Oleandrin enhances radiotherapy sensitivity in lung cancer by inhibiting the ATM/ATR‐mediated DNA damage response
Fuente:
Wiley Open Access
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Artículo Open Access |
| Published: |
Wiley
2024
|
| Subjects: | |
| Online Access: | |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1867012011816124416 |
|---|---|
| author | Qiong Wu Xue Liu Li‐min Wang Yu‐hong Yang Li‐fang Pan Jing‐jing Zhang Yu‐qing Wang Qing‐hua Yao Sheng‐lin Ma Shi‐rong Zhang |
| author_facet | Qiong Wu Xue Liu Li‐min Wang Yu‐hong Yang Li‐fang Pan Jing‐jing Zhang Yu‐qing Wang Qing‐hua Yao Sheng‐lin Ma Shi‐rong Zhang Qiong Wu Xue Liu Li‐min Wang Yu‐hong Yang Li‐fang Pan Jing‐jing Zhang Yu‐qing Wang Qing‐hua Yao Sheng‐lin Ma Shi‐rong Zhang |
| collection | Wiley Open Access |
| contents | Oleandrin enhances radiotherapy sensitivity in lung cancer by inhibiting the ATM/ATR‐mediated DNA damage response Qiong Wu Xue Liu Li‐min Wang Yu‐hong Yang Li‐fang Pan Jing‐jing Zhang Yu‐qing Wang Qing‐hua Yao Sheng‐lin Ma Shi‐rong Zhang Phytotherapy Research AbstractDespite 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. 10.1002/ptr.8237 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| doi_str_mv | 10.1002/ptr.8237 |
| format | Artículo Open Access |
| id | wiley_oa_10_1002_ptr_8237 |
| institution | Wiley Open Access |
| license_str_mv | http://onlinelibrary.wiley.com/termsAndConditions#vor |
| publishDate | 2024 |
| publisher | Wiley |
| record_format | wiley_oa |
| spellingShingle | Oleandrin enhances radiotherapy sensitivity in lung cancer by inhibiting the ATM/ATR‐mediated DNA damage response Qiong Wu Xue Liu Li‐min Wang Yu‐hong Yang Li‐fang Pan Jing‐jing Zhang Yu‐qing Wang Qing‐hua Yao Sheng‐lin Ma Shi‐rong Zhang Phytotherapy Research Oleandrin enhances radiotherapy sensitivity in lung cancer by inhibiting the ATM/ATR‐mediated DNA damage response Qiong Wu Xue Liu Li‐min Wang Yu‐hong Yang Li‐fang Pan Jing‐jing Zhang Yu‐qing Wang Qing‐hua Yao Sheng‐lin Ma Shi‐rong Zhang Phytotherapy Research AbstractDespite 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. 10.1002/ptr.8237 http://onlinelibrary.wiley.com/termsAndConditions#vor |
| title | Oleandrin enhances radiotherapy sensitivity in lung cancer by inhibiting the ATM/ATR‐mediated DNA damage response |
| topic | Phytotherapy Research |
| url | https://onlinelibrary.wiley.com/doi/10.1002/ptr.8237 |