Interferon-beta sensitizes human glioblastoma ...
Type de document :
Article dans une revue scientifique: Article original
DOI :
PMID :
URL permanente :
Titre :
Interferon-beta sensitizes human glioblastoma cells to the cyclin-dependent kinase inhibitor, tg02
Auteur(s) :
Lohmann, Birthe [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
Le Rhun, Emilie [Auteur]
Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192
Silginer, Manuela [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
Epskamp, Mirka [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
Weller, Michael [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
Universität Zürich [Zürich] = University of Zurich [UZH]
Le Rhun, Emilie [Auteur]
Protéomique, Réponse Inflammatoire, Spectrométrie de Masse (PRISM) - U1192
Silginer, Manuela [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
Epskamp, Mirka [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
Weller, Michael [Auteur]
Universität Zürich [Zürich] = University of Zurich [UZH]
Titre de la revue :
Oncology Letters
Nom court de la revue :
Oncol. Lett.
Numéro :
19
Pagination :
2649-2656
Éditeur :
Spandidos Publications
Date de publication :
2020-04-01
ISSN :
1792-1074
Mot(s)-clé(s) :
cyclin-dependent kinase
therapy
synergy
glioma
targeted
therapy
synergy
glioma
targeted
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Résumé en anglais : [en]
Novel treatments for glioblastoma, the most common malignant primary brain tumor, are urgently required. Type I interferons (IFN) are natural cytokines primarily involved in the defense against viral infections, which may ...
Lire la suite >Novel treatments for glioblastoma, the most common malignant primary brain tumor, are urgently required. Type I interferons (IFN) are natural cytokines primarily involved in the defense against viral infections, which may also serve a role in the control of cancer, notably in the suppression of the cancer stem cell phenotype. TG02 is a novel orally available cyclin-dependent kinase 9 inhibitor which induces glioma cell apoptosis without profound caspase activation, which is currently explored in early clinical trials in newly diagnosed and recurrent glioblastoma. In the present study, human glioma-initiating cell line models were used to explore whether IFN-beta modulates the anti-glioma activity of TG02. The present study employed immunoblotting to assess protein levels, several viability assays and gene silencing strategies to assess gene function. Pre-exposure to IFN-beta sensitized human glioma models to a subsequent exposure to TG02. Combination treatment was associated with increased DEVD-amc cleaving caspase activity that was blocked by the anti-apoptotic protein, BCL2. However, BCL2 did not protect from the synergistic effects of IFN and TG02 on glioma cell growth. Furthermore, although IFN strongly induced pro-apoptotic XIAP-associated factor (XAF) expression, disrupting XAF expression did not abrogate the synergy with TG02. Consistent with that, caspase 3 gene silencing did not abrogate the effects of TG02 or IFN-beta alone or in combination. Finally, it was observed that IFN-beta may indeed modulate the effects of TG02 upstream in the signaling cascade since inhibition of RNA polymerase II phosphorylation, a direct readout of the pharmacodynamic activity of TG02, was facilitated when glioma cells were pre-exposed to IFN-beta. In summary, these data suggest that type I IFN may be combined with TG02 to limit glioblastoma growth, but that the well characterized effects of IFN and TG02 on apoptotic signaling are dispensable for synergistic tumor growth inhibition. Instead, exploring how IFN signaling primes glioma cells for TG02-mediated direct target inhibition may help to design novel and effective pharmacological approaches to glioblastoma.Lire moins >
Lire la suite >Novel treatments for glioblastoma, the most common malignant primary brain tumor, are urgently required. Type I interferons (IFN) are natural cytokines primarily involved in the defense against viral infections, which may also serve a role in the control of cancer, notably in the suppression of the cancer stem cell phenotype. TG02 is a novel orally available cyclin-dependent kinase 9 inhibitor which induces glioma cell apoptosis without profound caspase activation, which is currently explored in early clinical trials in newly diagnosed and recurrent glioblastoma. In the present study, human glioma-initiating cell line models were used to explore whether IFN-beta modulates the anti-glioma activity of TG02. The present study employed immunoblotting to assess protein levels, several viability assays and gene silencing strategies to assess gene function. Pre-exposure to IFN-beta sensitized human glioma models to a subsequent exposure to TG02. Combination treatment was associated with increased DEVD-amc cleaving caspase activity that was blocked by the anti-apoptotic protein, BCL2. However, BCL2 did not protect from the synergistic effects of IFN and TG02 on glioma cell growth. Furthermore, although IFN strongly induced pro-apoptotic XIAP-associated factor (XAF) expression, disrupting XAF expression did not abrogate the synergy with TG02. Consistent with that, caspase 3 gene silencing did not abrogate the effects of TG02 or IFN-beta alone or in combination. Finally, it was observed that IFN-beta may indeed modulate the effects of TG02 upstream in the signaling cascade since inhibition of RNA polymerase II phosphorylation, a direct readout of the pharmacodynamic activity of TG02, was facilitated when glioma cells were pre-exposed to IFN-beta. In summary, these data suggest that type I IFN may be combined with TG02 to limit glioblastoma growth, but that the well characterized effects of IFN and TG02 on apoptotic signaling are dispensable for synergistic tumor growth inhibition. Instead, exploring how IFN signaling primes glioma cells for TG02-mediated direct target inhibition may help to design novel and effective pharmacological approaches to glioblastoma.Lire moins >
Langue :
Anglais
Audience :
Internationale
Vulgarisation :
Non
Établissement(s) :
INSERM
Université de Lille
Université de Lille
Collections :
Date de dépôt :
2022-06-15T13:59:27Z
2023-04-12T08:32:47Z
2023-04-12T08:32:47Z
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