Dual action of pyrimidine derivatives: Targeting tamoxifen resistance in breast cancer
Introduction: Approximately 70 % of patients with breast cancer (BC) have estrogen receptor (ER)-positive tumors. Endocrine therapy is the principal treatment for these patients. Tamoxifen (TAM), a selective ER modulator, is commonly administered to premenopausal patients with ER-positive BC. Howeve...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-08-01
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| Series: | Translational Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523325001494 |
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| author | Jie Yuan Geng Wang Narasimha M. Beeraka Hua Zhang Qun Wang Danfeng Zhang Minghua Wang Akshay Ravish Arunachalam Chinnathambi Sulaiman Ali Alharbi Kanchugarakoppal S. Rangappa Vladimir N. Nikolenko Basappa Basappa Li Yang |
| author_facet | Jie Yuan Geng Wang Narasimha M. Beeraka Hua Zhang Qun Wang Danfeng Zhang Minghua Wang Akshay Ravish Arunachalam Chinnathambi Sulaiman Ali Alharbi Kanchugarakoppal S. Rangappa Vladimir N. Nikolenko Basappa Basappa Li Yang |
| author_sort | Jie Yuan |
| collection | DOAJ |
| description | Introduction: Approximately 70 % of patients with breast cancer (BC) have estrogen receptor (ER)-positive tumors. Endocrine therapy is the principal treatment for these patients. Tamoxifen (TAM), a selective ER modulator, is commonly administered to premenopausal patients with ER-positive BC. However, resistance to TAM poses a major clinical hurdle as TAM-resistant BC cells often show increased proliferation and motility as well as undergo epithelial-mesenchymal transition (EMT). Objective: Pyrimidine-based small molecules were reported as both nuclear factor kappa B (NF-κB) and Wnt/β-Catenin pathway regulators. This report discovered oxazine (TRX-01) linked pyrimidine as an inhibitor of NF-kB and triazole (TTP-5) linked pyrimidine as an inhibitor of Wnt/β-Catenin signaling in TAM-resistant MCF-7 breast cancer cells (MCF-7R). Methods: Colony formation, wound healing, and Transwell assays were conducted to assess cell migration and invasion. MTT assay was used to evaluate cytotoxic effects. Western blotting was used to determine the signaling mechanisms for NF-κB and EMT phenotypes. Xenograft models were utilized to examine the in vivo effectiveness of TRX-01. Results: TRX-01 reversed TAM resistance in MCF-7R cells, whereas TTP-5 reduced the motility of MCF-7R cells. Additionally, TRX-01 inhibited the activation of the NF-κB signaling pathway in MCF-7R cells, whereas TTP-5 inhibited the EMT-like phenotype of MCF-7R cells by impairing the activation of Wnt/β-catenin signaling. The differences in the functions of the two pyrimidine structures are attributed to their additional structures bearing both TRX-01 and TTP-05. Conclusion: Pyrimidine-based TRX-01 and TTP-5 lead structures are promising agents for inhibiting the progression of TAM-resistant breast cancer cells. These results support the need for additional comprehensive in vivo and clinical studies to confirm the efficacy and safety of these compounds. |
| format | Article |
| id | doaj-art-6eda9b7b505f4fe9a9661b1bb66aee6a |
| institution | DOAJ |
| issn | 1936-5233 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj-art-6eda9b7b505f4fe9a9661b1bb66aee6a2025-08-20T03:20:56ZengElsevierTranslational Oncology1936-52332025-08-015810241810.1016/j.tranon.2025.102418Dual action of pyrimidine derivatives: Targeting tamoxifen resistance in breast cancerJie Yuan0Geng Wang1Narasimha M. Beeraka2Hua Zhang3Qun Wang4Danfeng Zhang5Minghua Wang6Akshay Ravish7Arunachalam Chinnathambi8Sulaiman Ali Alharbi9Kanchugarakoppal S. Rangappa10Vladimir N. Nikolenko11Basappa Basappa12Li Yang13Department of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China; Department of General Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, ChinaDepartment of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, ChinaDepartment of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str., Moscow 119991, RussiaDepartment of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, ChinaDepartment of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, ChinaDepartment of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, ChinaDepartment of Breast, Thyroid and Vascular