Unveiling the Anti-Angiogenic Potential of Small-Molecule (Kinase) Inhibitors for Application in Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation leading to joint damage and systemic complications. Angiogenesis promotes inflammation and contributes to RA progression. This study evaluated potential anti-angiogenic effects of several compounds including smal...
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2025-01-01
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| author | Fatemeh Khodadust Eva M. L. Philippon Maarten M. Steinz Jan Piet van Hamburg Johan van Meerloo Judy R. van Beijnum Gerrit Jansen Sander W. Tas Conny J. van der Laken |
| author_facet | Fatemeh Khodadust Eva M. L. Philippon Maarten M. Steinz Jan Piet van Hamburg Johan van Meerloo Judy R. van Beijnum Gerrit Jansen Sander W. Tas Conny J. van der Laken |
| author_sort | Fatemeh Khodadust |
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| description | Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation leading to joint damage and systemic complications. Angiogenesis promotes inflammation and contributes to RA progression. This study evaluated potential anti-angiogenic effects of several compounds including small-molecule kinase inhibitors, such as sunitinib (pan-kinase inhibitor), tofacitinib (JAK-inhibitor), NIKi (NF-κB-inducing kinase inhibitor), and the integrin-targeting peptide fluciclatide, using a scratch assay and 3D spheroid-based models of angiogenesis. For all drugs tested in the low micromolar range (1–25 μM), sunitinib (as positive anti-angiogenetic control) showed marked inhibition of endothelial cell (EC) migration and sprouting, effectively reducing both scratch closure and sprout formation. Tofacitinib exhibited marginal effectiveness in the scratch assay, but performed better in the 3D models (55% inhibition), whereas NIKi showed around 50% anti-angiogenic effects in both models. Fluciclatide changed EC morphology rather than migration, and only when stimulated with synovial fluid in spheroid model did it show inhibitory effects (at ≥2.5 µM), with none below this dosage. These results highlight the potential of NIKi and tofacitinib for angiogenesis inhibition and of fluciclatide for safe diagnostic targeting of microdose in RA, as well as the need for advanced screening models that mimic RA’s complex inflammatory pro-angiogenic environment. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-8e4767acdf474081af07393acce6c5b22025-01-24T13:26:41ZengMDPI AGCells2073-44092025-01-0114210210.3390/cells14020102Unveiling the Anti-Angiogenic Potential of Small-Molecule (Kinase) Inhibitors for Application in Rheumatoid ArthritisFatemeh Khodadust0Eva M. L. Philippon1Maarten M. Steinz2Jan Piet van Hamburg3Johan van Meerloo4Judy R. van Beijnum5Gerrit Jansen6Sander W. Tas7Conny J. van der Laken8Department of Rheumatology & Clinical Immunology, Amsterdam UMC, Meibergdreef 9, 1105 AZ Amsterdam, The NetherlandsDepartment of Rheumatology & Clinical Immunology, Amsterdam UMC, Meibergdreef 9, 1105 AZ Amsterdam, The NetherlandsDepartment of Rheumatology & Clinical Immunology, Amsterdam UMC, Meibergdreef 9, 1105 AZ Amsterdam, The NetherlandsDepartment of Rheumatology & Clinical Immunology, Amsterdam UMC, Meibergdreef 9, 1105 AZ Amsterdam, The NetherlandsDepartment of Hematology, Amsterdam UMC, De Boelelaan 1117, 1081 HV Amsterdam, The NetherlandsAngiogenesis Laboratory, Department of Medical Oncology, Amsterdam UMC, De Boelelaan 1117, 1081 HV Amsterdam, The NetherlandsDepartment of Rheumatology & Clinical Immunology, Amsterdam UMC, Meibergdreef 9, 1105 AZ Amsterdam, The NetherlandsDepartment of Rheumatology & Clinical Immunology, Amsterdam UMC, Meibergdreef 9, 1105 AZ Amsterdam, The NetherlandsDepartment of Rheumatology & Clinical Immunology, Amsterdam UMC, Meibergdreef 9, 1105 AZ Amsterdam, The NetherlandsRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation leading to joint damage and systemic complications. Angiogenesis promotes inflammation and contributes to RA progression. This study evaluated potential anti-angiogenic effects of several compounds including small-molecule kinase inhibitors, such as sunitinib (pan-kinase inhibitor), tofacitinib (JAK-inhibitor), NIKi (NF-κB-inducing kinase inhibitor), and the integrin-targeting peptide fluciclatide, using a scratch assay and 3D spheroid-based models of angiogenesis. For all drugs tested in the low micromolar range (1–25 μM), sunitinib (as positive anti-angiogenetic control) showed marked inhibition of endothelial cell (EC) migration and sprouting, effectively reducing both scratch closure and sprout formation. Tofacitinib exhibited marginal effectiveness in the scratch assay, but performed better in the 3D models (55% inhibition), whereas NIKi showed around 50% anti-angiogenic effects in both models. Fluciclatide changed EC morphology rather than migration, and only when stimulated with synovial fluid in spheroid model did it show inhibitory effects (at ≥2.5 µM), with none below this dosage. These results highlight the potential of NIKi and tofacitinib for angiogenesis inhibition and of fluciclatide for safe diagnostic targeting of microdose in RA, as well as the need for advanced screening models that mimic RA’s complex inflammatory pro-angiogenic environment.https://www.mdpi.com/2073-4409/14/2/102angiogenesisrheumatoid arthritis3D modelspheroidsmall-molecule inhibitorsendothelial cells |
| spellingShingle | Fatemeh Khodadust Eva M. L. Philippon Maarten M. Steinz Jan Piet van Hamburg Johan van Meerloo Judy R. van Beijnum Gerrit Jansen Sander W. Tas Conny J. van der Laken Unveiling the Anti-Angiogenic Potential of Small-Molecule (Kinase) Inhibitors for Application in Rheumatoid Arthritis Cells angiogenesis rheumatoid arthritis 3D model spheroid small-molecule inhibitors endothelial cells |
| title | Unveiling the Anti-Angiogenic Potential of Small-Molecule (Kinase) Inhibitors for Application in Rheumatoid Arthritis |
| title_full | Unveiling the Anti-Angiogenic Potential of Small-Molecule (Kinase) Inhibitors for Application in Rheumatoid Arthritis |
| title_fullStr | Unveiling the Anti-Angiogenic Potential of Small-Molecule (Kinase) Inhibitors for Application in Rheumatoid Arthritis |
| title_full_unstemmed | Unveiling the Anti-Angiogenic Potential of Small-Molecule (Kinase) Inhibitors for Application in Rheumatoid Arthritis |
| title_short | Unveiling the Anti-Angiogenic Potential of Small-Molecule (Kinase) Inhibitors for Application in Rheumatoid Arthritis |
| title_sort | unveiling the anti angiogenic potential of small molecule kinase inhibitors for application in rheumatoid arthritis |
| topic | angiogenesis rheumatoid arthritis 3D model spheroid small-molecule inhibitors endothelial cells |
| url | https://www.mdpi.com/2073-4409/14/2/102 |
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