A mitochondria-targeting dihydroartemisinin derivative as a reactive oxygen species -based immunogenic cell death inducer

• Published in: iScience 2024-01, Vol.27 (1), p.108702-108702, Article 108702
• Main Authors: Zhao, Hong-Yang, Li, Kun-Heng, Wang, Dan-Dan, Zhang, Zhi-Li, Xu, Zi-Jian, Qi, Ming-Hui, Huang, Shi-Wen
• Format: Article
• Language: English
• Subjects: Cell biology; Immunology; Medical biochemistry
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2023.108702

Immunogenic cell death (ICD) can activate the anticancer immune response and its occurrence requires high reliance on oxidative stress. Inducing mitochondrial reactive oxygen species (ROS) is a desirable capability for ICD inducers. However, in the category of ICD-associated drugs, numerous reported ICD inducers are a series of anthracyclines and weak in ICD induction. Herein, a mitochondria-targeting dihydroartemisinin derivative (T-D) was synthesized by conjugating triphenylphosphonium (TPP) to dihydroartemisinin (DHA). T-D can selectively accumulate in mitochondria to trigger ROS generation, leading to the loss of mitochondrial membrane potential (ΔΨm) and ER stress. Notably, T-D exhibits far more potent ICD-inducing properties than its parent compound. In vivo, T-D-treated breast cancer cell vaccine inhibits metastasis to the lungs and tumor growth. These results indicate that T-D is an excellent ROS-based ICD inducer with the specific function of trigging vigorous ROS in mitochondria and sets an example for incorporating artemisinin-based drugs into the ICD field. [Display omitted] •A mitochondria-targeting dihydroartemisinin derivative (TPP-DHA，T-D) was synthesized•T-D can selectively accumulate in mitochondria to trigger ROS generation•T-D exhibits far more potent ICD-inducing properties than its parent compound Medical biochemistry; Immunology; Cell biology