Celecoxib-Induced Modulation of Colon Cancer CD133 Expression Occurs through AKT Inhibition and Is Monitored by 89Zr Immuno-PET
We developed an immuno-PET technique that monitors modulation of tumor CD133 expression, which is required for the success of CD133-targeted therapies. Methods. Anti-CD133 antibodies were subjected to sulfhydryl moiety-specific 89Zr conjugation. 89Zr-CD133 IgG was evaluated for specific activity and...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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SAGE Publications
2022-01-01
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| Series: | Molecular Imaging |
| Online Access: | http://dx.doi.org/10.1155/2022/4906934 |
| _version_ | 1797288125661184000 |
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| author | Kyung-Ho Jung Jin Hee Lee Mina Kim Eun Ji Lee Young Seok Cho Kyung-Han Lee |
| author_facet | Kyung-Ho Jung Jin Hee Lee Mina Kim Eun Ji Lee Young Seok Cho Kyung-Han Lee |
| author_sort | Kyung-Ho Jung |
| collection | DOAJ |
| description | We developed an immuno-PET technique that monitors modulation of tumor CD133 expression, which is required for the success of CD133-targeted therapies. Methods. Anti-CD133 antibodies were subjected to sulfhydryl moiety-specific 89Zr conjugation. 89Zr-CD133 IgG was evaluated for specific activity and radiolabel stability. Colon cancer cells underwent binding assays and Western blotting. Biodistribution and PET studies were performed in mice. Results. 89Zr-CD133 IgG showed excellent target specificity with 97.2±0.7% blocking of HT29 cell binding by an excess antibody. Intravenous 89Zr-CD133 IgG followed biexponential blood clearance and showed CD133-specific uptake in HT29 tumors. 89Zr-CD133 IgG PET/CT and biodistribution studies confirmed high HT29 tumor uptake with lower activities in the blood and normal organs. In HT29 cells, celecoxib dose-dependently decreased CD133 expression and 89Zr-CD133 IgG binding that reached 19.9±2.1% (P<0.005) and 50.3±10.9% (P<0.001) of baseline levels by 50 μM, respectively. Celecoxib treatment of mice significantly suppressed tumor CD133 expression to 67.5±7.8% of controls (P<0.005) and reduced tumor 89Zr-CD133 IgG uptake from 15.5±1.4% at baseline to 12.3±2.0%ID/g (P<0.01). Celecoxib-induced CD133 reduction in HT29 cells and tumors was associated with substantial suppression of AKT activation. There were also reduced HIF-1α accumulation and IκBα/NFκB phosphorylation. Conclusion. 89Zr-CD133 IgG PET provides high-contrast tumor imaging and monitors celecoxib treatment-induced modulation of tumor CD133 expression, which was found to occur through AKT inhibition. This technique may thus be useful for screening drugs that can effectively suppress colon cancer stem cells. |
| first_indexed | 2024-03-07T18:44:47Z |
| format | Article |
| id | doaj.art-c1bd544dfa994b10912ff4d7b8517129 |
| institution | Directory Open Access Journal |
| issn | 1536-0121 |
| language | English |
| last_indexed | 2024-03-07T18:44:47Z |
| publishDate | 2022-01-01 |
| publisher | SAGE Publications |
| record_format | Article |
| series | Molecular Imaging |
| spelling | doaj.art-c1bd544dfa994b10912ff4d7b85171292024-03-02T03:06:34ZengSAGE PublicationsMolecular Imaging1536-01212022-01-01202210.1155/2022/4906934Celecoxib-Induced Modulation of Colon Cancer CD133 Expression Occurs through AKT Inhibition and Is Monitored by 89Zr Immuno-PETKyung-Ho Jung0Jin Hee Lee1Mina Kim2Eun Ji Lee3Young Seok Cho4Kyung-Han Lee5Department of Nuclear MedicineDepartment of Nuclear MedicineDepartment of Nuclear MedicineDepartment of Nuclear MedicineDepartment of Nuclear MedicineDepartment of Nuclear MedicineWe developed an immuno-PET technique that monitors modulation of tumor CD133 expression, which is required for the success of CD133-targeted therapies. Methods. Anti-CD133 antibodies were subjected to sulfhydryl moiety-specific 89Zr conjugation. 89Zr-CD133 IgG was evaluated for specific activity and radiolabel stability. Colon cancer cells underwent binding assays and Western blotting. Biodistribution and PET studies were performed in mice. Results. 89Zr-CD133 IgG showed excellent target specificity with 97.2±0.7% blocking of HT29 cell binding by an excess antibody. Intravenous 89Zr-CD133 IgG followed biexponential blood clearance and showed CD133-specific uptake in HT29 tumors. 89Zr-CD133 IgG PET/CT and biodistribution studies confirmed high HT29 tumor uptake with lower activities in the blood and normal organs. In HT29 cells, celecoxib dose-dependently decreased CD133 expression and 89Zr-CD133 IgG binding that reached 19.9±2.1% (P<0.005) and 50.3±10.9% (P<0.001) of baseline levels by 50 μM, respectively. Celecoxib treatment of mice significantly suppressed tumor CD133 expression to 67.5±7.8% of controls (P<0.005) and reduced tumor 89Zr-CD133 IgG uptake from 15.5±1.4% at baseline to 12.3±2.0%ID/g (P<0.01). Celecoxib-induced CD133 reduction in HT29 cells and tumors was associated with substantial suppression of AKT activation. There were also reduced HIF-1α accumulation and IκBα/NFκB phosphorylation. Conclusion. 89Zr-CD133 IgG PET provides high-contrast tumor imaging and monitors celecoxib treatment-induced modulation of tumor CD133 expression, which was found to occur through AKT inhibition. This technique may thus be useful for screening drugs that can effectively suppress colon cancer stem cells.http://dx.doi.org/10.1155/2022/4906934 |
| spellingShingle | Kyung-Ho Jung Jin Hee Lee Mina Kim Eun Ji Lee Young Seok Cho Kyung-Han Lee Celecoxib-Induced Modulation of Colon Cancer CD133 Expression Occurs through AKT Inhibition and Is Monitored by 89Zr Immuno-PET Molecular Imaging |
| title | Celecoxib-Induced Modulation of Colon Cancer CD133 Expression Occurs through AKT Inhibition and Is Monitored by 89Zr Immuno-PET |
| title_full | Celecoxib-Induced Modulation of Colon Cancer CD133 Expression Occurs through AKT Inhibition and Is Monitored by 89Zr Immuno-PET |
| title_fullStr | Celecoxib-Induced Modulation of Colon Cancer CD133 Expression Occurs through AKT Inhibition and Is Monitored by 89Zr Immuno-PET |
| title_full_unstemmed | Celecoxib-Induced Modulation of Colon Cancer CD133 Expression Occurs through AKT Inhibition and Is Monitored by 89Zr Immuno-PET |
| title_short | Celecoxib-Induced Modulation of Colon Cancer CD133 Expression Occurs through AKT Inhibition and Is Monitored by 89Zr Immuno-PET |
| title_sort | celecoxib induced modulation of colon cancer cd133 expression occurs through akt inhibition and is monitored by 89zr immuno pet |
| url | http://dx.doi.org/10.1155/2022/4906934 |
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