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Isothermal kinase-triggered supramolecular assemblies as drug sensitizers
Protein kinases, the main regulators of a vast map of cellular processes, are the most attractive targets in drug discovery. Despite a few successful examples of protein kinase inhibitors, the drug discovery strategy of downregulating protein kinase activity has been quite limited and often fails ev...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145944/ https://www.ncbi.nlm.nih.gov/pubmed/34084370 http://dx.doi.org/10.1039/c9sc04317a |
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author | Liu, Dongdong Miao, Zhe Wu, Chengling He, Fangfei Ren, Peng Bai, Shuo Jiang, Xingyu Gao, Yuan |
author_facet | Liu, Dongdong Miao, Zhe Wu, Chengling He, Fangfei Ren, Peng Bai, Shuo Jiang, Xingyu Gao, Yuan |
author_sort | Liu, Dongdong |
collection | PubMed |
description | Protein kinases, the main regulators of a vast map of cellular processes, are the most attractive targets in drug discovery. Despite a few successful examples of protein kinase inhibitors, the drug discovery strategy of downregulating protein kinase activity has been quite limited and often fails even in animal models. Here, we utilize protein kinase A (PKA) activity to design PKA-triggered supramolecular assemblies with anticancer activities. Grafting a suitable peptide to PNIPAM raises the critical temperature of the LCST polymer above body temperature. Interestingly, the corresponding phosphorylated polymer has a critical temperature below body temperature, making this peptide-appended PNIPAM a suitable polymer for the PKA-triggered supramolecular assembly process. PKA-triggered assembly occurs selectively in PKA-upregulated MCF-7 cells, which disturbs the cytoskeleton and sensitizes cancer cells against doxorubicin. The chemosensitization is also observed in vivo to identify effective tumor inhibitors with satisfactory biocompatibility. Overall, this phosphorylation-induced (in principle, PKA-catalyzed) supramolecular assembly opens up a promising chemotherapy strategy for combating kinase-upregulated cancer. |
format | Online Article Text |
id | pubmed-8145944 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-81459442021-06-02 Isothermal kinase-triggered supramolecular assemblies as drug sensitizers Liu, Dongdong Miao, Zhe Wu, Chengling He, Fangfei Ren, Peng Bai, Shuo Jiang, Xingyu Gao, Yuan Chem Sci Chemistry Protein kinases, the main regulators of a vast map of cellular processes, are the most attractive targets in drug discovery. Despite a few successful examples of protein kinase inhibitors, the drug discovery strategy of downregulating protein kinase activity has been quite limited and often fails even in animal models. Here, we utilize protein kinase A (PKA) activity to design PKA-triggered supramolecular assemblies with anticancer activities. Grafting a suitable peptide to PNIPAM raises the critical temperature of the LCST polymer above body temperature. Interestingly, the corresponding phosphorylated polymer has a critical temperature below body temperature, making this peptide-appended PNIPAM a suitable polymer for the PKA-triggered supramolecular assembly process. PKA-triggered assembly occurs selectively in PKA-upregulated MCF-7 cells, which disturbs the cytoskeleton and sensitizes cancer cells against doxorubicin. The chemosensitization is also observed in vivo to identify effective tumor inhibitors with satisfactory biocompatibility. Overall, this phosphorylation-induced (in principle, PKA-catalyzed) supramolecular assembly opens up a promising chemotherapy strategy for combating kinase-upregulated cancer. The Royal Society of Chemistry 2019-12-06 /pmc/articles/PMC8145944/ /pubmed/34084370 http://dx.doi.org/10.1039/c9sc04317a Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/ |
spellingShingle | Chemistry Liu, Dongdong Miao, Zhe Wu, Chengling He, Fangfei Ren, Peng Bai, Shuo Jiang, Xingyu Gao, Yuan Isothermal kinase-triggered supramolecular assemblies as drug sensitizers |
title | Isothermal kinase-triggered supramolecular assemblies as drug sensitizers |
title_full | Isothermal kinase-triggered supramolecular assemblies as drug sensitizers |
title_fullStr | Isothermal kinase-triggered supramolecular assemblies as drug sensitizers |
title_full_unstemmed | Isothermal kinase-triggered supramolecular assemblies as drug sensitizers |
title_short | Isothermal kinase-triggered supramolecular assemblies as drug sensitizers |
title_sort | isothermal kinase-triggered supramolecular assemblies as drug sensitizers |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8145944/ https://www.ncbi.nlm.nih.gov/pubmed/34084370 http://dx.doi.org/10.1039/c9sc04317a |
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