VP3.15, a dual GSK-3β/PDE7 inhibitor, reduces glioblastoma tumor growth though changes in the tumor microenvironment in a PTEN wild-type context
Glioblastoma (GB) is an incurable cancer of the brain, and there is an urgent need to identify effective treatments. This may be achieved by either identifying new molecules or through drug repurposing. To ascertain the therapeutic potential of known GSK-3β and/or PDE7 inhibitors in GB, a drug scree...
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Elsevier
2025-07-01
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| Series: | Neurotherapeutics |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S1878747925000546 |
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| author | Maria Castello-Pons Maria A. Ramirez-Gonzalez Patricia Iglesias-Hernández Nermina Logo Lendo Carlos Rodriguez-Martín Laura Quiralte Juan-Manuel Sepúlveda-Sánchez Olaya de Dios Carmen Gil Ana Martínez Pilar Sánchez-Gómez Sergio Casas-Tinto |
| author_facet | Maria Castello-Pons Maria A. Ramirez-Gonzalez Patricia Iglesias-Hernández Nermina Logo Lendo Carlos Rodriguez-Martín Laura Quiralte Juan-Manuel Sepúlveda-Sánchez Olaya de Dios Carmen Gil Ana Martínez Pilar Sánchez-Gómez Sergio Casas-Tinto |
| author_sort | Maria Castello-Pons |
| collection | DOAJ |
| description | Glioblastoma (GB) is an incurable cancer of the brain, and there is an urgent need to identify effective treatments. This may be achieved by either identifying new molecules or through drug repurposing. To ascertain the therapeutic potential of known GSK-3β and/or PDE7 inhibitors in GB, a drug screening was conducted using a Drosophila melanogaster glioma model. VP3.15, a dual inhibitor with anti-inflammatory and neuroprotective roles in multiple sclerosis, was selected for further investigation. VP3.15 demonstrated robust anti-tumor efficacy against a panel of human and mouse GB cells; however, its capacity to inhibit orthotopic growth was only observed in a wild-type PTEN cell line. The in vivo dependence on PTEN was further suggested with the results in fly gliomas. The analysis of the VP3.15-treated tissues revealed a notable reduction in the number of myeloid cells and in the degree of vascularization. Mechanistic studies indicate that VP3.15 diminishes the production of GAL9, a key molecule that stimulates pro-angiogenic macrophages. Our findings substantiate the pro-tumoral function of GSK-3β, which might depend on the PTEN genetic status. Furthermore, we have delineated the therapeutic potential of VP3.15, which acts through the inhibition of the supportive role of the GB microenvironment. This molecule could be safely and effectively utilized after PTEN characterization in GB patients. |
| format | Article |
| id | doaj-art-6737ccc35fe0418b8af414ba7b3e234a |
| institution | Kabale University |
| issn | 1878-7479 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurotherapeutics |
| spelling | doaj-art-6737ccc35fe0418b8af414ba7b3e234a2025-08-20T03:36:39ZengElsevierNeurotherapeutics1878-74792025-07-01224e0057610.1016/j.neurot.2025.e00576VP3.15, a dual GSK-3β/PDE7 inhibitor, reduces glioblastoma tumor growth though changes in the tumor microenvironment in a PTEN wild-type contextMaria Castello-Pons0Maria A. Ramirez-Gonzalez1Patricia Iglesias-Hernández2Nermina Logo Lendo3Carlos Rodriguez-Martín4Laura Quiralte5Juan-Manuel Sepúlveda-Sánchez6Olaya de Dios7Carmen Gil8Ana Martínez9Pilar Sánchez-Gómez10Sergio Casas-Tinto11Neurooncology Unit, Instituto de Salud Carlos III-UFIEC, Madrid, Spain; PhD Programme on Biomedical Sciences and Public Health, Universidad Nacional de Educación a Distancia, UNED-ISCIII 28040 Madrid, SpainNeurooncology Unit, Instituto de Salud Carlos III-UFIEC, Madrid, SpainNeurooncology Unit, Instituto de Salud Carlos III-UFIEC, Madrid, Spain; PhD Programme on Biomedical Sciences and Public Health, Universidad Nacional de Educación a Distancia, UNED-ISCIII 28040 Madrid, SpainInstituto Cajal-CSIC, Avda. Doctor Arce 37, 28002 Madrid, SpainDrosophila Models of Human Disease Unit, Instituto de Salud Carlos