Resetting amino acid metabolism of cancer cells by ATB0,+-targeted nanoparticles for enhanced anticancer therapy
Reprogramed cellular metabolism is one of the most significant hallmarks of cancer. All cancer cells exhibit increased demand for specific amino acids, and become dependent on either an exogenous supply or upregulated de novo synthesis. The resultant enhanced availability of amino acids supports the...
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| Format: | Article |
| Language: | English |
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KeAi Communications Co., Ltd.
2022-03-01
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| Series: | Bioactive Materials |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2452199X2100342X |
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| author | Longfa Kou Xinyu Jiang Yingying Tang Xing Xia Yingtao Li Aimin Cai Hailun Zheng Hailin Zhang Vadivel Ganapathy Qing Yao Ruijie Chen |
| author_facet | Longfa Kou Xinyu Jiang Yingying Tang Xing Xia Yingtao Li Aimin Cai Hailun Zheng Hailin Zhang Vadivel Ganapathy Qing Yao Ruijie Chen |
| author_sort | Longfa Kou |
| collection | DOAJ |
| description | Reprogramed cellular metabolism is one of the most significant hallmarks of cancer. All cancer cells exhibit increased demand for specific amino acids, and become dependent on either an exogenous supply or upregulated de novo synthesis. The resultant enhanced availability of amino acids supports the reprogramed metabolic pathways and fuels the malignant growth and metastasis of cancers by providing energy and critical metabolic intermediates, facilitating anabolism, and activating signaling networks related to cell proliferation and growth. Therefore, pharmacologic blockade of amino acid entry into cancer cells is likely to have a detrimental effect on cancer cell growth. Here we developed a nanoplatform (LJ@Trp-NPs) to therapeutically target two transporters, SLC6A14 (ATB0,+) and SLC7A5 (LAT1), that are known to be essential for the sustenance of amino acid metabolism in most cancers. The LJ@Trp-NPs uses tryptophan to guide SLC6A14-targeted delivery of JPH203, a high-affinity inhibitor of SLC7A5. In the process, SLC6A14 is also down-regulated. We tested the ability of this strategy to synergize with the anticancer efficacy of lapatinib, an inhibitor of EGFR/HER1/HER2-assocated kinase. These studies show that blockade of amino acid entry amplifies the anticancer effect of lapatinib via interference with mTOR signaling, promotion of apoptosis, and suppression of cell proliferation and metastasis. This represents the first study to evaluate the impact of amino acid starvation on the anticancer efficacy of widely used kinase inhibitor. |
| first_indexed | 2024-04-24T08:44:09Z |
| format | Article |
| id | doaj.art-47b7ad8bcfda4cf491996bdbf169cfe7 |
| institution | Directory Open Access Journal |
| issn | 2452-199X |
| language | English |
| last_indexed | 2024-04-24T08:44:09Z |
| publishDate | 2022-03-01 |
| publisher | KeAi Communications Co., Ltd. |
| record_format | Article |
| series | Bioactive Materials |
| spelling | doaj.art-47b7ad8bcfda4cf491996bdbf169cfe72024-04-16T14:05:06ZengKeAi Communications Co., Ltd.Bioactive Materials2452-199X2022-03-0191528Resetting amino acid metabolism of cancer cells by ATB0,+-targeted nanoparticles for enhanced anticancer therapyLongfa Kou0Xinyu Jiang1Yingying Tang2Xing Xia3Yingtao Li4Aimin Cai5Hailun Zheng6Hailin Zhang7Vadivel Ganapathy8Qing Yao9Ruijie Chen10Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, ChinaDepartment of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, ChinaDepartment of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, ChinaDepartment of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, ChinaDepartment of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Department of Children's Respiration Disease, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, ChinaDepartment of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, ChinaDepartment of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, ChinaDepartment of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Department of Children's Respiration Disease, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, ChinaDepartment of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USADepartment of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, China; Corresponding author. 109 Xueyuan West Road, Wenzhou 325027, China University Town, Wenzhou, 325035, China.Department of Pharmacy, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, China; Corresponding author. 109 Xueyuan West Road, Wenzhou, 325027, China.Reprogramed cellular metabolism is one of the most significant hallmarks of cancer. All cancer cells exhibit increased demand for specific amino acids, and become dependent on either an exogenous supply or upregulated de novo synthesis. The resultant enhanced availability of amino acids supports the reprogramed metabolic pathways and fuels the malignant growth and metastasis of cancers by providing energy and critical metabolic intermediates, facilitating anabolism, and activating signaling networks related to cell proliferation and growth. Therefore, pharmacologic blockade of amino acid entry into cancer cells is likely to have a detrimental effect on cancer cell growth. Here we developed a nanoplatform (LJ@Trp-NPs) to therapeutically target two transporters, SLC6A14 (ATB0,+) and SLC7A5 (LAT1), that are known to be essential for the sustenance of amino acid metabolism in most cancers. The LJ@Trp-NPs uses tryptophan to guide SLC6A14-targeted delivery of JPH203, a high-affinity inhibitor of SLC7A5. In the process, SLC6A14 is also down-regulated. We tested the ability of this strategy to synergize with the anticancer efficacy of lapatinib, an inhibitor of EGFR/HER1/HER2-assocated kinase. These studies show that blockade of amino acid entry amplifies the anticancer effect of lapatinib via interference with mTOR signaling, promotion of apoptosis, and suppression of cell proliferation and metastasis. This represents the first study to evaluate the impact of amino acid starvation on the anticancer efficacy of widely used kinase inhibitor.http://www.sciencedirect.com/science/article/pii/S2452199X2100342XAmino acid deliveryATB0,+ targetingNanoparticlesCancer therapymTOR |
| spellingShingle | Longfa Kou Xinyu Jiang Yingying Tang Xing Xia Yingtao Li Aimin Cai Hailun Zheng Hailin Zhang Vadivel Ganapathy Qing Yao Ruijie Chen Resetting amino acid metabolism of cancer cells by ATB0,+-targeted nanoparticles for enhanced anticancer therapy Bioactive Materials Amino acid delivery ATB0,+ targeting Nanoparticles Cancer therapy mTOR |
| title | Resetting amino acid metabolism of cancer cells by ATB0,+-targeted nanoparticles for enhanced anticancer therapy |
| title_full | Resetting amino acid metabolism of cancer cells by ATB0,+-targeted nanoparticles for enhanced anticancer therapy |
| title_fullStr | Resetting amino acid metabolism of cancer cells by ATB0,+-targeted nanoparticles for enhanced anticancer therapy |
| title_full_unstemmed | Resetting amino acid metabolism of cancer cells by ATB0,+-targeted nanoparticles for enhanced anticancer therapy |
| title_short | Resetting amino acid metabolism of cancer cells by ATB0,+-targeted nanoparticles for enhanced anticancer therapy |
| title_sort | resetting amino acid metabolism of cancer cells by atb0 targeted nanoparticles for enhanced anticancer therapy |
| topic | Amino acid delivery ATB0,+ targeting Nanoparticles Cancer therapy mTOR |
| url | http://www.sciencedirect.com/science/article/pii/S2452199X2100342X |
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