Toxicity modelling of Plk1-targeted therapies in genetically engineered mice and cultured primary mammalian cells

High attrition rates of novel anti-cancer drugs highlight the need for improved models to predict toxicity. Although polo-like kinase 1 (Plk1) inhibitors are attractive candidates for drug development, the role of Plk1 i
High attrition rates of novel anti-cancer drugs highlight the need for improved models to predict toxicity. Although polo-like kinase 1 (Plk1) inhibitors are attractive candidates for drug development, the role of Plk1 in primary cells remains widely unexplored. Therefore, we evaluated the utility of an RNA interference-based model to assess responses to an inducible knockdown (iKD) of Plk1 in adult mice. Here we show that Plk1 silencing can be achieved in several organs, although adverse events are rare. We compared responses in Plk1-iKD mice with those in primary cells kept under controlled culture conditions. In contrast to the addiction of many cancer cell lines to the non-oncogene Plk1, the primary cells' proliferation, spindle assembly and apoptosis exhibit only a low dependency on Plk1. Responses to Plk1-depletion, both in cultured primary cells and in our iKD-mouse model, correspond well and thus provide the basis for using validated iKD mice in predicting responses to therapeutic interventions.
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Author:Monika Raab, Sven Kappel, Andrea Krämer, Mourad Sanhaji, Yves Matthess, Elisabeth Kurunci-Csacsko, Julia Calzada-Wack, Birgit Rathkolb, Jan Rozman, Thure Adler, Dirk H. Busch, Irene Esposito, Helmut Fuchs, Valérie Gailus-Durner, Martin Klingenspor, Eckhard Wolf, Nicole Sänger, Florian Prinz, Martin Hrabé de Angelis, Jost Seibler, Juping Yuan, Martin Bergmann, Rainald Knecht, Bertolt Kreft, Klaus Strebhardt
URN:urn:nbn:de:hebis:30:3-289400
DOI:http://dx.doi.org/10.1038/ncomms1395
ISSN:2041-1723
Parent Title (English):Nature Communications
Publisher:Nature Publishing Group
Place of publication:London
Document Type:Article
Language:English
Date of Publication (online):2011/07/19
Date of first Publication:2011/07/19
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2013/02/18
Volume:2
Issue:Article number: 395
Pagenumber:11
Note:
License: This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivative Works 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
HeBIS PPN:332475417
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung-Nicht kommerziell-Keine Bearbeitung 3.0

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