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This study reveals a new mechanism by which Oleandrin targets ATM and ATR kinase\u2010mediated radiosensitization in lung cancer. Various assays, including clonogenic, Comet, immunofluorescence staining, apoptosis and Cell cycle assays, were conducted to evaluate the impact of oleandrin on radiation\u2010induced double\u2010strand break repair and cell cycle distribution. Western blot analysis was utilized to investigate alterations in signal transduction pathways related to double\u2010strand break repair. The efficacy and toxicity of the combined therapy were assessed in a preclinical xenotransplantation model. Functionally, Oleandrin weakens the DNA damage repair ability and enhances the radiation sensitivity of lung cells. Mechanistically, Oleandrin inhibits ATM and ATR kinase activities, blocking the transmission of ATM\u2010CHK2 and ATR\u2010CHK1 cell cycle checkpoint signaling axes. This accelerates the passage of tumor cells through the G2 phase after radiotherapy, substantially facilitating the rapid entry of large numbers of inadequately repaired cells into mitosis and ultimately triggering mitotic catastrophe. The combined treatment of Oleandrin and radiotherapy demonstrated superior inhibition of tumor proliferation compared to either treatment alone. Our findings highlight Oleandrin as a novel and effective inhibitor of ATM and ATR kinase, offering new possibilities for the development of clinical radiosensitizing adjuvants.<\/jats:p>","DOI":"10.1002\/ptr.8237","type":"journal-article","created":{"date-parts":[[2024,6,22]],"date-time":"2024-06-22T09:54:10Z","timestamp":1719050050000},"page":"4151-4167","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Oleandrin enhances radiotherapy sensitivity in lung cancer by inhibiting the <scp>ATM<\/scp>\/<scp>ATR<\/scp>\u2010mediated <scp>DNA<\/scp> damage response"],"prefix":"10.1002","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2552-3241","authenticated-orcid":false,"given":"Qiong","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Integrated Chinese and Western Medicine Zhejiang Cancer Hospital  Hangzhou Zhejiang China"},{"name":"Hangzhou Institute of Medicine (HIM) Chinese Academy 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