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...

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Bibliographic Details
Published in:Chemical science (Cambridge) 2020-02, Vol.11 (7), p.175-176
Main Authors: 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
Format: Article
Language:English
Subjects:
Chemistry
Deoxyribonucleic acid
DNA
Enzymes
Fluorescence
Inhibitors
Natural products
Photoluminescence
Prostate
Regulators
Robustness
Screening
Toxicity
Uracil
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Summary: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 discovery of UDG inhibitors against prostate cancer by using a robust photoluminescence screening assay that can avoid false negatives arising from the background fluorescence.
ISSN:2041-6520
2041-6539
DOI:10.1039/c9sc05623h