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

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.

• Authors: Sophie L Kerschner-Morales, Marie Kühne, Sabine Becker, James F Beck, Jürgen Sonnemann
• Journal: Journal of cancer research and clinical oncology (J Cancer Res Clin Oncol) Vol. 146 Issue 11 Pg. 2871-2883 (Nov 2020) ISSN: 1432-1335 [Electronic] Germany
• PMID: 32770382 (Publication Type: Journal Article)

Chemical References

• 2-(3-(4-((2,6-dimethylmorpholino)methyl)styryl)-1H-indazol-6-yl)-5'-methoxyspiro(cyclopropane-1,3'-indolin)-2'-one
• Indazoles
• Indoles
• Pyrimidines
• Sulfones
• centrinone
• PLK4 protein, human
• Protein Serine-Threonine Kinases

Topics

• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Bone Neoplasms (pathology)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Humans
• Indazoles (pharmacology)
• Indoles (pharmacology)
• Membrane Potential, Mitochondrial (drug effects)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Pyrimidines (pharmacology)
• Sarcoma, Ewing (pathology)
• Sulfones (pharmacology)