TClC effectively suppresses the growth and metastasis of NSCLC via polypharmacology
Despite significant advances in targeted therapies and immunotherapies, non-small cell lung cancer (NSCLC) continues to present a global health challenge, with a modest five-year survival rate of 28 %, largely due to the emergence of treatment-resistant and metastatic tumors. In response, we synthes...
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KeAi Communications Co., Ltd.
2025-03-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2452199X24005036 |
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| author | Jing Lu Ying Zhang Chunyan Yan Jingwen Liu Dan Qi Yue Zhou Qinwen Wang Juechen Yang Jing Jiang Benhao Wu Meiling Yang Weiwei Zhang Xin Zhang Xiaoyu Shi Yan Zhang Kun Liu Yongcai Liang Chaoyang Wang Hanyu Yang Yuqing Gao Yuping Sun Ronghu Ke Jason H. Huang Min Wu Hongbo Wang Chunlei Li Shuang Zhou Bin Guo Erxi Wu Guoying Zhang |
| author_facet | Jing Lu Ying Zhang Chunyan Yan Jingwen Liu Dan Qi Yue Zhou Qinwen Wang Juechen Yang Jing Jiang Benhao Wu Meiling Yang Weiwei Zhang Xin Zhang Xiaoyu Shi Yan Zhang Kun Liu Yongcai Liang Chaoyang Wang Hanyu Yang Yuqing Gao Yuping Sun Ronghu Ke Jason H. Huang Min Wu Hongbo Wang Chunlei Li Shuang Zhou Bin Guo Erxi Wu Guoying Zhang |
| author_sort | Jing Lu |
| collection | DOAJ |
| description | Despite significant advances in targeted therapies and immunotherapies, non-small cell lung cancer (NSCLC) continues to present a global health challenge, with a modest five-year survival rate of 28 %, largely due to the emergence of treatment-resistant and metastatic tumors. In response, we synthesized a novel bioactive compound, ethyl 6-chlorocoumarin-3-carboxylyl L-theanine (TClC), which significantly inhibited NSCLC growth, epithelial mesenchymal transition (EMT), migration, and invasion in vitro and tumor growth and metastasis in vivo without inducing toxicity. TClC disrupts autocrine loops that promote tumor progression, particularly in stem-like CD133-positive NSCLC (CD133+ LC) cells, which are pivotal in tumor metastasis. Through targeted molecular assays, we identified direct binding targets of TClC, including Akt, NF-κB, β-catenin, EZH2, and PD-L1. This interaction not only suppresses the expression of oncogenic factors and cancer stem cell markers but also downregulates the expression of a multidrug resistance transporter, underscoring the compound's polypharmacological potential. These results position TClC as a promising candidate for NSCLC treatment, signaling a new era in the development of cancer therapies that directly target multiple critical cancer pathways. |
| format | Article |
| id | doaj-art-cff710ae71ab4234b9bdb62630b83ea2 |
| institution | Kabale University |
| issn | 2452-199X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Bioactive Materials |
| spelling | doaj-art-cff710ae71ab4234b9bdb62630b83ea22025-01-26T05:04:23ZengKeAi Communications Co., Ltd.Bioactive Materials2452-199X2025-03-0145567583TClC effectively suppresses the growth and metastasis of NSCLC via polypharmacologyJing Lu0Ying Zhang1Chunyan Yan2Jingwen Liu3Dan Qi4Yue Zhou5Qinwen Wang6Juechen Yang7Jing Jiang8Benhao Wu9Meiling Yang10Weiwei Zhang11Xin Zhang12Xiaoyu Shi13Yan Zhang14Kun Liu15Yongcai Liang16Chaoyang Wang17Hanyu Yang18Yuqing Gao19Yuping Sun20Ronghu Ke21Jason H. Huang22Min Wu23Hongbo Wang24Chunlei Li25Shuang Zhou26Bin Guo27Erxi Wu28Guoying Zhang29School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, ChinaSchool of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, China; Shandong Yingdong Yinghao Biotechnology Inc., Yantai, Shandong, 264670, China; Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND, 58105, USASchool of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, China; Department of Pharmacy, Yantai Yuhuangding Hospital, Yantai, Shandong, 264000, ChinaDepartment of Pharmacological & Pharmaceutical Sciences, University of Houston, Houston, TX, 77204, USANeuroscience Institute and Department of Neurosurgery, Baylor Scott & White Health, Temple, TX, 76502, USA; Department of Neurosurgery, Baylor College of Medicine, Temple, TX, 76502, USADepartment of Statistics, North Dakota State University, Fargo, ND, 58102, USAThe Center of Non-Traumatic Treatment and Diagnosis of Tumor, Binzhou Medical College affiliated The PLA 107 Hospital, Yantai, Shandong, 264002, China; Outpatient Department, No. 26 Rest Center for Retired Cadres, Haidian district, Beijing, 100036, ChinaDepartment of Biomedical Informatics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USARemeGen, Ltd, Yantai, 264000, Shandong, China; Department of Pharmacology, Binzhou Medical University, Yantai, 264003, Shandong, ChinaShandong Yingdong Yinghao Biotechnology Inc., Yantai, Shandong, 264670, ChinaSchool of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, China; Shandong Yingdong Yinghao Biotechnology Inc., Yantai, Shandong, 264670, ChinaSchool of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, China; Shandong Yingdong Yinghao Biotechnology Inc., Yantai, Shandong, 264670, ChinaSchool of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, China; Shandong Yingdong Yinghao Biotechnology Inc., Yantai, Shandong, 264670, ChinaSchool of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, China; Shandong Yingdong Yinghao Biotechnology Inc., Yantai, Shandong, 264670, ChinaSchool of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, China; Shandong