bibliographicCitation>
    <foaf:homepage rdf:resource="http://localhost:8080/"/>
    <bibo:uri rdf:resource="http://kops.uni-konstanz.de/handle/123456789/21534"/>
    <dcterms:rights rdf:resource="https://rightsstatements.org/page/InC/1.0/"/>
    <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/>
    <dc:creator>Birk, Martina</dc:creator>
    <dc:contributor>Schmidt, Mathias</dc:contributor>
    <dc:creator>Bürkle, Alexander</dc:creator>
    <dc:rights>terms-of-use</dc:rights>
    <dcterms:title>Cell cycle-dependent cytotoxicity and mitotic spindle checkpoint dependency of investigational and approved antimitotic agents</dcterms:title>
    <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2013-02-07T08:37:32Z</dcterms:available>
    <dc:creator>Pekari, Klaus</dc:creator>
    <dc:contributor>Birk, Martina</dc:contributor>
  </rdf:Description>
</rdf:RDF>
Internal note
xmlui.Submission.submit.DescribeStep.inputForms.label.kops_note_fromSubmitter
Contact
URL of original publication
Test date of URL
Examination date of dissertation
Method of financing
Comment on publication
Alliance license
Corresponding Authors der Uni Konstanz vorhanden
International Co-Authors
Bibliography of Konstanz
Yes
Refereed