Anticancer effect of the antirheumatic drug leflunomide on oral squamous cell carcinoma by the inhibition of tumor angiogenesis
Abstract Objectives Leflunomide (LEF) is a conventional synthetic disease-modifying antirheumatic drug and suppresses T-cell proliferation and activity by inhibiting pyrimidine synthesis using dihydroorotase dehydrogenase (DHODH); however, several studies have demonstrated that LEF possesses antican...
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| Format: | Article |
| Language: | English |
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Springer
2025-01-01
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| Series: | Discover Oncology |
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| Online Access: | https://doi.org/10.1007/s12672-025-01763-5 |
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| author | Chieko Niwata Takayuki Nakagawa Takako Naruse Miyuki Sakuma Nao Yamakado Misaki Akagi Shigehiro Ono Kei Tobiume Jing Gao Eijiro Jimi Kouji Ohta Tomonao Aikawa |
| author_facet | Chieko Niwata Takayuki Nakagawa Takako Naruse Miyuki Sakuma Nao Yamakado Misaki Akagi Shigehiro Ono Kei Tobiume Jing Gao Eijiro Jimi Kouji Ohta Tomonao Aikawa |
| author_sort | Chieko Niwata |
| collection | DOAJ |
| description | Abstract Objectives Leflunomide (LEF) is a conventional synthetic disease-modifying antirheumatic drug and suppresses T-cell proliferation and activity by inhibiting pyrimidine synthesis using dihydroorotase dehydrogenase (DHODH); however, several studies have demonstrated that LEF possesses anticancer and antiangiogenic effects in some malignant tumors. Therefore, we investigated the anticancer and antiangiogenic effects of LEF on oral squamous cell carcinoma (OSCC). Methods To evaluate the inhibitory effect of LEF on OSCC, cell proliferation and wound-healing assays using human OSCC cell lines were performed. The DHODH inhibitory effect of LEF was evaluated by Western blot. To assess the suppression of pyrimidine biosynthesis induced by LEF on OSCC, cell proliferation assays with or without uridine supplementation were performed. The antiangiogenic effect of LEF was evaluated by in vitro tube formation assay using immortalized human umbilical vein endothelial cells, which were electroporatically transfected with hTERT. The tumor-suppressive effect of LEF in vivo was examined in both immunodeficient and syngeneic mice by implanting mouse OSCC cells. Tumor vascularization was evaluated by immunohistochemistry of the tumor extracted from syngeneic mice. Results LEF dose-dependently inhibited OSCC proliferation and migration. LEF significantly inhibited DHODH expression, and uridine supplementation rescued the inhibitory effect of LEF. LEF dose-dependently suppressed endothelial tube formation. In the animal study, LEF significantly suppressed tumor growth in both immunodeficient and syngeneic mice. Histologically, LEF decreased DHODH expression and tumor vascularization. Conclusion LEF is a potent anticancer agent with antiangiogenic effects on OSCC and might be clinically applicable to OSCC by drug repositioning. |
| format | Article |
| id | doaj-art-038a5f4cf9ea4be5bdce7f17a2aad83a |
| institution | Kabale University |
| issn | 2730-6011 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Springer |
| record_format | Article |
| series | Discover Oncology |
| spelling | doaj-art-038a5f4cf9ea4be5bdce7f17a2aad83a2025-01-19T12:29:13ZengSpringerDiscover Oncology2730-60112025-01-0116111310.1007/s12672-025-01763-5Anticancer effect of the antirheumatic drug leflunomide on oral squamous cell carcinoma by the inhibition of tumor angiogenesisChieko Niwata0Takayuki Nakagawa1Takako Naruse2Miyuki Sakuma3Nao Yamakado4Misaki Akagi5Shigehiro Ono6Kei Tobiume7Jing Gao8Eijiro Jimi9Kouji Ohta10Tomonao Aikawa11Department of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityDepartment of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityDepartment of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityDepartment of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityDepartment