Development of a novel thymidylate synthase (TS) inhibitor capable of up-regulating P53 expression and inhibiting angiogenesis in NSCLC
Introduction: The development of a new type of Thymidylate synthase (TS) inhibitor that could inhibit cancer cells' proliferation and anti-angiogenesis is of great significance for cancer's clinical treatment. Objectives: Our research hopes to develop a TS inhibitor that is more effective...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-11-01
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| Series: | Journal of Advanced Research |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2090123220301673 |
| _version_ | 1819291305238331392 |
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| author | Xin-yang Li De-pu Wang Guo-qing Lu Kai-li Liu Ting-jian Zhang Shuai Li Kamara Mohamed O Wen-han Xue Xin-hua Qian Fan-hao Meng |
| author_facet | Xin-yang Li De-pu Wang Guo-qing Lu Kai-li Liu Ting-jian Zhang Shuai Li Kamara Mohamed O Wen-han Xue Xin-hua Qian Fan-hao Meng |
| author_sort | Xin-yang Li |
| collection | DOAJ |
| description | Introduction: The development of a new type of Thymidylate synthase (TS) inhibitor that could inhibit cancer cells' proliferation and anti-angiogenesis is of great significance for cancer's clinical treatment. Objectives: Our research hopes to develop a TS inhibitor that is more effective than the current first-line clinical treatment of pemetrexed (PTX) and provide a new reference for the clinical treatment of non-small cell lung cancer (NSCLC). Methods: We obtained a series of novel TS inhibitors by chemical synthesis. Moreover, TS assay and molecular docking to verify the target compound's inhibitory mode. Use MTT assay, colony-forming assay, flow cytometry, and western blot to verify the compound's inhibitory effect on cancer cell proliferation and its mechanism; and explore the compound’s effect on angiogenesis in vitro and in vivo. Further, explore the hit compound's anti-cancer ability through the xenograft tumor model and the orthotopic cancer murine model. Results: A series of N-(3-(5-phenyl-1,3,4-oxadiazole-2-yl) phenyl)-2,4-dihydroxypyrimidine-5-sulfamide derivatives were synthesized as TS inhibitors for the first time. All target compounds significantly inhibited hTS enzyme activity and demonstrated significant antitumor activity against five cancer cell lines. Notably, 7f had a high selectivity index (SI) and unique inhibitory effects on eight NSCLC cells. In-depth research indicated that 7f could induce apoptosis by the mitochondrial pathway in A549 and PC-9 cells through the upregulation of wild-type P53 protein expression. Additionally, 7f was shown to inhibit angiogenesis in vitro and in vivo. In vivo studies, compared to PTX, 7f significantly inhibited tumor growth in A549 cell xenografts and had a higher therapeutic index (TGI). Moreover, 7f could prolong the survival of the orthotopic lung cancer murine model more effectively than PTX. Conclusion: The anti-angiogenic effect of 7f provides a new reference for the development of TS inhibitors and the clinical treatment of NSCLC. |
| first_indexed | 2024-12-24T03:36:31Z |
| format | Article |
| id | doaj.art-4f83fc20ee194913a0ab24d90932a074 |
| institution | Directory Open Access Journal |
| issn | 2090-1232 |
| language | English |
| last_indexed | 2024-12-24T03:36:31Z |
| publishDate | 2020-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Advanced Research |
| spelling | doaj.art-4f83fc20ee194913a0ab24d90932a0742022-12-21T17:17:02ZengElsevierJournal of Advanced Research2090-12322020-11-012695110Development of a novel thymidylate synthase (TS) inhibitor capable of up-regulating P53 expression and inhibiting angiogenesis in NSCLCXin-yang Li0De-pu Wang1Guo-qing Lu2Kai-li Liu3Ting-jian Zhang4Shuai Li5Kamara Mohamed O6Wen-han Xue7Xin-hua Qian8Fan-hao Meng9School of Pharmacy, China Medical University, Shenyang 110122, China; Department of Pharmacy, Shengjing Hospital of China Medical University, Shenyang 110122, ChinaSchool of Pharmacy, China Medical University, Shenyang 110122, ChinaSchool of