Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antineoplastic Agents / toxicity*
-
Apoptosis / genetics
-
Blotting, Northern
-
Cell Cycle Proteins / antagonists & inhibitors*
-
Cell Cycle Proteins / genetics
-
Cell Cycle Proteins / metabolism
-
Cells, Cultured
-
DNA Primers / genetics
-
Drug Evaluation, Preclinical
-
Flow Cytometry
-
Fluorescent Antibody Technique
-
Gene Dosage / genetics
-
Gene Knockdown Techniques
-
Genetic Engineering / methods
-
Humans
-
Mice
-
Mice, Transgenic
-
Neoplasms / drug therapy*
-
Polo-Like Kinase 1
-
Protein Serine-Threonine Kinases / antagonists & inhibitors*
-
Protein Serine-Threonine Kinases / genetics
-
Protein Serine-Threonine Kinases / metabolism
-
Proto-Oncogene Proteins / antagonists & inhibitors*
-
Proto-Oncogene Proteins / genetics
-
Proto-Oncogene Proteins / metabolism
-
RNA Interference / drug effects*
-
Reverse Transcriptase Polymerase Chain Reaction
-
Toxicity Tests / methods*
-
Transfection
Substances
-
Antineoplastic Agents
-
Cell Cycle Proteins
-
DNA Primers
-
Proto-Oncogene Proteins
-
Protein Serine-Threonine Kinases