of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityDepartment of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityDepartment of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityGraduate School of Biomedical & Health Sciences (Dentistry & Oral Health Sciences), Hiroshima UniversityLaboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu UniversityLaboratory of Molecular and Cellular Biochemistry, Faculty of Dental Science, Kyushu UniversityDepartment of Public Oral Health, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityDepartment of Oral and Maxillofacial Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima UniversityAbstract Objectives Leflunomide (LEF) is a conventional synthetic disease-modifying antirheumatic drug and suppresses T-cell proliferation and activity by inhibiting pyrimidine synthesis using dihydroorotase dehydrogenase (DHODH); however, several studies have demonstrated that LEF possesses anticancer and antiangiogenic effects in some malignant tumors. Therefore, we investigated the anticancer and antiangiogenic effects of LEF on oral squamous cell carcinoma (OSCC). Methods To evaluate the inhibitory effect of LEF on OSCC, cell proliferation and wound-healing assays using human OSCC cell lines were performed. The DHODH inhibitory effect of LEF was evaluated by Western blot. To assess the suppression of pyrimidine biosynthesis induced by LEF on OSCC, cell proliferation assays with or without uridine supplementation were performed. The antiangiogenic effect of LEF was evaluated by in vitro tube formation assay using immortalized human umbilical vein endothelial cells, which were electroporatically transfected with hTERT. The tumor-suppressive effect of LEF in vivo was examined in both immunodeficient and syngeneic mice by implanting mouse OSCC cells. Tumor vascularization was evaluated by immunohistochemistry of the tumor extracted from syngeneic mice. Results LEF dose-dependently inhibited OSCC proliferation and migration. LEF significantly inhibited DHODH expression, and uridine supplementation rescued the inhibitory effect of LEF. LEF dose-dependently suppressed endothelial tube formation. In the animal study, LEF significantly suppressed tumor growth in both immunodeficient and syngeneic mice. Histologically, LEF decreased DHODH expression and tumor vascularization. Conclusion LEF is a potent anticancer agent with antiangiogenic effects on OSCC and might be clinically applicable to OSCC by drug repositioning.https://doi.org/10.1007/s12672-025-01763-5LeflunomideOral squamous cell carcinomaSyngeneic miceDrug repositioning |
| spellingShingle | Chieko Niwata Takayuki Nakagawa Takako Naruse Miyuki Sakuma Nao Yamakado Misaki Akagi Shigehiro Ono Kei Tobiume Jing Gao Eijiro Jimi Kouji Ohta Tomonao Aikawa Anticancer effect of the antirheumatic drug leflunomide on oral squamous cell carcinoma by the inhibition of tumor angiogenesis Discover Oncology Leflunomide Oral squamous cell carcinoma Syngeneic mice Drug repositioning |
| title | Anticancer effect of the antirheumatic drug leflunomide on oral squamous cell carcinoma by the inhibition of tumor angiogenesis |
| title_full | Anticancer effect of the antirheumatic drug leflunomide on oral squamous cell carcinoma by the inhibition of tumor angiogenesis |
| title_fullStr | Anticancer effect of the antirheumatic drug leflunomide on oral squamous cell carcinoma by the inhibition of tumor angiogenesis |
| title_full_unstemmed | Anticancer effect of the antirheumatic drug leflunomide on oral squamous cell carcinoma by the inhibition of tumor angiogenesis |
| title_short | Anticancer effect of the antirheumatic drug leflunomide on oral squamous cell carcinoma by the inhibition of tumor angiogenesis |
| title_sort | anticancer effect of the antirheumatic drug leflunomide on oral squamous cell carcinoma by the inhibition of tumor angiogenesis |
| topic | Leflunomide Oral squamous cell carcinoma Syngeneic mice Drug repositioning |
| url | https://doi.org/10.1007/s12672-025-01763-5 |
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