Su-Ying Wen1,2, Cheng-Yen Tsai3,4, Pei-Ying Pai5, Yi-Wei Chen6, Yao-Chih Yang6, Ritu Aneja7, Chih-Yang Huang8,9,10, Wei-Wen Kuo6. 1. Department of Dermatology, Taipei City Hospital, Renai Branch, Taipei, Taiwan. 2. Center for General Education, Mackay Junior College of Medicine, Nursing, and Management, Taipei, Taiwan. 3. Department of Pediatrics, China Medical University Beigang Hospital, Yunlin, Taiwan, 651, Republic of China. 4. School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung, Taiwan, 404, Republic of China. 5. Department of Pathology, China Medical University Hospital, Taichung, Taiwan. 6. Department of Biological Science and Technology, College of Biopharmaceutical and Food Sciences, China Medical University, Taichung, Taiwan, 404, Republic of China. 7. Department of Biology, Georgia State University, Atlanta, Georgia, 30303. 8. Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan, 404, Republic of China. 9. Department of Chinese Medicine, China Medical University Hospital, Taichung, Taiwan, 404, Republic of China. 10. Department of Health and Nutrition Biotechnology, Asia University, Taichung, Taiwan, 413, Republic of China.
Abstract
BACKGROUND: Doxorubicin (Dox) is an effective anticancer agent. However, its effectiveness is limited by its cardiotoxic effects. It has also been reported that the mitogen-activated protein kinase family and NF-κB can be activated by Dox treatment. DATS has been shown to be a potent antioxidant with cardioprotective effects. We investigate whether Dox induces cardiac apoptosis through JNK- and ERK-dependent NF-κB upregulation that can be reduced by DATS treatment. METHODS AND MATERIAL: H9c2 cells were treated with 0.5-1.5 μM Dox for 24 hours. Dox promoted apoptosis and ROS generation and inhibited viability in a dose-dependent manner. Then, the phosphorylation levels of JNK, ERK, and NF-κB evaluated by western blot were elevated. We used inhibitors of JNK, ERK, and NF-κB to determine which of these proteins were involved in Dox-induced apoptosis. Furthermore, Dox-exposed cells were treated with DATS at doses of 1, 5, and 10 μM, and the data demonstrated that ROS generation and apoptotic proteins were decreased and that ERK and NF-κB were downregulated in a dose-dependent manner. Additionally, six-week-old rats were divided into three groups (n = 6 per group) designed as an eight-week study. Normal, Dox (at dose 3.75 mg/kg by ip) administered with or without DATS (at dose 40 mg/kg by gavage) treatment groups. The results indicate that cardiac dysfunction, apoptosis, and JNK, ERK, and NF-κB activation by Dox were reversed by treatment with DATS. CONCLUSION: DATS appears to suppress Dox-induced cardiomyocyte apoptosis by inhibiting NADPH oxidase-related ROS production and the downstream JNK/ERK/NF-κB signaling pathway; DATS may possess clinical therapeutic potential by blocking Dox-induced cardiotoxicity.
BACKGROUND:Doxorubicin (Dox) is an effective anticancer agent. However, its effectiveness is limited by its cardiotoxic effects. It has also been reported that the mitogen-activated protein kinase family and NF-κB can be activated by Dox treatment. DATS has been shown to be a potent antioxidant with cardioprotective effects. We investigate whether Dox induces cardiac apoptosis through JNK- and ERK-dependent NF-κB upregulation that can be reduced by DATS treatment. METHODS AND MATERIAL: H9c2 cells were treated with 0.5-1.5 μM Dox for 24 hours. Dox promoted apoptosis and ROS generation and inhibited viability in a dose-dependent manner. Then, the phosphorylation levels of JNK, ERK, and NF-κB evaluated by western blot were elevated. We used inhibitors of JNK, ERK, and NF-κB to determine which of these proteins were involved in Dox-induced apoptosis. Furthermore, Dox-exposed cells were treated with DATS at doses of 1, 5, and 10 μM, and the data demonstrated that ROS generation and apoptotic proteins were decreased and that ERK and NF-κB were downregulated in a dose-dependent manner. Additionally, six-week-old rats were divided into three groups (n = 6 per group) designed as an eight-week study. Normal, Dox (at dose 3.75 mg/kg by ip) administered with or without DATS (at dose 40 mg/kg by gavage) treatment groups. The results indicate that cardiac dysfunction, apoptosis, and JNK, ERK, and NF-κB activation by Dox were reversed by treatment with DATS. CONCLUSION:DATS appears to suppress Dox-induced cardiomyocyte apoptosis by inhibiting NADPH oxidase-related ROS production and the downstream JNK/ERK/NF-κB signaling pathway; DATS may possess clinical therapeutic potential by blocking Dox-induced cardiotoxicity.
Authors: Hao Geng; Wenhao Guo; Lei Feng; Dongdong Xie; Liangkuan Bi; Yi Wang; Tao Zhang; Zhaofeng Liang; Dexin Yu Journal: J Int Med Res Date: 2021-03 Impact factor: 1.671