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TQFL12, a novel synthetic derivative of TQ,inhibits triple-negative breast cancer metastasis and invasion through activating AMPK/ACC pathway |
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| Authors: | Chunli Wei Hui Zou Ting Xiao Xiaoyan Liu Qianqian Wang Jingliang Cheng Shangyi Fu Jiangzhou Peng Xin Xie Junjiang Fu |
| Institution: | 1. Key Laboratory of Epigenetics and Oncology, the Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China
Contribution: Data curation (equal), Investigation (equal), Validation (equal), Writing - original draft (equal), Writing - review & editing (equal);2. Key Laboratory of Epigenetics and Oncology, the Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, School of Medicine, Hunan Normal University, Changsha, China Contribution: Investigation (equal), Resources (equal), Writing - review & editing (equal);3. Key Laboratory of Epigenetics and Oncology, the Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China Contribution: Investigation (equal);4. Chronic Disease Research Center, Medical College, Dalian University, Dalian, China Contribution: Validation (equal);5. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA School of Medicine, Baylor College of Medicine, Houston, TX, USA;6. Department of Thoracic Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, China;7. Department of Orthopedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China;8. Key Laboratory of Epigenetics and Oncology, the Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, China |
| Abstract: | Thymoquinone (TQ) has been reported as an anti-tumour drug widely studied in various tumours, and its mechanism and effect of which has become a focus of current research. However, previous studies from our laboratory and other groups found that TQ showed weak anti-tumour effects in many cancer cell lines and animal models. Therefore, it is necessary to modify and optimize the structure of TQ to obtain new chemical entities with high efficiency and low toxicity as candidates for development of new drugs in treating cancer. Therefore, we designed and synthesized several TQ derivatives. Systematic analysis, including in vitro and in vivo, was conducted on a panel of triple-negative breast cancer (TNBC) cells and mouse model to demonstrate whether TQFL12, a new TQ derivative, is more efficient than TQ. We found that the anti-proliferative effect of TQFL12 against TNBC cells is significantly stronger than TQ. We also demonstrated TQFL12 affects different aspects in breast cancer development including cell proliferation, migration, invasion and apoptosis. Moreover, TQFL12 inhibited tumour growth and metastasis in cancer cell–derived xenograft mouse model, with less toxicity compared with TQ. Finally, mechanism research indicated that TQFL12 increased AMPK/ACC activity by stabilizing AMPKα, while molecular docking supported the direct interaction between TQFL12 and AMPKα. Taken together, our findings suggest that TQFL12, as a novel chemical entity, possesses a better inhibitory effect on TNBC cells and less toxicity in both in vitro and in vivo studies. As such, TQFL12 could serve as a potential therapeutic agent for breast cancer. |
| Keywords: | AMPK anti-cancer metastasis thymoquinone derivative triple-negative breast cancer |