Jixia Wang1, Huan Qi1, Xiuli Zhang2, Wei Si1, Fangfang Xu1, Tao Hou1, Han Zhou1, Anhui Wang3, Guohui Li3, Yanfang Liu1, Ye Fang4, Hai-Long Piao5, Xinmiao Liang6. 1. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. 2. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226019, China. Electronic address: zhangxiuli@dicp.ac.cn. 3. Laboratory of Molecular Modeling and Design, State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. 4. Biochemical Technologies, Science and Technology Division, Corning, NY 14831, United States. 5. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. Electronic address: hpiao@dicp.ac.cn. 6. CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; Co-innovation Center of Neuroregeneration, Nantong University, Nantong 226019, China. Electronic address: liangxm@dicp.ac.cn.
Abstract
BACKGROUND: Triple-negative breast cancer (TNBC) is one of the most aggressive and poor prognosis breast cancers. Currently, chemotherapy with conventional cytotoxic agents is the only available option to treat TNBC. Hence, we identified new therapeutic agents against TNBC from traditional Chinese medicine Radix Bupleuri and unveiled the molecule mechanism of anti-TNBC effects. METHODS: Multi-component bioactivity and structure-guided methods were used to identify the most effective anti-TNBC compound Saikosaponin D (SSD) from Radix Bupleuri. Cell viability and apoptosis assays were employed to demonstrate the effect of SSD on the proliferation and apoptosis of TNBC cells. Dynamic mass redistribution assay, TopFlash assay, western blotting, and special agonist were applied to dissect the potential molecular mechanisms of SSD. RESULTS: We screened twenty fractions in Radix Bupleuri and identified SSD as the most effective component to inhibit the proliferation of TNBC cells. Investigating the interaction of SSD with the frequently overexpressed targets in TNBC led to the identification that it markedly suppressed Wnt/β-catenin signaling, but did not act on epidermal growth factor receptor and neurotensin receptor-1. Moreover, we demonstrated that SSD significantly repressed β-catenin and its downstream target genes, resulting in TNBC cell apoptosis. Specifically, docking of SSD to the crystal structure of β-catenin suggested that SSD interacted with β-catenin via hydrogen bonds and hydrophobic interaction. CONCLUSION: We identified the most effective component SSD from Radix Bupleuri in inhibiting the proliferation of TNBC cells by targeting β-catenin signaling. Given the important role of Wnt/β-catenin signaling in breast cancer, SSD may present an opportunity to discover new therapeutics for the treatment of TNBC.
BACKGROUND: Triple-negative breast cancer (TNBC) is one of the most aggressive and poor prognosis breast cancers. Currently, chemotherapy with conventional cytotoxic agents is the only available option to treat TNBC. Hence, we identified new therapeutic agents against TNBC from traditional Chinese medicine Radix Bupleuri and unveiled the molecule mechanism of anti-TNBC effects. METHODS: Multi-component bioactivity and structure-guided methods were used to identify the most effective anti-TNBC compound Saikosaponin D (SSD) from Radix Bupleuri. Cell viability and apoptosis assays were employed to demonstrate the effect of SSD on the proliferation and apoptosis of TNBC cells. Dynamic mass redistribution assay, TopFlash assay, western blotting, and special agonist were applied to dissect the potential molecular mechanisms of SSD. RESULTS: We screened twenty fractions in Radix Bupleuri and identified SSD as the most effective component to inhibit the proliferation of TNBC cells. Investigating the interaction of SSD with the frequently overexpressed targets in TNBC led to the identification that it markedly suppressed Wnt/β-catenin signaling, but did not act on epidermal growth factor receptor and neurotensin receptor-1. Moreover, we demonstrated that SSD significantly repressed β-catenin and its downstream target genes, resulting in TNBC cell apoptosis. Specifically, docking of SSD to the crystal structure of β-catenin suggested that SSD interacted with β-catenin via hydrogen bonds and hydrophobic interaction. CONCLUSION: We identified the most effective component SSD from Radix Bupleuri in inhibiting the proliferation of TNBC cells by targeting β-catenin signaling. Given the important role of Wnt/β-catenin signaling in breast cancer, SSD may present an opportunity to discover new therapeutics for the treatment of TNBC.