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Artocarpin induces cell apoptosis in human osteosarcoma cells through endoplasmic reticulum stress and reactive oxygen species |
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| Authors: | Chiang-Wen Lee Miao-Ching Chi Tsung-Ming Chang Ju-Fang Liu |
| Institution: | 1. Department of Nursing, Division of Basic Medical Sciences, and Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chia-Yi, Taiwan, Republic of China
Research Center for Industry of Human Ecology and Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan, Taiwan, Republic of China Department of Rehabilitation, Chang Gung Memorial Hospital, Chia-Yi, Taiwan, Republic of China Lee and Chi have contributed equally to this work.;2. Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Chiayi County, Taiwan, Republic of China Department of Respiratory Care, Chang Gung University of Science and Technology, Chiayi County, Taiwan, Republic of China Division of Pulmonary and Critical Care Medicine, Chiayi Chang Gung Memorial Hospital, Taiwan, Republic of China Lee and Chi have contributed equally to this work.;3. Department of Physiology, School of Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China;4. Central Laboratory, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan, Republic of China |
| Abstract: | Osteosarcoma is a malignant primary bone tumor that responds poorly to both chemotherapy and radiation therapy. However, because of side effects and drug resistance in chemotherapy and the insufficiency of an effective adjuvant therapy for osteosarcoma, it is necessary to research novel treatments. This study was the first to investigate the anticancer effects of the flavonoid derivative artocarpin in osteosarcoma. Artocarpin induced cell apoptosis in three human osteosarcoma cell lines—U2OS, MG63, and HOS. Artocarpin was also associated with increased intracellular reactive oxygen species (ROS). Mitochondrial dysfunction was followed by the release of cytochrome c from mitochondria and accompanied by decreased antiapoptotic Bcl-2 and Bcl-xL and increased proapoptotic protein Bak and Bax. Artocarpin triggered endoplasmic reticulum (ER) stress, as indicated by changes in cytosol calcium levels and increased glucose-regulated protein 78 and 94 expressions, and also increased calpains expression and activity. Animal studies revealed a dramatic 40% reduction in tumor volume after 18 days of treatment. This study demonstrated a novel anticancer activity of artocarpin against human osteosarcoma cells and in murine tumor models. In summary, artocarpin significantly induced cell apoptosis through ROS, ER stress, mitochondria, and the caspase pathway, and may thus be a novel anticancer treatment for osteosarcoma. |
| Keywords: | artocarpin apoptosis ER stress osteosarcoma ROS |