Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2
Abstract Background Hexokinase (HK) is the rate-limiting enzyme in the first reaction of glycolysis. And Hexokinase 2 (HK2) is most closely related to malignant tumor which expresses at higher level compared with normal cells. HK2 plays a pivotal role in tumor initiation and maintenance, which provi...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-04-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13046-017-0530-4 |
| _version_ | 1818425153391951872 |
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| author | Wei Li Mengzhu Zheng Shuangping Wu Suyu Gao Mei Yang Zhimei Li Qiuxia Min Weiguang Sun Lixia Chen Guangya Xiang Hua Li |
| author_facet | Wei Li Mengzhu Zheng Shuangping Wu Suyu Gao Mei Yang Zhimei Li Qiuxia Min Weiguang Sun Lixia Chen Guangya Xiang Hua Li |
| author_sort | Wei Li |
| collection | DOAJ |
| description | Abstract Background Hexokinase (HK) is the rate-limiting enzyme in the first reaction of glycolysis. And Hexokinase 2 (HK2) is most closely related to malignant tumor which expresses at higher level compared with normal cells. HK2 plays a pivotal role in tumor initiation and maintenance, which provides a new target for cancer therapy. Methods Structure-based virtual ligand screening was used in hit identification from ZINC Drug Database. Microscale thermophoresis assay was performed to evaluate the binding affinity. Enzyme inhibition, cytotoxicity, apoptosis, intracellular ATP level, mitochondrial membrane potential (MMP), glucose uptake and lactate production experiments were undertaken in SW480 cells to identify Benz as a HK2 inhibitor. Western blot was used to test protein expression. SW480 cells xenograft mouse models were used for in vivo study. Nano-particles of Benz were prepared to improve the antitumor efficacy and tumor targeting of Benz. HPLC was used to measure the concentration of free Benz in tumor tissues. Results Benserazide (Benz), was identified as a selective HK2 inhibitor, could specifically bind to HK2 and significantly inhibit HK2 enzymatic activity in vitro. In addition, Benz reduced glucose uptake, lactate production and intracellular ATP level, and could cause cell apoptosis and an increased loss of MMP as well. In vivo study indicated that intraperitoneal (ip) injection of Benz at 300 and 600 mg/Kg suppressed cancer growth in tumor-bearing mice and no toxicity shown. To further improve the antitumor efficacy and tumor targeting of Benz, nano-particles of Benz was prepared. Liposomal Benz at 100 and 200 mg/Kg performed potent inhibitory effects on tumor-bearing mice, showing reduced dose and better efficacy. Conclusions Our study provides a new direction for the development of Benz and its analogues as novel antitumor agents for cancer therapy. |
| first_indexed | 2024-12-14T14:09:25Z |
| format | Article |
| id | doaj.art-c84227859c0449d7b927b44ce1593012 |
| institution | Directory Open Access Journal |
| issn | 1756-9966 |
| language | English |
| last_indexed | 2024-12-14T14:09:25Z |
| publishDate | 2017-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj.art-c84227859c0449d7b927b44ce15930122022-12-21T22:58:23ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662017-04-0136111210.1186/s13046-017-0530-4Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2Wei Li0Mengzhu Zheng1Shuangping Wu2Suyu Gao3Mei Yang4Zhimei Li5Qiuxia Min6Weiguang Sun7Lixia Chen8Guangya Xiang9Hua Li10Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and TechnologyHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and TechnologyHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and TechnologySchool of Traditional Chinese Materia Medica, Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical UniversitySchool of Public Health, Wuhan University of Science and TechnologyHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and TechnologyHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and TechnologyHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and TechnologySchool of Traditional Chinese Materia Medica, Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical UniversityHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and TechnologyHubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Background Hexokinase (HK) is the rate-limiting enzyme in the first reaction of glycolysis. And Hexokinase 2 (HK2) is most closely related to malignant tumor which expresses at higher level compared with normal cells. HK2 plays a pivotal role in tumor initiation and maintenance, which provides a new target for cancer therapy. Methods Structure-based virtual ligand screening was used in hit identification from ZINC Drug Database. Microscale thermophoresis assay was performed to evaluate the binding affinity. Enzyme inhibition, cytotoxicity, apoptosis, intracellular ATP level, mitochondrial membrane potential (MMP), glucose uptake and lactate production experiments were undertaken in SW480 cells to identify Benz as a HK2 inhibitor. Western blot was used to test protein expression. SW480 cells xenograft mouse models were used for in vivo study. Nano-particles of Benz were prepared to improve the antitumor efficacy and tumor targeting of Benz. HPLC was used to measure the concentration of free Benz in tumor tissues. Results Benserazide (Benz), was identified as a selective HK2 inhibitor, could specifically bind to HK2 and significantly inhibit HK2 enzymatic activity in vitro. In addition, Benz reduced glucose uptake, lactate production and intracellular ATP level, and could cause cell apoptosis and an increased loss of MMP as well. In vivo study indicated that intraperitoneal (ip) injection of Benz at 300 and 600 mg/Kg suppressed cancer growth in tumor-bearing mice and no toxicity shown. To further improve the antitumor efficacy and tumor targeting of Benz, nano-particles of Benz was prepared. Liposomal Benz at 100 and 200 mg/Kg performed potent inhibitory effects on tumor-bearing mice, showing reduced dose and better efficacy. Conclusions Our study provides a new direction for the development of Benz and its analogues as novel antitumor agents for cancer therapy.http://link.springer.com/article/10.1186/s13046-017-0530-4BenserazideColorectal cancerDrug repurposingHK2 inhibitorStructure-based virtual ligand screening |
| spellingShingle | Wei Li Mengzhu Zheng Shuangping Wu Suyu Gao Mei Yang Zhimei Li Qiuxia Min Weiguang Sun Lixia Chen Guangya Xiang Hua Li Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2 Journal of Experimental & Clinical Cancer Research Benserazide Colorectal cancer Drug repurposing HK2 inhibitor Structure-based virtual ligand screening |
| title | Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2 |
| title_full | Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2 |
| title_fullStr | Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2 |
| title_full_unstemmed | Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2 |
| title_short | Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2 |
| title_sort | benserazide a dopadecarboxylase inhibitor suppresses tumor growth by targeting hexokinase 2 |
| topic | Benserazide Colorectal cancer Drug repurposing HK2 inhibitor Structure-based virtual ligand screening |
| url | http://link.springer.com/article/10.1186/s13046-017-0530-4 |
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