Combination of 5-fluorouracil and thymoquinone targets stem cell gene signature in colorectal cancer cells

Journal article


Publication Details

Author(s): Ndreshkjana B, Capci Karagoez A, Klein V, Chanvorachote P, Muenzner JK, Hübner K, Steinmann S, Erlenbach-Wuensch K, Geppert C, Agaimy A, Ballout F, El-Baba C, Gali-Muhtasib H, Roehe AV, Hartmann A, Tsogoeva S, Schneider-Stock R
Journal: Cell Death & Disease
Publication year: 2019
Volume: 10
Journal issue: 6
ISSN: 2041-4889


Abstract

Cancer stem cells (CSCs) residing in colorectal cancer tissues have tumorigenic capacity and contribute to chemotherapeutic resistance and disease relapse. It is well known that the survival of colorectal CSCs after 5-fluorouracil (5-FU)-based therapy leads to cancer recurrence. Thus CSCs represent a promising drug target. Here, we designed and synthesized novel hybrid molecules linking 5-FU with the plant-derived compound thymoquinone (TQ) and tested the potential of individual compounds and their combination to eliminate colorectal CSCs. Both, Combi and SARB hybrid showed augmented cytotoxicity against colorectal cancer cells, but were non-toxic to organoids prepared from healthy murine small intestine. NanoString analysis revealed a unique signature of deregulated gene expression in response to the combination of TQ and 5-FU (Combi) and SARB treatment. Importantly, two principle stem cell regulatory pathways WNT/ß-Catenin and PI3K/AKT were found to be downregulated after Combi and hybrid treatment. Furthermore, both treatments strikingly eliminated CD133+ CSC population, accompanying the depleted self-renewal capacity by eradicating long-term propagated 3D tumor cell spheres at sub-toxic doses. In vivo xenografts on chicken eggs of SARB-treated HCT116 cells showed a prominent nuclear ß-Catenin and E-cadherin staining. This was in line with the reduced transcriptional activity of ß-Catenin and diminished cell adhesion under SARB exposure. In contrast to 5-FU, both, Combi and SARB treatment effectively reduced the angiogenic capacity of the remaining resistant tumor cells. Taken together, combination or hybridization of single compounds target simultaneously a broader spectrum of oncogenic pathways leading to an effective eradication of colorectal cancer cells.


FAU Authors / FAU Editors

Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie
Capci Karagoez, Aysun
Interdisziplinäres Zentrum für Molekulare Materialien
Geppert, Carol
Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie
Hartmann, Arndt Prof. Dr. med.
Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie
Hübner, Kerstin
Pathologisches Institut
Klein, Volker
Lehrstuhl für Organische Chemie I
Ndreshkjana, Benardina
Professur für Experimentelle Tumorpathologie
Schneider-Stock, Regine Prof. Dr.
Professur für Experimentelle Tumorpathologie
Steinmann, Sara
Professur für Experimentelle Tumorpathologie
Tsogoeva, Svetlana Prof. Dr.
Professur für Organische Chemie


External institutions with authors

American University of Beirut (AUB) / الجامعة الأميركية في بيروت‎‎
Chulalongkorn University / จุฬาลงกรณ์มหาวิทยาลัย
Universidade Federal do Rio Grande do Sul (UFRGS)


How to cite

APA:
Ndreshkjana, B., Capci Karagoez, A., Klein, V., Chanvorachote, P., Muenzner, J.K., Hübner, K.,... Schneider-Stock, R. (2019). Combination of 5-fluorouracil and thymoquinone targets stem cell gene signature in colorectal cancer cells. Cell Death & Disease, 10(6). https://dx.doi.org/10.1038/s41419-019-1611-4

MLA:
Ndreshkjana, Benardina, et al. "Combination of 5-fluorouracil and thymoquinone targets stem cell gene signature in colorectal cancer cells." Cell Death & Disease 10.6 (2019).

BibTeX: 

Last updated on 2019-03-06 at 09:53