Yingdong Yinghao Biotechnology Inc., Yantai, Shandong, 264670, ChinaSchool of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, ChinaSchool of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, ChinaDepartment of Thoracic Surgery, Yantai Yuhuangding Hospital, Yantai, Shandong, 264000, ChinaShiyao Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., LTD., State Key Laboratory of New Pharmaceutical Preparations and Excipients, Shijiazhuang, 050035, ChinaShiyao Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., LTD., State Key Laboratory of New Pharmaceutical Preparations and Excipients, Shijiazhuang, 050035, ChinaPhase I Clinical Trial Center, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250013, ChinaNeuroscience Institute and Department of Neurosurgery, Baylor Scott & White Health, Temple, TX, 76502, USANeuroscience Institute and Department of Neurosurgery, Baylor Scott & White Health, Temple, TX, 76502, USA; College of Medicine, Texas A&M University, College Station, TX, 77843, USA; Department of Neurosurgery, Baylor College of Medicine, Temple, TX, 76502, USADrug Discovery Center, Wenzhou Institute University of Chinese Academy of Sciences, Wenzhou, 325001, China; Department of Critical Care Medicine, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 646000, ChinaSchool of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, ChinaShiyao Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., LTD., State Key Laboratory of New Pharmaceutical Preparations and Excipients, Shijiazhuang, 050035, China; Corresponding author.Department of Pharmacological & Pharmaceutical Sciences, University of Houston, Houston, TX, 77204, USA; Corresponding author.Department of Pharmacological & Pharmaceutical Sciences, University of Houston, Houston, TX, 77204, USA; Corresponding author.Neuroscience Institute and Department of Neurosurgery, Baylor Scott & White Health, Temple, TX, 76502, USA; College of Medicine, Texas A&M University, College Station, TX, 77843, USA; College of Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, TX, 77843, USA; Department of Neurosurgery, Baylor College of Medicine, Temple, TX, 76502, USA; LIVESTRONG Cancer Institutes and Department of Oncology, Dell Medical School, the University of Texas at Austin, Austin, TX, 78712, USA; Corresponding author. Neuroscience Institute and Department of Neurosurgery, Baylor Scott & White Health, Temple, TX, 76502, USA.School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, Shandong, 264005, China; Corresponding author.Despite significant advances in targeted therapies and immunotherapies, non-small cell lung cancer (NSCLC) continues to present a global health challenge, with a modest five-year survival rate of 28 %, largely due to the emergence of treatment-resistant and metastatic tumors. In response, we synthesized a novel bioactive compound, ethyl 6-chlorocoumarin-3-carboxylyl L-theanine (TClC), which significantly inhibited NSCLC growth, epithelial mesenchymal transition (EMT), migration, and invasion in vitro and tumor growth and metastasis in vivo without inducing toxicity. TClC disrupts autocrine loops that promote tumor progression, particularly in stem-like CD133-positive NSCLC (CD133+ LC) cells, which are pivotal in tumor metastasis. Through targeted molecular assays, we identified direct binding targets of TClC, including Akt, NF-κB, β-catenin, EZH2, and PD-L1. This interaction not only suppresses the expression of oncogenic factors and cancer stem cell markers but also downregulates the expression of a multidrug resistance transporter, underscoring the compound's polypharmacological potential. These results position TClC as a promising candidate for NSCLC treatment, signaling a new era in the development of cancer therapies that directly target multiple critical cancer pathways.http://www.sciencedirect.com/science/article/pii/S2452199X24005036Non-small cell lung cancerMetastasisTea derivativePolypharmacological effectCancer stem cell markers |
| spellingShingle | Jing Lu Ying Zhang Chunyan Yan Jingwen Liu Dan Qi Yue Zhou Qinwen Wang Juechen Yang Jing Jiang Benhao Wu Meiling Yang Weiwei Zhang Xin Zhang Xiaoyu Shi Yan Zhang Kun Liu Yongcai Liang Chaoyang Wang Hanyu Yang Yuqing Gao Yuping Sun Ronghu Ke Jason H. Huang Min Wu Hongbo Wang Chunlei Li Shuang Zhou Bin Guo Erxi Wu Guoying Zhang TClC effectively suppresses the growth and metastasis of NSCLC via polypharmacology Bioactive Materials Non-small cell lung cancer Metastasis Tea derivative Polypharmacological effect Cancer stem cell markers |
| title | TClC effectively suppresses the growth and metastasis of NSCLC via polypharmacology |
| title_full | TClC effectively suppresses the growth and metastasis of NSCLC via polypharmacology |
| title_fullStr | TClC effectively suppresses the growth and metastasis of NSCLC via polypharmacology |
| title_full_unstemmed | TClC effectively suppresses the growth and metastasis of NSCLC via polypharmacology |
| title_short | TClC effectively suppresses the growth and metastasis of NSCLC via polypharmacology |
| title_sort | tclc effectively suppresses the growth and metastasis of nsclc via polypharmacology |
| topic | Non-small cell lung cancer Metastasis Tea derivative Polypharmacological effect Cancer stem cell markers |
| url | http://www.sciencedirect.com/science/article/pii/S2452199X24005036 |
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