4.6 Article

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

期刊

JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
卷 149, 期 11, 页码 8605-8617

出版社

SPRINGER
DOI: 10.1007/s00432-023-04804-0

关键词

Ewing's sarcoma; ATR; Ribonucleotide reductase; VE821; Triapine; Didox

类别

向作者/读者索取更多资源

The present study aimed to explore the effectiveness of combined inhibition of ATR and ribonucleotide reductase (RNR) as a new strategy for the treatment of Ewing's sarcoma. The results showed that the combination of ATR and RNR inhibitors had synergistic effects on Ewing's sarcoma cells in vitro, inducing apoptosis. This study reveals the potential of combining ATR and RNR inhibitors as a new treatment strategy for Ewing's sarcoma.
PurposeEwing's sarcoma is a highly malignant childhood tumour whose outcome has hardly changed over the past two decades despite numerous attempts at chemotherapy intensification. It is therefore essential to identify new treatment options. The present study was conducted to explore the effectiveness of combined inhibition of two promising targets, ATR and ribonucleotide reductase (RNR), in Ewing's sarcoma cells.MethodsEffects of the ATR inhibitor VE821 in combination with the RNR inhibitors triapine and didox were assessed in three Ewing's sarcoma cell lines with different TP53 status (WE-68, SK-ES-1, A673) by flow cytometric analysis of cell death, mitochondrial depolarisation and cell cycle distribution as well as by caspase 3/7 activity determination, by immunoblotting and by real-time RT-PCR. Interactions between inhibitors were evaluated by combination index analysis.ResultsSingle ATR or RNR inhibitor treatment produced small to moderate effects, while their combined treatment produced strong synergistic ones. ATR and RNR inhibitors elicited synergistic cell death and cooperated in inducing mitochondrial depolarisation, caspase 3/7 activity and DNA fragmentation, evidencing an apoptotic form of cell death. All effects were independent of functional p53. In addition, VE821 in combination with triapine increased p53 level and induced p53 target gene expression (CDKN1A, BBC3) in p53 wild-type Ewing's sarcoma cells.ConclusionOur study reveals that combined targeting of ATR and RNR was effective against Ewing's sarcoma in vitro and thus rationalises an in vivo exploration into the potential of combining ATR and RNR inhibitors as a new strategy for the treatment of this challenging disease.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.6
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据