A robust photoluminescence screening assay identifies uracil-DNA glycosylase inhibitors against prostate cancer

Guodong Li, Stuart Adam Henry, Hao Liu, Tian Shu Kang, Sang Cuo Nao, Yichao Zhao, Chun Wu, Jianwen Jin, Jia Tong Zhang, Chung Hang Leung, Philip Wai Hong Chan, Edmond Dik Lung MA

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1750-1760
Number of pages11
JournalChemical Science
Volume11
Issue number7
DOIs
Publication statusPublished - 21 Feb 2020

Scopus Subject Areas

  • Chemistry(all)

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