Pharmacy, China Medical University, Shenyang 110122, ChinaSchool of Pharmacy, China Medical University, Shenyang 110122, ChinaSchool of Pharmacy, China Medical University, Shenyang 110122, ChinaSchool of Pharmacy, China Medical University, Shenyang 110122, ChinaSchool of Pharmacy, China Medical University, Shenyang 110122, ChinaSchool of Pharmacy, China Medical University, Shenyang 110122, ChinaSchool of Pharmacy, China Medical University, Shenyang 110122, ChinaSchool of Pharmacy, China Medical University, Shenyang 110122, China; Corresponding author at: School of Pharmacy, China Medical University, Shenyang, 77 Puhe Road, 110122, China.Introduction: The development of a new type of Thymidylate synthase (TS) inhibitor that could inhibit cancer cells' proliferation and anti-angiogenesis is of great significance for cancer's clinical treatment. Objectives: Our research hopes to develop a TS inhibitor that is more effective than the current first-line clinical treatment of pemetrexed (PTX) and provide a new reference for the clinical treatment of non-small cell lung cancer (NSCLC). Methods: We obtained a series of novel TS inhibitors by chemical synthesis. Moreover, TS assay and molecular docking to verify the target compound's inhibitory mode. Use MTT assay, colony-forming assay, flow cytometry, and western blot to verify the compound's inhibitory effect on cancer cell proliferation and its mechanism; and explore the compound’s effect on angiogenesis in vitro and in vivo. Further, explore the hit compound's anti-cancer ability through the xenograft tumor model and the orthotopic cancer murine model. Results: A series of N-(3-(5-phenyl-1,3,4-oxadiazole-2-yl) phenyl)-2,4-dihydroxypyrimidine-5-sulfamide derivatives were synthesized as TS inhibitors for the first time. All target compounds significantly inhibited hTS enzyme activity and demonstrated significant antitumor activity against five cancer cell lines. Notably, 7f had a high selectivity index (SI) and unique inhibitory effects on eight NSCLC cells. In-depth research indicated that 7f could induce apoptosis by the mitochondrial pathway in A549 and PC-9 cells through the upregulation of wild-type P53 protein expression. Additionally, 7f was shown to inhibit angiogenesis in vitro and in vivo. In vivo studies, compared to PTX, 7f significantly inhibited tumor growth in A549 cell xenografts and had a higher therapeutic index (TGI). Moreover, 7f could prolong the survival of the orthotopic lung cancer murine model more effectively than PTX. Conclusion: The anti-angiogenic effect of 7f provides a new reference for the development of TS inhibitors and the clinical treatment of NSCLC.http://www.sciencedirect.com/science/article/pii/S2090123220301673 |
| spellingShingle | Xin-yang Li De-pu Wang Guo-qing Lu Kai-li Liu Ting-jian Zhang Shuai Li Kamara Mohamed O Wen-han Xue Xin-hua Qian Fan-hao Meng Development of a novel thymidylate synthase (TS) inhibitor capable of up-regulating P53 expression and inhibiting angiogenesis in NSCLC Journal of Advanced Research |
| title | Development of a novel thymidylate synthase (TS) inhibitor capable of up-regulating P53 expression and inhibiting angiogenesis in NSCLC |
| title_full | Development of a novel thymidylate synthase (TS) inhibitor capable of up-regulating P53 expression and inhibiting angiogenesis in NSCLC |
| title_fullStr | Development of a novel thymidylate synthase (TS) inhibitor capable of up-regulating P53 expression and inhibiting angiogenesis in NSCLC |
| title_full_unstemmed | Development of a novel thymidylate synthase (TS) inhibitor capable of up-regulating P53 expression and inhibiting angiogenesis in NSCLC |
| title_short | Development of a novel thymidylate synthase (TS) inhibitor capable of up-regulating P53 expression and inhibiting angiogenesis in NSCLC |
| title_sort | development of a novel thymidylate synthase ts inhibitor capable of up regulating p53 expression and inhibiting angiogenesis in nsclc |
| url | http://www.sciencedirect.com/science/article/pii/S2090123220301673 |
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