DNA damage repair promotion in colonic epithelial cells by andrographolide downregulated cGAS‒STING pathway activation and contributed to the relief of CPT-11-induced intestinal mucositis

• Published in: Acta pharmaceutica Sinica. B Vol. 12; no. 1; pp. 262 - 273
• Main Authors: Wang, Yuanyuan, Wei, Bin, Wang, Danping, Wu, Jingjing, Gao, Jianhua, Zhong, Haiqing, Sun, Yang, Xu, Qiang, Liu, Wen, Gu, Yanhong, Guo, Wenjie
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2022; Elsevier
• Subjects: Andrographolide; cGAS‒STING; CPT-11; Gastrointestinal mucositis; Homologous recombination; Original; Gastrointestinal mucositis; cGAS‒STING; CPT-11; Andrographolide; Homologous recombination
• ISSN: 2211-3835; 2211-3843
• DOI: 10.1016/j.apsb.2021.03.043

Gastrointestinal mucositis is one of the most debilitating side effects of the chemotherapeutic agent irinotecan (CPT-11). Andrographolide, a natural bicyclic diterpenoid lactone, has been reported to possess anti-colitis activity. In this study, andrographolide treatment was found to significantly relieve CPT-11-induced colitis in tumor-bearing mice without decreasing the tumor suppression effect of CPT-11. CPT-11 causes DNA damage and the release of double-stranded DNA (dsDNA) from the intestine, leading to cyclic-GMP-AMP synthase (cGAS)‒stimulator of interferon genes (STING)-mediated colitis, which was significantly decreased by andrographolide both in vivo and in vitro. Mechanistic studies revealed that andrographolide could promote homologous recombination (HR) repair and downregulate dsDNA‒cGAS‒STING signaling and contribute to the improvement of CPT-11-induced gastrointestinal mucositis. These results suggest that andrographolide may be a novel agent to relieve gastrointestinal mucositis caused by CPT-11. Andrographolide could accelerate HR repair of DNA damage-induced by elevating expression of RAD51 and downregulate cGAS‒STING, thereby improving mucosal damage. [Display omitted]