| Online-Ressource |
Verfasst von: | Hage, Carina [VerfasserIn]  |
| Giese, Nathalia [VerfasserIn]  |
| Giese, Thomas [VerfasserIn]  |
| Schönsiegel, Frank [VerfasserIn]  |
| Nwaeburu, Clifford C. [VerfasserIn]  |
| Herr, Ingrid [VerfasserIn]  |
Titel: | The novel c-Met inhibitor cabozantinib overcomes gemcitabine resistance and stem cell signaling in pancreatic cancer |
Verf.angabe: | C Hage, V Rausch, N Giese, T Giese, F Schönsiegel, S Labsch, C Nwaeburu, J Mattern, J Gladkich and I Herr |
E-Jahr: | 2013 |
Jahr: | 9 May 2013 |
Umfang: | 10 S. |
Fussnoten: | Gesehen am 19.10.2021 |
Titel Quelle: | Enthalten in: Cell death & disease |
Ort Quelle: | London [u.a.] : Nature Publishing Group, 2010 |
Jahr Quelle: | 2013 |
Band/Heft Quelle: | 4(2013,5) Artikel-Nummer e627, 10 Seiten |
ISSN Quelle: | 2041-4889 |
Abstract: | Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignancies. Cancer stem cells (CSCs), which are not targeted by current therapies, may be the reason for pronounced therapy resistance. A new treatment option in phase II trials is cabozantinib that inhibits the pancreatic CSC surface marker and tyrosine kinase receptor c-Met. The purpose of this study was to evaluate the effect of cabozantinib to stem-like features and therapy resistance. Established PDA cell lines, a gemcitabine-resistant subclone, non-malignant pancreatic ductal cells and primary spheroidal cultures from patient tumors were analyzed by MTT-assay, flow cytometry, colony and spheroid formation assays, western blotting, qRT-PCR, antibody protein array, immunohistochemistry and morphological features. Cabozantinib inhibited viability and spheroid formation and induced apoptosis in malignant cells with minor effects in non-malignant cells. After long-term cabozantinib treatment, PDA cells had altered anti- and pro-apoptotic signaling, but still responded to cabozantinib, as apoptosis only slightly decreased and viability only slightly increased suggesting a low resistance-inducing potential of cabozantinib. In parallel, c-Met expression and the pluripotency transcription factor SOX2 were downregulated, which might counteract development of full therapy resistance in long-term treated subclones. In single-treatment studies, cabozantinib increased efficacy of gemcitabine. Most importantly, cabozantinib strongly induced apoptosis and reduced viability in PDA cell lines, which are completely resistant toward gemcitabine. In primary, CSC-enriched spheroidal cultures cabozantinib downregulated CSC markers SOX2, c-Met and CD133 and induced apoptosis. These findings suggest that the clinical use of cabozantinib may be more effective than current chemotherapeutics. |
DOI: | doi:10.1038/cddis.2013.158 |
URL: | Bitte beachten Sie: Dies ist ein Bibliographieeintrag. Ein Volltextzugriff für Mitglieder der Universität besteht hier nur, falls für die entsprechende Zeitschrift/den entsprechenden Sammelband ein Abonnement besteht oder es sich um einen OpenAccess-Titel handelt.
Volltext ; Verlag: https://doi.org/10.1038/cddis.2013.158 |
| Volltext: https://www.nature.com/articles/cddis2013158 |
| DOI: https://doi.org/10.1038/cddis.2013.158 |
Datenträger: | Online-Ressource |
Sprache: | eng |
K10plus-PPN: | 1749056720 |
Verknüpfungen: | → Zeitschrift |
¬The¬ novel c-Met inhibitor cabozantinib overcomes gemcitabine resistance and stem cell signaling in pancreatic cancer / Hage, Carina [VerfasserIn]; 9 May 2013 (Online-Ressource)