Latest documents http://publikationen.ub.uni-frankfurt.de/index/index/ Mon, 18 Feb 2013 16:26:04 +0100 Mon, 18 Feb 2013 16:26:04 +0100 http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/28940 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. 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 Hrabě de Angelis; Jost Seibler; Juping Yuan; Martin Bergmann; Rainald Knecht; Bertolt Kreft; Klaus Strebhardt article http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/28940 Mon, 18 Feb 2013 16:26:04 +0100 http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/6384 Background Cyclin B1, the regulatory subunit of cyclin-dependent kinase 1 (Cdk1), is essential for the transition from G2 phase to mitosis. Cyclin B1 is very often found to be overexpressed in primary breast and cervical cancer cells as well as in cancer cell lines. Its expression is correlated with the malignancy of gynecological cancers. Methods In order to explore cyclin B1 as a potential target for gynecological cancer therapy, we studied the effect of small interfering RNA (siRNA) on different gynecological cancer cell lines by monitoring their proliferation rate, cell cycle profile, protein expression and activity, apoptosis induction and colony formation. Tumor formation in vivo was examined using mouse xenograft models. Results Downregulation of cyclin B1 inhibited proliferation of several breast and cervical cancer cell lines including MCF-7, BT-474, SK-BR-3, MDA-MB-231 and HeLa. After combining cyclin B1 siRNA with taxol, we observed an increased apoptotic rate accompanied by an enhanced antiproliferative effect in breast cancer cells. Furthermore, control HeLa cells were progressively growing, whereas the tumor growth of HeLa cells pre-treated with cyclin B1 siRNA was strongly inhibited in nude mice, indicating that cyclin B1 is indispensable for tumor growth in vivo. Conclusion Our data support the notion of cyclin B1 being essential for survival and proliferation of gynecological cancer cells. Concordantly, knockdown of cyclin B1 inhibits proliferation in vitro as well as in vivo. Moreover, targeting cyclin B1 sensitizes breast cancer cells to taxol, suggesting that specific cyclin B1 targeting is an attractive strategy for the combination with conventionally used agents in gynecological cancer therapy. Ilija Androic; Andrea Krämer; Ruilan Yan; Franz Rödel; Regine Gätje; Manfred Kaufmann; Klaus Strebhardt; Juping Yuan article http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/6384 Mon, 27 Apr 2009 09:09:56 +0200