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Anticancer effects of the PLK4 inhibitors CFI-400945 and centrinone in Ewing's sarcoma cells
Sophie L Kerschner-Morales1,2, Marie Kühne3, Sabine Becker1,2
1Department of Paediatric Haematology and Oncology, Children's Clinic, Jena University Hospital, Jena, Germany.
Purpose:
Polo-like kinase 4 (PLK4) inhibitors, such as CFI-400945 and centrinone, are emerging as promising antineoplastic agents. However, their effectiveness against Ewing's sarcoma, a highly aggressive childhood cancer, remains to be established.
Methods:
CFI-400945 and centrinone were tested in three Ewing's sarcoma cell lines with different TP53 status. Effects were assessed by flow-cytometric analyses of cell death, dissipation of the mitochondrial transmembrane potential and cell cycle distribution, by cell viability assay as well as by caspase 3/7 activity measurement, by immunoblotting and by immunofluorescence microscopy.
Results:
CFI-400945 and centrinone elicited cell death in p53 wild-type and mutant Ewing's sarcoma cells. Both agents induced mitochondrial membrane depolarisation, caspase 3/7 activation, PARP1 cleavage and DNA fragmentation, indicating an apoptotic form of cell death. In addition, the PLK4 inhibitors induced a G2/M cell cycle arrest, particularly when cell killing was attenuated by the pan-caspase inhibitor z-VAD-fmk. Moreover, CFI-400945 treatment produced polyploidy.
Conclusion:
Our findings show that PLK4 inhibitors were effective against Ewing's sarcoma cells in vitro and thus provide a rationale for their evaluation in vivo.
Insights
Polo-like kinase 4 (PLK4) inhibitors effectively induce apoptosis and cell cycle arrest in Ewing's sarcoma cells, regardless of TP53 status. These findings support further investigation of PLK4 inhibitors as potential treatments for this aggressive childhood cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Polo-like kinase 4 (PLK4) inhibitors are novel antineoplastic agents.
- Ewing's sarcoma is a highly aggressive pediatric cancer with limited treatment options.
Purpose of the Study:
- To evaluate the efficacy of PLK4 inhibitors, CFI-400945 and centrinone, against Ewing's sarcoma cell lines.
- To determine the mechanism of action of PLK4 inhibitors in Ewing's sarcoma.
Main Methods:
- Testing CFI-400945 and centrinone in three Ewing's sarcoma cell lines with varying TP53 status.
- Assessing cell death, mitochondrial membrane potential, cell cycle distribution, and caspase activity via flow cytometry and immunoblotting.
Main Results:
- Both PLK4 inhibitors induced apoptosis, characterized by mitochondrial depolarization, caspase 3/7 activation, PARP1 cleavage, and DNA fragmentation.
- A G2/M cell cycle arrest was observed, particularly when apoptosis was inhibited.
- CFI-400945 treatment resulted in polyploidy.
Conclusions:
- PLK4 inhibitors demonstrate in vitro efficacy against Ewing's sarcoma cells.
- These findings provide a strong rationale for in vivo evaluation of PLK4 inhibitors for Ewing's sarcoma treatment.
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