Surgery, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, ChinaLaboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore 570006, Karnataka, IndiaDepartment of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi ArabiaDepartment of Botany and Microbiology, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi ArabiaLaboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore 570006, Karnataka, IndiaDepartment of Human Anatomy and Histology, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), 8/2 Trubetskaya Str., Moscow 119991, RussiaLaboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore 570006, Karnataka, India; Corresponding author at: Laboratory of Chemical Biology, Department of Studies in Organic Chemistry, University of Mysore, Mysore, Karnataka 570006, India.Department of Clinical Laboratory Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China; Corresponding author at: Department of Clinical Laboratory Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei, China.Introduction: Approximately 70 % of patients with breast cancer (BC) have estrogen receptor (ER)-positive tumors. Endocrine therapy is the principal treatment for these patients. Tamoxifen (TAM), a selective ER modulator, is commonly administered to premenopausal patients with ER-positive BC. However, resistance to TAM poses a major clinical hurdle as TAM-resistant BC cells often show increased proliferation and motility as well as undergo epithelial-mesenchymal transition (EMT). Objective: Pyrimidine-based small molecules were reported as both nuclear factor kappa B (NF-κB) and Wnt/β-Catenin pathway regulators. This report discovered oxazine (TRX-01) linked pyrimidine as an inhibitor of NF-kB and triazole (TTP-5) linked pyrimidine as an inhibitor of Wnt/β-Catenin signaling in TAM-resistant MCF-7 breast cancer cells (MCF-7R). Methods: Colony formation, wound healing, and Transwell assays were conducted to assess cell migration and invasion. MTT assay was used to evaluate cytotoxic effects. Western blotting was used to determine the signaling mechanisms for NF-κB and EMT phenotypes. Xenograft models were utilized to examine the in vivo effectiveness of TRX-01. Results: TRX-01 reversed TAM resistance in MCF-7R cells, whereas TTP-5 reduced the motility of MCF-7R cells. Additionally, TRX-01 inhibited the activation of the NF-κB signaling pathway in MCF-7R cells, whereas TTP-5 inhibited the EMT-like phenotype of MCF-7R cells by impairing the activation of Wnt/β-catenin signaling. The differences in the functions of the two pyrimidine structures are attributed to their additional structures bearing both TRX-01 and TTP-05. Conclusion: Pyrimidine-based TRX-01 and TTP-5 lead structures are promising agents for inhibiting the progression of TAM-resistant breast cancer cells. These results support the need for additional comprehensive in vivo and clinical studies to confirm the efficacy and safety of these compounds.http://www.sciencedirect.com/science/article/pii/S1936523325001494Breast cancerTAM resistanceEMTWnt/β-cateninNF-κBXenograft model |
| spellingShingle | Jie Yuan Geng Wang Narasimha M. Beeraka Hua Zhang Qun Wang Danfeng Zhang Minghua Wang Akshay Ravish Arunachalam Chinnathambi Sulaiman Ali Alharbi Kanchugarakoppal S. Rangappa Vladimir N. Nikolenko Basappa Basappa Li Yang Dual action of pyrimidine derivatives: Targeting tamoxifen resistance in breast cancer Translational Oncology Breast cancer TAM resistance EMT Wnt/β-catenin NF-κB Xenograft model |
| title | Dual action of pyrimidine derivatives: Targeting tamoxifen resistance in breast cancer |
| title_full | Dual action of pyrimidine derivatives: Targeting tamoxifen resistance in breast cancer |
| title_fullStr | Dual action of pyrimidine derivatives: Targeting tamoxifen resistance in breast cancer |
| title_full_unstemmed | Dual action of pyrimidine derivatives: Targeting tamoxifen resistance in breast cancer |
| title_short | Dual action of pyrimidine derivatives: Targeting tamoxifen resistance in breast cancer |
| title_sort | dual action of pyrimidine derivatives targeting tamoxifen resistance in breast cancer |
| topic | Breast cancer TAM resistance EMT Wnt/β-catenin NF-κB Xenograft model |
| url | http://www.sciencedirect.com/science/article/pii/S1936523325001494 |
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