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A mitochondria-targeting dihydroartemisinin derivative as a reactive oxygen species -based immunogenic cell death
Hong-Yang Zhao1, Kun-Heng Li1, Dan-Dan Wang1
1Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan 430072, People's Republic of China.
Abstract:
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.
Insights
A novel mitochondria-targeting dihydroartemisinin derivative (T-D) effectively induces immunogenic cell death (ICD) by generating reactive oxygen species (ROS). This T-D compound shows potent anticancer effects, inhibiting tumor growth and metastasis.
Area of Science:
- Biochemistry
- Immunology
- Oncology
Background:
- Immunogenic cell death (ICD) is crucial for activating anticancer immune responses, heavily relying on oxidative stress.
- Current ICD inducers, like anthracyclines, are often weak and lack targeted mitochondrial action.
- Mitochondrial reactive oxygen species (ROS) generation is a key goal for effective ICD induction.
Purpose of the Study:
- To synthesize and evaluate a novel mitochondria-targeting dihydroartemisinin derivative (T-D) as a potent ICD inducer.
- To investigate the mechanism of T-D-induced ICD, focusing on ROS generation and mitochondrial function.
- To assess the in vivo efficacy of T-D in inhibiting breast cancer progression.
Main Methods:
- Synthesis of a mitochondria-targeting dihydroartemisinin derivative (T-D) by conjugating triphenylphosphonium (TPP) to dihydroartemisinin (DHA).
- Evaluation of T-D's ability to selectively accumulate in mitochondria and induce ROS generation, mitochondrial membrane potential loss, and ER stress.
- Assessment of T-D's ICD-inducing potency compared to its parent compound.
- In vivo studies using a T-D-treated breast cancer cell vaccine to evaluate inhibition of metastasis and tumor growth.
Main Results:
- The synthesized T-D selectively accumulates in mitochondria, triggering significant ROS generation.
- T-D effectively induces loss of mitochondrial membrane potential and ER stress, leading to potent ICD.
- T-D exhibits significantly stronger ICD-inducing properties than the parent dihydroartemisinin compound.
- In vivo, a T-D-based breast cancer cell vaccine successfully inhibited lung metastasis and tumor growth.
Conclusions:
- T-D is a highly effective ROS-based ICD inducer with targeted mitochondrial action.
- The study demonstrates the potential of artemisinin-based drugs in cancer immunotherapy through ICD induction.
- T-D offers a promising strategy for enhancing anticancer immune responses and treating breast cancer.
