Metformin mitigates gastrointestinal radiotoxicity and radiosensitises P53 mutation colorectal tumours via optimising autophagy
Long Chen, Fengying Liao, Zhongyong Jiang, Chi Zhang, Ziwen Wang, Peng Luo, Qingzhi Jiang, Jie Wu, Qing Wang, Min Luo, Xueru Li, Yu Leng, Le Ma, Gufang Shen, Zelin Chen, Yu Wang, Xu Tan, Yibo Gan, Dengqun Liu, Yunsheng Liu, Chunmeng Shi
Abstract
BACKGROUND AND PURPOSE: There is an urgent but unmet need for mitigating radiation-induced intestinal toxicity while radio sensitising tumours for abdominal radiotherapy. We aimed to investigate the effects of metformin on radiation-induced intestinal toxicity and radiosensitivity of colorectal tumours. EXPERIMENTAL APPROACH: Acute and chronic histological injuries of the intestine from mice were used to assess radioprotection and IEC-6 cell line was used to investigate the mechanisms in vitro. The fractionated abdominal radiation model of HCT116 and HT29 tumour grafts was used to determine the effects on colorectal cancer. KEY RESULTS: Metformin alleviated radiation-induced acute and chronic intestinal toxicity by optimising mitophagy which was AMPK-dependent. In addition, our data indicated that metformin increased the radiosensitivity of colorectal tumours with P53 mutation both in vitro and in vivo. CONCLUSION AND IMPLICATIONS: Metformin may be a radiotherapy adjuvant agent for colorectal cancers especially those carrying P53 mutation. Our findings provide a new strategy for further precise clinical trials for metformin on radiotherapy.