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Synergistic anticancer activity of combined ATR and ribonucleotide reductase inhibition in Ewing's sarcoma cells

Max-Johann Sturm1,2, Julián Andrés Henao-Restrepo3, Sabine Becker1,2

  • 1Department of Paediatric and Adolescent Medicine, Jena University Hospital, Friedrich Schiller University Jena, Am Klinikum 1, 07747, Jena, Germany.

Journal of Cancer Research and Clinical Oncology
|April 25, 2023
PubMed
Abstract

Insights

Combined inhibition of ATR and ribonucleotide reductase (RNR) shows synergistic effectiveness against Ewing's sarcoma cells in vitro. This novel therapeutic strategy warrants further investigation for treating this challenging childhood cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Ewing's sarcoma is a highly malignant childhood tumor with limited treatment advancements.
  • Current chemotherapy intensification has not significantly improved outcomes over two decades.
  • New therapeutic strategies targeting specific molecular pathways are essential.

Purpose of the Study:

  • To investigate the efficacy of combined inhibition of ATR (Ataxia Telangiectasia and Rad3-related) and RNR (ribonucleotide reductase) in Ewing's sarcoma cells.
  • To explore a novel therapeutic approach for Ewing's sarcoma treatment.
  • To assess the synergistic effects of targeting ATR and RNR pathways.

Main Methods:

  • Utilized three Ewing's sarcoma cell lines with varying TP53 status.
  • Assessed effects of ATR inhibitor VE821 combined with RNR inhibitors (triapine, didox) using flow cytometry.
  • Analyzed cell death, mitochondrial depolarization, cell cycle distribution, caspase 3/7 activity, and gene expression via immunoblotting and RT-PCR.
  • Evaluated drug interactions using combination index analysis.

Main Results:

  • Combined ATR and RNR inhibition demonstrated strong synergistic effects on cell death, exceeding individual inhibitor efficacy.
  • Synergistic effects included increased mitochondrial depolarization, caspase 3/7 activity, and DNA fragmentation, indicating apoptosis.
  • These effects were independent of TP53 functional status.
  • Combination treatment with VE821 and triapine upregulated p53 levels and target gene expression in p53 wild-type cells.

Conclusions:

  • Combined targeting of ATR and RNR is a highly effective in vitro strategy against Ewing's sarcoma.
  • This approach rationalizes further in vivo studies for a new treatment strategy.
  • The findings support the potential of combining ATR and RNR inhibitors for Ewing's sarcoma therapy.
Keywords:
ATRDidoxEwing’s sarcomaRibonucleotide reductaseTriapineVE821

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