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 <i>TP53</i> 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 <i>TP53</i>-muta...
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MDPI AG
2023-05-01
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| Online Access: | https://www.mdpi.com/2073-4409/12/11/1471 |
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| author | Yu-Li Su Ling-Yi Xiao Shih-Yu Huang Chia-Che Wu Li-Chung Chang Yi-Hua Chen Hao-Lun Luo Chun-Chieh Huang Ting-Ting Liu Jei-Ming Peng |
| author_facet | Yu-Li Su Ling-Yi Xiao Shih-Yu Huang Chia-Che Wu Li-Chung Chang Yi-Hua Chen Hao-Lun Luo Chun-Chieh Huang Ting-Ting Liu Jei-Ming Peng |
| author_sort | Yu-Li Su |
| collection | DOAJ |
| description | Urothelial carcinoma (UC) is characterized by a high incidence of <i>TP53</i> 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 <i>TP53</i>-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 <i>TP53</i> 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. |
| first_indexed | 2024-03-11T03:10:34Z |
| format | Article |
| id | doaj.art-6a121f4ddd694b90a5aae424155b7be5 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T03:10:34Z |
| publishDate | 2023-05-01 |
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| series | Cells |
| spelling | doaj.art-6a121f4ddd694b90a5aae424155b7be52023-11-18T07:40:32ZengMDPI AGCells2073-44092023-05-011211147110.3390/cells12111471Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage ProcessYu-Li Su0Ling-Yi Xiao1Shih-Yu Huang2Chia-Che Wu3Li-Chung Chang4Yi-Hua Chen5Hao-Lun Luo6Chun-Chieh Huang7Ting-Ting Liu8Jei-Ming Peng9Division of Hematology Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung 83301, TaiwanDivision of Hematology Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung 83301, TaiwanDivision of Hematology Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung 83301, TaiwanDivision of Hematology Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung 83301, TaiwanDivision of Hematology Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung 83301, TaiwanDivision of Hematology Oncology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung 83301, TaiwanDepartment of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung 83301, TaiwanDepartment of Radiation Oncology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung 83301, TaiwanDepartment of Pathology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University, College of Medicine, Kaohsiung 83301, TaiwanInstitute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, TaiwanUrothelial carcinoma (UC) is characterized by a high incidence of <i>TP53</i> 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 <i>TP53</i>-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 <i>TP53</i> 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.https://www.mdpi.com/2073-4409/12/11/1471WEE1urothelial carcinomachemotherapyDNA damagecell cycle<i>TP53</i> mutation |
| spellingShingle | Yu-Li Su Ling-Yi Xiao Shih-Yu Huang Chia-Che Wu Li-Chung Chang Yi-Hua Chen Hao-Lun Luo Chun-Chieh Huang Ting-Ting Liu Jei-Ming Peng Inhibiting WEE1 Augments the Antitumor Efficacy of Cisplatin in Urothelial Carcinoma by Enhancing the DNA Damage Process Cells WEE1 urothelial carcinoma chemotherapy DNA damage cell cycle <i>TP53</i> mutation |
| 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 | WEE1 urothelial carcinoma chemotherapy DNA damage cell cycle <i>TP53</i> mutation |
| url | https://www.mdpi.com/2073-4409/12/11/1471 |
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