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A robust photoluminescence screening assay identifies uracil-DNA glycosylase inhibitors against prostate cancer
Many cancers have developed resistance to 5-FU, due to removal by the enzyme uracil-DNA glycosylase (UDG), a type of base excision repair enzyme (BER) that can excise uracil and 5-fluorouracil (5-FU) from DNA. However, the development of UDG inhibitor screening methods, especially for the rapid and...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148385/ https://www.ncbi.nlm.nih.gov/pubmed/34123270 http://dx.doi.org/10.1039/c9sc05623h |
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author | Li, Guodong Henry, Stuart Adam Liu, Hao Kang, Tian-Shu Nao, Sang-Cuo Zhao, Yichao Wu, Chun Jin, Jianwen Zhang, Jia-Tong Leung, Chung-Hang Wai Hong Chan, Philip Ma, Dik-Lung |
author_facet | Li, Guodong Henry, Stuart Adam Liu, Hao Kang, Tian-Shu Nao, Sang-Cuo Zhao, Yichao Wu, Chun Jin, Jianwen Zhang, Jia-Tong Leung, Chung-Hang Wai Hong Chan, Philip Ma, Dik-Lung |
author_sort | Li, Guodong |
collection | PubMed |
description | Many cancers have developed resistance to 5-FU, due to removal by the enzyme uracil-DNA glycosylase (UDG), a type of base excision repair enzyme (BER) that can excise uracil and 5-fluorouracil (5-FU) from DNA. However, the development of UDG inhibitor screening methods, especially for the rapid and efficient screening of natural product/natural product-like compounds, is still limited so far. We developed herein a robust time-resolved photoluminescence method for screening UDG inhibitors, which could significantly improve sensitivity over the screening method based on the conventional steady-state spectroscopy, reducing the substantial fluorescence background interference. As a proof-of-concept, two potential UDG inhibitors were identified from a database of natural products and approved drugs. Co-treatment of these two compounds with 5-FU showed synergistic cytotoxicity, providing the basis for treating drug-resistant cancers. Overall, this method provides an avenue for the rapid screening of small molecule regulators of other BER enzyme activities that can avoid false negatives arising from the background fluorescence. |
format | Online Article Text |
id | pubmed-8148385 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-81483852021-06-11 A robust photoluminescence screening assay identifies uracil-DNA glycosylase inhibitors against prostate cancer Li, Guodong Henry, Stuart Adam Liu, Hao Kang, Tian-Shu Nao, Sang-Cuo Zhao, Yichao Wu, Chun Jin, Jianwen Zhang, Jia-Tong Leung, Chung-Hang Wai Hong Chan, Philip Ma, Dik-Lung Chem Sci Chemistry Many cancers have developed resistance to 5-FU, due to removal by the enzyme uracil-DNA glycosylase (UDG), a type of base excision repair enzyme (BER) that can excise uracil and 5-fluorouracil (5-FU) from DNA. However, the development of UDG inhibitor screening methods, especially for the rapid and efficient screening of natural product/natural product-like compounds, is still limited so far. We developed herein a robust time-resolved photoluminescence method for screening UDG inhibitors, which could significantly improve sensitivity over the screening method based on the conventional steady-state spectroscopy, reducing the substantial fluorescence background interference. As a proof-of-concept, two potential UDG inhibitors were identified from a database of natural products and approved drugs. Co-treatment of these two compounds with 5-FU showed synergistic cytotoxicity, providing the basis for treating drug-resistant cancers. Overall, this method provides an avenue for the rapid screening of small molecule regulators of other BER enzyme activities that can avoid false negatives arising from the background fluorescence. The Royal Society of Chemistry 2020-01-10 /pmc/articles/PMC8148385/ /pubmed/34123270 http://dx.doi.org/10.1039/c9sc05623h Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by/3.0/ |
spellingShingle | Chemistry Li, Guodong Henry, Stuart Adam Liu, Hao Kang, Tian-Shu Nao, Sang-Cuo Zhao, Yichao Wu, Chun Jin, Jianwen Zhang, Jia-Tong Leung, Chung-Hang Wai Hong Chan, Philip Ma, Dik-Lung A robust photoluminescence screening assay identifies uracil-DNA glycosylase inhibitors against prostate cancer |
title | A robust photoluminescence screening assay identifies uracil-DNA glycosylase inhibitors against prostate cancer |
title_full | A robust photoluminescence screening assay identifies uracil-DNA glycosylase inhibitors against prostate cancer |
title_fullStr | A robust photoluminescence screening assay identifies uracil-DNA glycosylase inhibitors against prostate cancer |
title_full_unstemmed | A robust photoluminescence screening assay identifies uracil-DNA glycosylase inhibitors against prostate cancer |
title_short | A robust photoluminescence screening assay identifies uracil-DNA glycosylase inhibitors against prostate cancer |
title_sort | robust photoluminescence screening assay identifies uracil-dna glycosylase inhibitors against prostate cancer |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148385/ https://www.ncbi.nlm.nih.gov/pubmed/34123270 http://dx.doi.org/10.1039/c9sc05623h |
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