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

Ndreshkjana B, Capci Karagöz A, Klein V, Chanvorachote P, Muenzner JK, Hübner K, Steinmann S, Erlenbach-Wuensch K, Geppert CI, Agaimy A, Ballout F, El-Baba C, Gali-Muhtasib H, Roehe AV, Hartmann A, Tsogoeva S, Schneider-Stock R (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Cell Death & Disease Nature Publishing Group: Open Access Journals - Option B / Nature Publishing Group

Book Volume: 10

Article Number: 379

Journal Issue: 6

DOI: 10.1038/s41419-019-1611-4

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.

Authors with CRIS profile

Benardina Ndreshkjana Professur für Experimentelle Tumorpathologie Aysun Capci Karagöz Interdisziplinäres Zentrum für Molekulare Materialien Volker Klein Lehrstuhl für Organische Chemie I Kerstin Hübner Institute of Pathology Sara Steinmann Professur für Experimentelle Tumorpathologie Carol-Immanuel Geppert Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Abbas Agaimy Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Arndt Hartmann Lehrstuhl für Allgemeine Pathologie und Pathologische Anatomie Svetlana Tsogoeva Professur für Organische Chemie Regine Schneider-Stock Professur für Experimentelle Tumorpathologie

Involved external institutions

Universidade Federal do Rio Grande do Sul (UFRGS) BR Brazil (BR) American University of Beirut (AUB) / الجامعة الأميركية في بيروت‎‎ LB Lebanon (LB) Chulalongkorn University / จุฬาลงกรณ์มหาวิทยาลัย TH Thailand (TH)

How to cite

APA:

Ndreshkjana, B., Capci Karagöz, 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).

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