A robust luminescent assay for screening alkyladenine DNA glycosylase inhibitors to overcome DNA repair and temozolomide drug resistance

Ying-Qi Song; Guo-Dong Li; Dou Niu; Feng Chen; Shaozhen Jing; Vincent Kam Wai Wong; Wanhe Wang; Chung-Hang Leung

doi:10.1016/j.jpha.2023.04.010

Volume 13 Issue 5

May 2023

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Article Navigation > Journal of Pharmaceutical Analysis > 2023 > 13(5): 514-522

Ying-Qi Song, Guo-Dong Li, Dou Niu, Feng Chen, Shaozhen Jing, Vincent Kam Wai Wong, Wanhe Wang, Chung-Hang Leung. A robust luminescent assay for screening alkyladenine DNA glycosylase inhibitors to overcome DNA repair and temozolomide drug resistance[J]. Journal of Pharmaceutical Analysis, 2023, 13(5): 514-522. doi: 10.1016/j.jpha.2023.04.010

Citation:

Ying-Qi Song, Guo-Dong Li, Dou Niu, Feng Chen, Shaozhen Jing, Vincent Kam Wai Wong, Wanhe Wang, Chung-Hang Leung. A robust luminescent assay for screening alkyladenine DNA glycosylase inhibitors to overcome DNA repair and temozolomide drug resistance[J]. Journal of Pharmaceutical Analysis, 2023, 13(5): 514-522. doi: 10.1016/j.jpha.2023.04.010

Citation:

Ying-Qi Song, Guo-Dong Li, Dou Niu, Feng Chen, Shaozhen Jing, Vincent Kam Wai Wong, Wanhe Wang, Chung-Hang Leung. A robust luminescent assay for screening alkyladenine DNA glycosylase inhibitors to overcome DNA repair and temozolomide drug resistance[J]. Journal of Pharmaceutical Analysis, 2023, 13(5): 514-522. doi: 10.1016/j.jpha.2023.04.010

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A robust luminescent assay for screening alkyladenine DNA glycosylase inhibitors to overcome DNA repair and temozolomide drug resistance

doi: 10.1016/j.jpha.2023.04.010

a. State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, 999078, China;
b. Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Macao, 999078, China;
c. Institute of Medical Research, Northwestern Polytechnical University, Xi'an, 710072, China;
d. Dr. Neher's Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macao, 999078, China

Funds:

This work is supported by the Science and Technology Development Fund (Grant Nos.: 0007/2020/A1 and 0020/2022/A1), the State Key Laboratory of Quality Research in Chinese Medicine, University of Macau (Grant No.: SKL-QRCM(UM)-2020-2022), the University of Macau (Grant Nos.: MYRG2019-00002-ICMS and MYRG2020-00017-ICMS), 2022 Internal Research Grant of SKLQRCM (University of Macau) (Grant No.: QRCM-IRG2022-011), the National Natural Science Foundation of China (Grant No.: 22101230), the Natural Science Basic Research Program of Shaanxi (Grant No.: 2021JQ-089), and the Natural Science Foundation of Chongqing, China (Grant No.: cstc2021jcyj-msxmX0659).

Received Date: Jan. 06, 2023
Accepted Date: Apr. 15, 2023
Rev Recd Date: Mar. 22, 2023
Publish Date: Apr. 19, 2023

Abstract

Abstract

Temozolomide (TMZ) is an anticancer agent used to treat glioblastoma, typically following radiation therapy and/or surgical resection. However, despite its effectiveness, at least 50% of patients do not respond to TMZ, which is associated with repair and/or tolerance of TMZ-induced DNA lesions. Studies have demonstrated that alkyladenine DNA glycosylase (AAG), an enzyme that triggers the base excision repair (BER) pathway by excising TMZ-induced N3-methyladenine (3meA) and N7-methylguanine lesions, is overexpressed in glioblastoma tissues compared to normal tissues. Therefore, it is essential to develop a rapid and efficient screening method for AAG inhibitors to overcome TMZ resistance in glioblastomas. Herein, we report a robust time-resolved photoluminescence platform for identifying AAG inhibitors with improved sensitivity compared to conventional steady-state spectroscopic methods. As a proof-of-concept, this assay was used to screen 1440 food and drug administration-approved drugs against AAG, resulting in the repurposing of sunitinib as a potential AAG inhibitor. Sunitinib restored glioblastoma (GBM) cancer cell sensitivity to TMZ, inhibited GBM cell proliferation and stem cell characteristics, and induced GBM cell cycle arrest. Overall, this strategy offers a new method for the rapid identification of small-molecule inhibitors of BER enzyme activities that can prevent false negatives due to a fluorescent background.
- Drug screening,
- Alkyladenine DNA glycosylase,
- N3-methyladenine,
- Glioblastoma,
- Temozolomide,
- Sunitinib

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References(37)

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