Identification of synthetic lethality of PLK1 inhibition and microtubule-destabilizing drugs

Polo-like kinase 1 (PLK1) is frequently overexpressed in cancer, which correlates with poor prognosis. Therefore, we investigated PLK1 as therapeutic target using rhabdomyosarcoma (RMS) as a model. Here, we identify a novel synthetic lethal interaction of PLK1 inhibitors and microtubule-destabilizin...

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Bibliographic Details
Published in:Cell death and differentiation 2015-12, Vol.22 (12), p.1946-1956
Main Authors: Hugle, M, Belz, K, Fulda, S
Format: Article
Language:English
Subjects:
631/67
Animals
Apoptosis
Apoptosis - drug effects
bcl-2 Homologous Antagonist-Killer Protein - antagonists & inhibitors
bcl-2 Homologous Antagonist-Killer Protein - genetics
bcl-2 Homologous Antagonist-Killer Protein - metabolism
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Cycle Analysis
Cell Cycle Checkpoints - drug effects
Cell Cycle Proteins - antagonists & inhibitors
Cell Cycle Proteins - metabolism
Disease Models, Animal
Drug Synergism
Humans
Life Sciences
Mice
Mitochondria - drug effects
Mitochondria - metabolism
Myeloid Cell Leukemia Sequence 1 Protein - genetics
Myeloid Cell Leukemia Sequence 1 Protein - metabolism
Original Paper
Polo-Like Kinase 1
Protein Kinase Inhibitors - toxicity
Protein Serine-Threonine Kinases - antagonists & inhibitors
Protein Serine-Threonine Kinases - metabolism
Proto-Oncogene Proteins - antagonists & inhibitors
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-bcl-2 - metabolism
Pteridines - toxicity
Reactive Oxygen Species - metabolism
Rhabdomyosarcoma - metabolism
Rhabdomyosarcoma - pathology
Signal Transduction - drug effects
Stem Cells
Transplantation, Heterologous
Tubulin Modulators - toxicity
Tumor Cells, Cultured
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Summary:Polo-like kinase 1 (PLK1) is frequently overexpressed in cancer, which correlates with poor prognosis. Therefore, we investigated PLK1 as therapeutic target using rhabdomyosarcoma (RMS) as a model. Here, we identify a novel synthetic lethal interaction of PLK1 inhibitors and microtubule-destabilizing drugs in preclinical RMS models and elucidate the underlying molecular mechanisms of this synergism. PLK1 inhibitors (i.e., BI 2536 and BI 6727) synergistically induce apoptosis together with microtubule-destabilizing drugs (i.e., vincristine (VCR), vinblastine (VBL) and vinorelbine (VNR)) in several RMS cell lines (combination index
ISSN:1350-9047
1476-5403
DOI:10.1038/cdd.2015.59