Cargando…
Combination of 5-fluorouracil and thymoquinone targets stem cell gene signature in colorectal cancer cells
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...
Autores principales: | , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522523/ https://www.ncbi.nlm.nih.gov/pubmed/31097715 http://dx.doi.org/10.1038/s41419-019-1611-4 |
_version_ | 1783419135424724992 |
---|---|
author | Ndreshkjana, Benardina Çapci, Aysun Klein, Volker Chanvorachote, Pithi Muenzner, Julienne K. Huebner, Kerstin Steinmann, Sara Erlenbach-Wuensch, Katharina Geppert, Carol I. Agaimy, Abbas Ballout, Farah El-Baba, Chirine Gali-Muhtasib, Hala Roehe, Adriana Vial Hartmann, Arndt Tsogoeva, Svetlana B. Schneider-Stock, Regine |
author_facet | Ndreshkjana, Benardina Çapci, Aysun Klein, Volker Chanvorachote, Pithi Muenzner, Julienne K. Huebner, Kerstin Steinmann, Sara Erlenbach-Wuensch, Katharina Geppert, Carol I. Agaimy, Abbas Ballout, Farah El-Baba, Chirine Gali-Muhtasib, Hala Roehe, Adriana Vial Hartmann, Arndt Tsogoeva, Svetlana B. Schneider-Stock, Regine |
author_sort | Ndreshkjana, Benardina |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6522523 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-65225232019-05-20 Combination of 5-fluorouracil and thymoquinone targets stem cell gene signature in colorectal cancer cells Ndreshkjana, Benardina Çapci, Aysun Klein, Volker Chanvorachote, Pithi Muenzner, Julienne K. Huebner, Kerstin Steinmann, Sara Erlenbach-Wuensch, Katharina Geppert, Carol I. Agaimy, Abbas Ballout, Farah El-Baba, Chirine Gali-Muhtasib, Hala Roehe, Adriana Vial Hartmann, Arndt Tsogoeva, Svetlana B. Schneider-Stock, Regine Cell Death Dis Article 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. Nature Publishing Group UK 2019-05-16 /pmc/articles/PMC6522523/ /pubmed/31097715 http://dx.doi.org/10.1038/s41419-019-1611-4 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Ndreshkjana, Benardina Çapci, Aysun Klein, Volker Chanvorachote, Pithi Muenzner, Julienne K. Huebner, Kerstin Steinmann, Sara Erlenbach-Wuensch, Katharina Geppert, Carol I. Agaimy, Abbas Ballout, Farah El-Baba, Chirine Gali-Muhtasib, Hala Roehe, Adriana Vial Hartmann, Arndt Tsogoeva, Svetlana B. Schneider-Stock, Regine Combination of 5-fluorouracil and thymoquinone targets stem cell gene signature in colorectal cancer cells |
title | Combination of 5-fluorouracil and thymoquinone targets stem cell gene signature in colorectal cancer cells |
title_full | Combination of 5-fluorouracil and thymoquinone targets stem cell gene signature in colorectal cancer cells |
title_fullStr | Combination of 5-fluorouracil and thymoquinone targets stem cell gene signature in colorectal cancer cells |
title_full_unstemmed | Combination of 5-fluorouracil and thymoquinone targets stem cell gene signature in colorectal cancer cells |
title_short | Combination of 5-fluorouracil and thymoquinone targets stem cell gene signature in colorectal cancer cells |
title_sort | combination of 5-fluorouracil and thymoquinone targets stem cell gene signature in colorectal cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522523/ https://www.ncbi.nlm.nih.gov/pubmed/31097715 http://dx.doi.org/10.1038/s41419-019-1611-4 |
work_keys_str_mv | AT ndreshkjanabenardina combinationof5fluorouracilandthymoquinonetargetsstemcellgenesignatureincolorectalcancercells AT capciaysun combinationof5fluorouracilandthymoquinonetargetsstemcellgenesignatureincolorectalcancercells AT kleinvolker combinationof5fluorouracilandthymoquinonetargetsstemcellgenesignatureincolorectalcancercells AT chanvorachotepithi combinationof5fluorouracilandthymoquinonetargetsstemcellgenesignatureincolorectalcancercells AT muenznerjuliennek combinationof5fluorouracilandthymoquinonetargetsstemcellgenesignatureincolorectalcancercells AT huebnerkerstin combinationof5fluorouracilandthymoquinonetargetsstemcellgenesignatureincolorectalcancercells AT steinmannsara combinationof5fluorouracilandthymoquinonetargetsstemcellgenesignatureincolorectalcancercells AT erlenbachwuenschkatharina combinationof5fluorouracilandthymoquinonetargetsstemcellgenesignatureincolorectalcancercells AT geppertcaroli combinationof5fluorouracilandthymoquinonetargetsstemcellgenesignatureincolorectalcancercells AT agaimyabbas combinationof5fluorouracilandthymoquinonetargetsstemcellgenesignatureincolorectalcancercells AT balloutfarah combinationof5fluorouracilandthymoquinonetargetsstemcellgenesignatureincolorectalcancercells AT elbabachirine combinationof5fluorouracilandthymoquinonetargetsstemcellgenesignatureincolorectalcancercells AT galimuhtasibhala combinationof5fluorouracilandthymoquinonetargetsstemcellgenesignatureincolorectalcancercells AT roeheadrianavial combinationof5fluorouracilandthymoquinonetargetsstemcellgenesignatureincolorectalcancercells AT hartmannarndt combinationof5fluorouracilandthymoquinonetargetsstemcellgenesignatureincolorectalcancercells AT tsogoevasvetlanab combinationof5fluorouracilandthymoquinonetargetsstemcellgenesignatureincolorectalcancercells AT schneiderstockregine combinationof5fluorouracilandthymoquinonetargetsstemcellgenesignatureincolorectalcancercells |