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Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage Process
Urothelial carcinoma (UC) is characterized by a high incidence of TP53 mutation, and overcoming resistance to cisplatin-based chemotherapy in UC is a major concern. Wee1 is a G2/M phase regulator that controls the DNA damage response to chemotherapy in TP53-mutant cancers. The combination of Wee1 bl...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10252844/ https://www.ncbi.nlm.nih.gov/pubmed/37296592 http://dx.doi.org/10.3390/cells12111471 |
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author | Su, Yu-Li Xiao, Ling-Yi Huang, Shih-Yu Wu, Chia-Che Chang, Li-Chung Chen, Yi-Hua Luo, Hao-Lun Huang, Chun-Chieh Liu, Ting-Ting Peng, Jei-Ming |
author_facet | Su, Yu-Li Xiao, Ling-Yi Huang, Shih-Yu Wu, Chia-Che Chang, Li-Chung Chen, Yi-Hua Luo, Hao-Lun Huang, Chun-Chieh Liu, Ting-Ting Peng, Jei-Ming |
author_sort | Su, Yu-Li |
collection | PubMed |
description | Urothelial carcinoma (UC) is characterized by a high incidence of TP53 mutation, and overcoming resistance to cisplatin-based chemotherapy in UC is a major concern. Wee1 is a G2/M phase regulator that controls the DNA damage response to chemotherapy in TP53-mutant cancers. The combination of Wee1 blockade with cisplatin has shown synergistic efficacy in several types of cancers, but little is known regarding UC. The antitumor efficacy of the Wee1 inhibitor (AZD-1775) alone or in combination with cisplatin was evaluated in UC cell lines and a xenograft mouse model. AZD-1775 enhanced the anticancer activity of cisplatin by increasing cellular apoptosis. AZD-1775 inhibited the G2/M checkpoint, improving the sensitivity of mutant TP53 UC cells to cisplatin by enhancing the DNA damage process. We confirmed that AZD-1775 combined with cisplatin reduced tumor volume and proliferation activity and increased the markers of cell apoptosis and DNA damage in the mouse xenograft model. In summary, the Wee1 inhibitor AZD-1775 combined with cisplatin elicited a promising anticancer efficacy in UC, and constitutes an innovative and promising therapeutic strategy. |
format | Online Article Text |
id | pubmed-10252844 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-102528442023-06-10 Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage Process Su, Yu-Li Xiao, Ling-Yi Huang, Shih-Yu Wu, Chia-Che Chang, Li-Chung Chen, Yi-Hua Luo, Hao-Lun Huang, Chun-Chieh Liu, Ting-Ting Peng, Jei-Ming Cells Article Urothelial carcinoma (UC) is characterized by a high incidence of TP53 mutation, and overcoming resistance to cisplatin-based chemotherapy in UC is a major concern. Wee1 is a G2/M phase regulator that controls the DNA damage response to chemotherapy in TP53-mutant cancers. The combination of Wee1 blockade with cisplatin has shown synergistic efficacy in several types of cancers, but little is known regarding UC. The antitumor efficacy of the Wee1 inhibitor (AZD-1775) alone or in combination with cisplatin was evaluated in UC cell lines and a xenograft mouse model. AZD-1775 enhanced the anticancer activity of cisplatin by increasing cellular apoptosis. AZD-1775 inhibited the G2/M checkpoint, improving the sensitivity of mutant TP53 UC cells to cisplatin by enhancing the DNA damage process. We confirmed that AZD-1775 combined with cisplatin reduced tumor volume and proliferation activity and increased the markers of cell apoptosis and DNA damage in the mouse xenograft model. In summary, the Wee1 inhibitor AZD-1775 combined with cisplatin elicited a promising anticancer efficacy in UC, and constitutes an innovative and promising therapeutic strategy. MDPI 2023-05-25 /pmc/articles/PMC10252844/ /pubmed/37296592 http://dx.doi.org/10.3390/cells12111471 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Su, Yu-Li Xiao, Ling-Yi Huang, Shih-Yu Wu, Chia-Che Chang, Li-Chung Chen, Yi-Hua Luo, Hao-Lun Huang, Chun-Chieh Liu, Ting-Ting Peng, Jei-Ming Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage Process |
title | Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage Process |
title_full | Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage Process |
title_fullStr | Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage Process |
title_full_unstemmed | Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage Process |
title_short | Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage Process |
title_sort | inhibiting wee1 augments the antitumor efficacy of cisplatin in urothelial carcinoma by enhancing the dna damage process |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10252844/ https://www.ncbi.nlm.nih.gov/pubmed/37296592 http://dx.doi.org/10.3390/cells12111471 |
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