Liensinine Inhibits Mitophagy to Potentiate Mitochondria-Targeting Artemisinin-Loaded Polymer Nanostructures for Breast Cancer Therapy

Artemisinin (ART) is a widely used antimalarial drug in the clinic. It also exhibits anticancer potential to inhibit a variety of cancer cells. Unfortunately, the anticancer activity of ART is moderate. Our previous study showed that mitochondria-targeting delivery of ART with poly(d,l-lactide-co-glycolide)/C18-PEG2000-TPP/DLPE-S-S-mPEG4000 (PLGA/CPT/DSSP) could induce severe mitochondrial damage and significantly enhance the anticancer efficiency of ART. However, we found the resistance of cancer cells to mitochondria-targeting ART treatment when increasing the drug concentration. In this work, we analyze the sequential response of MCF-7 cells to the treatment with ART-PLGA/CPT/DSSP, including the decrease of mitochondrial membrane potential, mitochondrial dysfunction, mitochondrial fission, increase of intracellular PINK1/Parkin, and LC3-II-mediated formation of mitophagosomes from damaged mitochondria. Finally, the mitophagosomes and lysosomes fuse to form mitolysosomes for the degradation and removal of damaged mitochondria. We further find that liensinine inhibits ART-induced mitophagy by blocking the formation of mitolysosomes, enhances reactive oxygen species (ROS) accumulation, amplifies mitochondrial damage, and synergistically potentiates in vitro and in vivo anticancer ability of ART when codelivery into the mitochondria of MCF-7 cells. This research provides insights into the resistance of breast cancer cells to ART via mitophagy and inhibition of mitophagy with liensinine for synergistic mitochondria-targeting cancer therapy.