Thymoquinone induces apoptosis and DNA damage in 5-Fluorouracil-resistant colorectal cancer stem/progenitor cells
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Farah Ballout1, Alissar Monzer1, Maamoun Fatfat1, Hala El Ouweini1, Miran A. Jaffa2, Rana Abdel-Samad3, Nadine Darwiche3, Wassim Abou-Kheir4 and Hala Gali-Muhtasib1,4
1 Department of Biology, American University of Beirut, Lebanon
2 Department of Epidemiology and Population Health, American University of Beirut, Lebanon
3 Department of Biochemistry and Molecular Genetics, American University of Beirut, Lebanon
4 Center for Drug Discovery and Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Lebanon
Keywords: thymoquinone; colorectal cancer stem cells; 5-Fluorouracil resistance; colonospheres; apoptosis
Received: October 08, 2019 Accepted: December 16, 2019 Published: August 04, 2020
The high recurrence rates of colorectal cancer have been associated with a small population of cancer stem cells (CSCs) that are resistant to the standard chemotherapeutic drug, 5-fluorouracil (5FU). Thymoquinone (TQ) has shown promising antitumor properties on numerous cancer systems both in vitro and in vivo; however, its effect on colorectal CSCs is poorly established. Here, we investigated TQ’s potential to target CSCs in a three-dimensional (3D) sphere-formation assay enriched for a population of colorectal cancer stem/progenitor cells. Our results showed a significant decrease in self-renewal potential of CSC populations enriched from 5FU-sensitive and resistant HCT116 cells at 10-fold lower concentrations when compared to 2D monolayers. TQ decreased the expression levels of colorectal stem cell markers CD44 and Epithelial Cell Adhesion Molecule EpCAM and proliferation marker Ki67 in colonospheres derived from both cell lines and reduced cellular migration and invasion. Further investigation revealed that TQ treatment led to increased TUNEL positivity and a dramatic increase in the amount of the DNA damage marker gamma H2AX particularly in 5FU-resistant colonospheres, suggesting that the diminished sphere forming ability in TQ-treated colonospheres is due to induction of DNA damage and apoptotic cell death. The intraperitoneal injection of TQ in mice inhibited tumor growth of spheres derived from 5FU-sensitive and 5FU-resistant HCT116 cells. Furthermore, TQ induced apoptosis and inhibited NF-κB and MEK signaling in mouse tumors. Altogether, our findings document TQ’s effect on colorectal cancer stem-like cells and provide insights into its underlying mechanism of action.
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