A novel compound modified from tanshinone inhibits tumor growth in vivo via activation of the intrinsic apoptotic pathway |
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Authors: | Hong-Lei Tian Ting Yu Nai-Ning Xu Chao Feng Li-Ying Zhou Hou-Wei Luo Donald C Chang Xiao-Feng Le Kathy Qian Luo |
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Institution: | 1. Department of Biochemistry, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong;2. Division of Bioengineering, School of Chemical and Biomedical Engineering, Nanyang Technological University, Singapore 637457, Singapore;3. Department of Chemical and Biomolecular Engineering, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong;4. Department of Natural Medical Chemistry, China Pharmaceutical University, Nanjing, China;5. Department of Biology, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong;6. Department of Experimental Therapeutics, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA |
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Abstract: | A novel compound, acetyltanshinone IIA (ATA) was obtained from chemical modifications of tanshinone TIIA (TIIA) isolated from a medicinal plant, Salvia miltiorrhiza. ATA exhibited increased water solubility and stronger apoptotic activity on multiple cancer cell lines than TIIA. ATA displayed a higher growth inhibition ability on breast cancer especially HER2 positive cells than normal cells and it inhibited xenografted tumor growth in mice. Mechanistic studies showed that ATA could induce significant reactive oxygen species (ROS) generation, Bax translocation to mitochondria, resulting in mitochondria damage, cytochrome c release, caspase-3 activation and apoptotic cell death. ATA-mediated ROS production and its downstream apoptotic events could be blocked by an antioxidant agent, propyl gallate, indicating the prominent role of ROS in ATA-induced apoptosis. Overexpression of Bcl-2 protein reduced ATA-induced cell death. In conclusion, ATA is a novel anticancer agent with potent in vitro and in vivo anticancer ability. ROS-mediated Bax activation should be the mechanism by which ATA induces apoptosis and inhibits tumor growth. |
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Keywords: | Breast cancer Anticancer drug Apoptosis Reactive oxygen species Tanshinone IIA |
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