Development of a novel thymidylate synthase (TS) inhibitor capable of up-regulating P53 expression and inhibiting angiogenesis in NSCLC
| Autor: | Wen-han Xue, Xin-yang Li, De-pu Wang, Kamara Mohamed O, Guo-qing Lu, Ting-jian Zhang, Fan-hao Meng, Shuai Li, Kai-li Liu, Xin-hua Qian |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Angiogenesis Thymidylate synthase Article 03 medical and health sciences 0302 clinical medicine In vivo medicine MTT assay lcsh:Science (General) ComputingMethodologies_COMPUTERGRAPHICS A549 cell lcsh:R5-920 Multidisciplinary biology Chemistry Cancer medicine.disease 030104 developmental biology Apoptosis 030220 oncology & carcinogenesis Cancer cell Cancer research biology.protein lcsh:Medicine (General) lcsh:Q1-390 |
| Zdroj: | Journal of Advanced Research, Vol 26, Iss, Pp 95-110 (2020) Journal of Advanced Research |
| ISSN: | 2090-1232 |
| Popis: | Graphical abstract 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. |
| Databáze: | OpenAIRE |
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