Oleandrin enhances radiotherapy sensitivity in lung cancer by inhibiting the ATM/ATR-mediated DNA damage response.

Autor: Wu Q; Department of Integrated Chinese and Western Medicine, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China., Liu X; Department of Integrated Chinese and Western Medicine, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China., Wang LM; Department of Respiratory Diseases, Affiliated Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China., Yang YH; Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People's Hospital, Hangzhou, China., Pan LF; Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People's Hospital, Hangzhou, China., Zhang JJ; Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People's Hospital, Hangzhou, China., Wang YQ; Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People's Hospital, Hangzhou, China., Yao QH; Department of Integrated Chinese and Western Medicine, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, China.; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, China.; The Second Affiliated Hospital of Zhejiang Chinese Medical University, Xinhua Hospital of Zhejiang Province, Hangzhou, Zhejiang, China., Ma SL; Department of Oncology, Affiliated Hangzhou First People's Hospital, Nanjing Medical University, Hangzhou, China., Zhang SR; Translational Medicine Research Center, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Hangzhou First People's Hospital, Hangzhou, China.
Jazyk: angličtina
Zdroj: Phytotherapy research : PTR [Phytother Res] 2024 Aug; Vol. 38 (8), pp. 4151-4167. Date of Electronic Publication: 2024 Jun 22.
DOI: 10.1002/ptr.8237
Abstrakt: Despite active clinical trials on the use of Oleandrin alone or in combination with other drugs for the treatment of solid tumors, the potential synergistic effect of Oleandrin with radiotherapy remains unknown. This study reveals a new mechanism by which Oleandrin targets ATM and ATR kinase-mediated 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-induced double-strand break repair and cell cycle distribution. Western blot analysis was utilized to investigate alterations in signal transduction pathways related to double-strand 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-CHK2 and ATR-CHK1 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.
(© 2024 John Wiley & Sons Ltd.)
Databáze: MEDLINE
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