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Journal of Cancer Research and Clinical Oncology

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Open Access 01-11-2020 | Ewing's Sarcoma | Original Article – Cancer Research

Anticancer effects of the PLK4 inhibitors CFI-400945 and centrinone in Ewing’s sarcoma cells

Authors: Sophie L. Kerschner-Morales, Marie Kühne, Sabine Becker, James F. Beck, Jürgen Sonnemann

Published in: Journal of Cancer Research and Clinical Oncology | Issue 11/2020

Abstract

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.

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Title: Anticancer effects of the PLK4 inhibitors CFI-400945 and centrinone in Ewing’s sarcoma cells
Authors: Sophie L. Kerschner-Morales
Marie Kühne
Sabine Becker
James F. Beck
Jürgen Sonnemann
Publication date: 01-11-2020
Publisher: Springer Berlin Heidelberg
Keywords: Ewing's Sarcoma
Ewing's sarcoma
Published in: Journal of Cancer Research and Clinical Oncology / Issue 11/2020
Print ISSN: 0171-5216
Electronic ISSN: 1432-1335
DOI: https://doi.org/10.1007/s00432-020-03346-z

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