Abstract
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.
Highlights
Colorectal cancer (CRC) is the third most common cancer in both men and women and the third leading cause of cancer-related deaths in the United States [1]
Our first objective was to investigate the in vitro effect of TQ on the growth of HCT116 5FU-sensitive and resistant colorectal cancer cell lines cultured in 2D monolayers
We have previously reported that intraperitoneal injections of TQ at doses up to 20 mg/kg are not toxic to mice and significantly delay tumor growth in a xenograft model of 5FU-sensitive HCT116 colorectal cancer [27]
Summary
Colorectal cancer (CRC) is the third most common cancer in both men and women and the third leading cause of cancer-related deaths in the United States [1]. For metastatic CRC, treatments typically include chemotherapy with conventional agents such as. Most of the colorectal cancer-associated mortality stems from the recurrence and metastatic spread of chemoresistant cells to other vital organs, mainly the liver and lungs [6]. A complete understanding of all the players remains to be uncovered; the presence www.oncotarget.com of chemotherapy-resistant cancer stem cells (CSCs) is one of the significant causes of tumor recurrence [7]. CSCs can self-renew [8] and are known to be resistant to chemotherapies such as 5FU or oxaliplatin [9]. There is a need to develop practical therapeutic approaches that target CSCs and prevent relapse [10, 11]
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