Frontiers in Pharmacology (May 2020)
Iron Promotes Dihydroartemisinin Cytotoxicity via ROS Production and Blockade of Autophagic Flux via Lysosomal Damage in Osteosarcoma
- Ying Shen,
- Ying Shen,
- Ying Shen,
- Bin Zhang,
- Bin Zhang,
- Bin Zhang,
- Yanwei Su,
- Yanwei Su,
- Yanwei Su,
- Shaikh Atik Badshah,
- Shaikh Atik Badshah,
- Xiaofei Wang,
- Xin Li,
- Xin Li,
- Xin Li,
- Yanru Xue,
- Yanru Xue,
- Yanru Xue,
- Li Xie,
- Li Xie,
- Zhe Wang,
- Zhe Wang,
- Zhouqi Yang,
- Zhouqi Yang,
- Ge Zhang,
- Peng Shang,
- Peng Shang
Affiliations
- Ying Shen
- Research and Development Institute in Shenzhen, Northwestern Polytechnical University, Shenzhen, China
- Ying Shen
- School of Life Science, Northwestern Polytechnical University, Xi’an, China
- Ying Shen
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environment Biophysics, School of Life Science, Northwestern Polytechnical University, Xi’an, China
- Bin Zhang
- Research and Development Institute in Shenzhen, Northwestern Polytechnical University, Shenzhen, China
- Bin Zhang
- School of Life Science, Northwestern Polytechnical University, Xi’an, China
- Bin Zhang
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environment Biophysics, School of Life Science, Northwestern Polytechnical University, Xi’an, China
- Yanwei Su
- Research and Development Institute in Shenzhen, Northwestern Polytechnical University, Shenzhen, China
- Yanwei Su
- School of Life Science, Northwestern Polytechnical University, Xi’an, China
- Yanwei Su
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environment Biophysics, School of Life Science, Northwestern Polytechnical University, Xi’an, China
- Shaikh Atik Badshah
- Research and Development Institute in Shenzhen, Northwestern Polytechnical University, Shenzhen, China
- Shaikh Atik Badshah
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environment Biophysics, School of Life Science, Northwestern Polytechnical University, Xi’an, China
- Xiaofei Wang
- Biomedical Experimental Center, Xi’an Jiaotong University, Xi’an, China
- Xin Li
- Research and Development Institute in Shenzhen, Northwestern Polytechnical University, Shenzhen, China
- Xin Li
- School of Life Science, Northwestern Polytechnical University, Xi’an, China
- Xin Li
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environment Biophysics, School of Life Science, Northwestern Polytechnical University, Xi’an, China
- Yanru Xue
- Research and Development Institute in Shenzhen, Northwestern Polytechnical University, Shenzhen, China
- Yanru Xue
- School of Life Science, Northwestern Polytechnical University, Xi’an, China
- Yanru Xue
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environment Biophysics, School of Life Science, Northwestern Polytechnical University, Xi’an, China
- Li Xie
- School of Life Science, Northwestern Polytechnical University, Xi’an, China
- Li Xie
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environment Biophysics, School of Life Science, Northwestern Polytechnical University, Xi’an, China
- Zhe Wang
- School of Life Science, Northwestern Polytechnical University, Xi’an, China
- Zhe Wang
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environment Biophysics, School of Life Science, Northwestern Polytechnical University, Xi’an, China
- Zhouqi Yang
- School of Life Science, Northwestern Polytechnical University, Xi’an, China
- Zhouqi Yang
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environment Biophysics, School of Life Science, Northwestern Polytechnical University, Xi’an, China
- Ge Zhang
- Law Sau Fai Institute for Advancing Translational Medicine in Bone & Joint Diseases (TMBJ), Hong Kong Baptist University, Hong Kong, Hong Kong
- Peng Shang
- Research and Development Institute in Shenzhen, Northwestern Polytechnical University, Shenzhen, China
- Peng Shang
- Key Laboratory for Space Bioscience and Biotechnology, Institute of Special Environment Biophysics, School of Life Science, Northwestern Polytechnical University, Xi’an, China
- DOI
- https://doi.org/10.3389/fphar.2020.00444
- Journal volume & issue
-
Vol. 11
Abstract
Osteosarcoma cellular iron concentration is higher than that in normal bone cells and other cell types. High levels of cellular iron help catalyze the Fenton reaction to produce reactive oxygen species (ROS), which promotes cancer cell proliferation. Dihydroartemisinin (DHA), a classic anti-malarial drug, kills plasmodium through iron-dependent ROS generation. In this research, we observed the anti-osteosarcoma effects and mechanisms of DHA. We found that DHA induced ROS production, caused mitochondrial damage, and activated autophagy via stimulation of the ROS/Erk1/2 pathway. As the storage site for a pool of ferrous iron, lysosomes are often the key organelles affected by drugs targeting iron. In this study, we observed that DHA induced lysosomal superoxide production, leading lysosomal membrane permeabilization (LMP), and autophagic flux blockage. By reducing or increasing cellular iron using deferoxamine (DFO) or ferric ammonium citrate (FAC), respectively, we found that DHA inhibited osteosarcoma in an iron-dependent manner. Therefore, iron may be a potential adjuvant for DHA in osteosarcoma treatment.
Keywords
