Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2020
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
_version_ 1783697826318909440
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
work_keys_str_mv AT liguodong arobustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT henrystuartadam arobustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT liuhao arobustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT kangtianshu arobustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT naosangcuo arobustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT zhaoyichao arobustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT wuchun arobustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT jinjianwen arobustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT zhangjiatong arobustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT leungchunghang arobustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT waihongchanphilip arobustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT madiklung arobustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT liguodong robustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT henrystuartadam robustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT liuhao robustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT kangtianshu robustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT naosangcuo robustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT zhaoyichao robustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT wuchun robustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT jinjianwen robustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT zhangjiatong robustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT leungchunghang robustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT waihongchanphilip robustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer
AT madiklung robustphotoluminescencescreeningassayidentifiesuracildnaglycosylaseinhibitorsagainstprostatecancer