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.
J Cell Physiol. 2019 Aug;234(8):13157-13168. doi: 10.1002/jcp.27986. Epub 2018 Dec 13.
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.
骨肉瘤是一种恶性原发性骨肿瘤，对化疗和放疗均反应不佳。然而，由于化疗的副作用和耐药性以及骨肉瘤有效的辅助治疗不足，有必要研究新的治疗方法。本研究首次探讨了黄酮类衍生物麻疯树素在骨肉瘤中的抗癌作用。麻疯树素诱导三种人骨肉瘤细胞系（U2OS、MG63 和 HOS）发生细胞凋亡。麻疯树素还与细胞内活性氧（ROS）的增加有关。线粒体功能障碍导致细胞色素 c 从线粒体释放，并伴有抗凋亡蛋白 Bcl-2 和 Bcl-xL 的减少以及促凋亡蛋白 Bak 和 Bax 的增加。麻疯树素引发内质网（ER）应激，表现为细胞质钙离子水平的变化、葡萄糖调节蛋白 78 和 94 的表达增加，以及钙蛋白酶表达和活性的增加。动物研究表明，治疗 18 天后肿瘤体积显著减少了 40%。本研究表明麻疯树素对人骨肉瘤细胞和鼠肿瘤模型具有新的抗癌活性。总之，麻疯树素通过 ROS、ER 应激、线粒体和半胱天冬酶途径显著诱导细胞凋亡，因此可能是骨肉瘤的一种新的抗癌治疗方法。