III-IIER, Madrid, SpainInstituto Cajal-CSIC, Avda. Doctor Arce 37, 28002 Madrid, SpainInstituto de Investigaciones Biomédicas I+12, Hospital 12 de Octubre, Madrid, SpainNeurooncology Unit, Instituto de Salud Carlos III-UFIEC, Madrid, SpainCentro de Investigaciones Biológicas Margarita Salas-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, (CIBERNED), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, SpainCentro de Investigaciones Biológicas Margarita Salas-CSIC, Ramiro de Maeztu 9, 28040 Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas, (CIBERNED), Instituto de Salud Carlos III, Av. Monforte de Lemos, 3-5, 28029 Madrid, SpainNeurooncology Unit, Instituto de Salud Carlos III-UFIEC, Madrid, Spain; Corresponding authors.Instituto Cajal-CSIC, Avda. Doctor Arce 37, 28002 Madrid, Spain; Drosophila Models of Human Disease Unit, Instituto de Salud Carlos III-IIER, Madrid, Spain; Corresponding authors.Glioblastoma (GB) is an incurable cancer of the brain, and there is an urgent need to identify effective treatments. This may be achieved by either identifying new molecules or through drug repurposing. To ascertain the therapeutic potential of known GSK-3β and/or PDE7 inhibitors in GB, a drug screening was conducted using a Drosophila melanogaster glioma model. VP3.15, a dual inhibitor with anti-inflammatory and neuroprotective roles in multiple sclerosis, was selected for further investigation. VP3.15 demonstrated robust anti-tumor efficacy against a panel of human and mouse GB cells; however, its capacity to inhibit orthotopic growth was only observed in a wild-type PTEN cell line. The in vivo dependence on PTEN was further suggested with the results in fly gliomas. The analysis of the VP3.15-treated tissues revealed a notable reduction in the number of myeloid cells and in the degree of vascularization. Mechanistic studies indicate that VP3.15 diminishes the production of GAL9, a key molecule that stimulates pro-angiogenic macrophages. Our findings substantiate the pro-tumoral function of GSK-3β, which might depend on the PTEN genetic status. Furthermore, we have delineated the therapeutic potential of VP3.15, which acts through the inhibition of the supportive role of the GB microenvironment. This molecule could be safely and effectively utilized after PTEN characterization in GB patients.http://www.sciencedirect.com/science/article/pii/S1878747925000546GSK-3βPDE7APTENGAL9Tumor microenvironmentMacrophages |
| spellingShingle | Maria Castello-Pons Maria A. Ramirez-Gonzalez Patricia Iglesias-Hernández Nermina Logo Lendo Carlos Rodriguez-Martín Laura Quiralte Juan-Manuel Sepúlveda-Sánchez Olaya de Dios Carmen Gil Ana Martínez Pilar Sánchez-Gómez Sergio Casas-Tinto VP3.15, a dual GSK-3β/PDE7 inhibitor, reduces glioblastoma tumor growth though changes in the tumor microenvironment in a PTEN wild-type context Neurotherapeutics GSK-3β PDE7A PTEN GAL9 Tumor microenvironment Macrophages |
| title | VP3.15, a dual GSK-3β/PDE7 inhibitor, reduces glioblastoma tumor growth though changes in the tumor microenvironment in a PTEN wild-type context |
| title_full | VP3.15, a dual GSK-3β/PDE7 inhibitor, reduces glioblastoma tumor growth though changes in the tumor microenvironment in a PTEN wild-type context |
| title_fullStr | VP3.15, a dual GSK-3β/PDE7 inhibitor, reduces glioblastoma tumor growth though changes in the tumor microenvironment in a PTEN wild-type context |
| title_full_unstemmed | VP3.15, a dual GSK-3β/PDE7 inhibitor, reduces glioblastoma tumor growth though changes in the tumor microenvironment in a PTEN wild-type context |
| title_short | VP3.15, a dual GSK-3β/PDE7 inhibitor, reduces glioblastoma tumor growth though changes in the tumor microenvironment in a PTEN wild-type context |
| title_sort | vp3 15 a dual gsk 3β pde7 inhibitor reduces glioblastoma tumor growth though changes in the tumor microenvironment in a pten wild type context |
| topic | GSK-3β PDE7A PTEN GAL9 Tumor microenvironment Macrophages |
| url | http://www.sciencedirect.com/science/article/pii/S1878747925000546 |
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