Xiaodi Gong1, Xin Pu2, Jing Wang1, Linlin Yang1, Yunxia Cui1, Lijuan Li1, Xiao Sun1, Jichang Liu2, Jingfeng Bai3, Yudong Wang1,4. 1. Department of Gynecologic Oncology, The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People's Republic of China. 2. State Key Laboratory of Chemical Engineering, School of Chemical Engineering, East China University of Science and Technology, Shanghai, People's Republic of China. 3. Biomedical Instrument Institute, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, People's Republic of China. 4. Shanghai Municipal Key Clinical Specialty, Female Tumor Reproductive Specialty, Shanghai, People's Republic of China.
Abstract
PURPOSE: Iron-based nanomaterials have recently been developed as excellent and potent Fenton reagents to reactive oxygen species (ROS) during chemodynamic therapy (CDT). The performance of the materials, however, can be impaired by the intrinsic antioxidant defense mechanism in organisms, such as autophagy. METHODS: The nanoscale metal-organic frameworks (nMOFs), nMIL-100 (Fe), were exploited and characterized. Also, the Fenton-like catalytic characteristics, anti-endometrial cancer (EC) effects and potential mechanisms of nMIL-100 (Fe) nanoparticles were investigated in vitro. RESULTS: The synthesized nMIL-100 (Fe) nanocatalyst catalyzed hydroxyl radicals (·OH) production in the presence of hydrogen peroxide (H2O2) and simultaneously depleted intracellular glutathione (GSH). Combining with H2O2, nMIL-100 (Fe) nanoparticles exhibited enhanced cytotoxicity for EC cells, especially for progesterone treatment-insensitive KLE cells, probably due to relatively lower expression of the catalase gene. The accumulated ·OH initiated PTEN induced putative kinase 1 (PINK1)/E3 ubiquitin-protein ligase Parkin-mediated cytoprotective mitophagy in turn to partially rescue ·OH-induced cell apoptosis. Furthermore, both pretreatments of EC cells with siRNA-mediated Parkin knockdown and Mdivi-1 (a mitophagy inhibitor) addition were sufficient to ensure nMIL-100 (Fe) synergizing with H2O2-induced oxidative damages. CONCLUSION: These results suggest that the degree of mitophagy should be taken into consideration to optimize therapeutic efficiency when developing ROS based-CDT for EC cancer therapies. Therefore, a nMIL-100 (Fe)-guided, elevated ROS and overwhelmed mitophagy-mediated therapeutic strategy may have greater promise for EC therapy compared with current treatment modalities.
PURPOSE: Iron-based nanomaterials have recently been developed as excellent and potent Fenton reagents to reactive oxygen species (ROS) during chemodynamic therapy (CDT). The performance of the materials, however, can be impaired by the intrinsic antioxidant defense mechanism in organisms, such as autophagy. METHODS: The nanoscale metal-organic frameworks (nMOFs), nMIL-100 (Fe), were exploited and characterized. Also, the Fenton-like catalytic characteristics, anti-endometrial cancer (EC) effects and potential mechanisms of nMIL-100 (Fe) nanoparticles were investigated in vitro. RESULTS: The synthesized nMIL-100 (Fe) nanocatalyst catalyzed hydroxyl radicals (·OH) production in the presence of hydrogen peroxide (H2O2) and simultaneously depleted intracellular glutathione (GSH). Combining with H2O2, nMIL-100 (Fe) nanoparticles exhibited enhanced cytotoxicity for EC cells, especially for progesterone treatment-insensitive KLE cells, probably due to relatively lower expression of the catalase gene. The accumulated ·OH initiated PTEN induced putative kinase 1 (PINK1)/E3 ubiquitin-protein ligase Parkin-mediated cytoprotective mitophagy in turn to partially rescue ·OH-induced cell apoptosis. Furthermore, both pretreatments of EC cells with siRNA-mediated Parkin knockdown and Mdivi-1 (a mitophagy inhibitor) addition were sufficient to ensure nMIL-100 (Fe) synergizing with H2O2-induced oxidative damages. CONCLUSION: These results suggest that the degree of mitophagy should be taken into consideration to optimize therapeutic efficiency when developing ROS based-CDT for EC cancer therapies. Therefore, a nMIL-100 (Fe)-guided, elevated ROS and overwhelmed mitophagy-mediated therapeutic strategy may have greater promise for EC therapy compared with current treatment modalities.