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Verfasst von:Hage, Carina [VerfasserIn]   i
 Giese, Nathalia [VerfasserIn]   i
 Giese, Thomas [VerfasserIn]   i
 Schönsiegel, Frank [VerfasserIn]   i
 Nwaeburu, Clifford C. [VerfasserIn]   i
 Herr, Ingrid [VerfasserIn]   i
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

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