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

• Published in: Phytotherapy research Vol. 38; no. 8; pp. 4151 - 4167
• Main Authors: Wu, Qiong, Liu, Xue, Wang, Li‐min, Yang, Yu‐hong, Pan, Li‐fang, Zhang, Jing‐jing, Wang, Yu‐qing, Yao, Qing‐hua, Ma, Sheng‐lin, Zhang, Shi‐rong
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.08.2024; Wiley Subscription Services, Inc
• Subjects: A549 Cells; Adjuvants; Animals; Apoptosis; Apoptosis - drug effects; Ataxia Telangiectasia Mutated Proteins - metabolism; ATM; ATR; Cardenolides - pharmacology; Cell cycle; Cell Line, Tumor; Cell proliferation; Cell Proliferation - drug effects; CHK1 protein; CHK2 protein; Clinical trials; Combined treatment; Damage assessment; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - drug effects; DNA damage repair; DNA repair; DNA Repair - drug effects; Effectiveness; G2 phase; Humans; Immunofluorescence; Impact analysis; Kinases; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - radiotherapy; Mice; Mice, Nude; Mitosis; Oleandrin; Radiation damage; Radiation therapy; Radiation Tolerance - drug effects; Radiation-Sensitizing Agents - pharmacology; radiosensitivity; Radiosensitization; Sensitivity analysis; Signal transduction; Signal Transduction - drug effects; Solid tumors; Synergistic effect; Toxicity; Tumor cells; Tumors; Xenograft Model Antitumor Assays; Xenotransplantation; DNA damage repair; ATM; Oleandrin; radiosensitivity; ATR
• ISSN: 0951-418X; 1099-1573; 1099-1573
• DOI: 10.1002/ptr.8237

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.