Abstract
Introduction: 5-fluorouracil (5-Fu) remains the standard chemotherapy for metastatic colorectal cancer (CRC), but drug resistance and unpredictable cardiotoxicity limit its effectiveness. The high recurrence rates and the common resistance are thought to be due to a population of self-renewing cancer stem cells (CSCs). The black seed extract Thymoquinone (TQ) is a promising anticancer molecule known to inhibit cancer cell growth and progression in numerous cancer systems both in vitro and in vivo. This project aims to investigate the effect and mechanism of action of TQ on colon cancer stem/progenitor cells using two isogenic HCT116 colon cancer cell lines that differ in their 5-Fu drug sensitivity.
Methods: Sphere-formation and propagation assays were used to assess the efficacy of TQ on targeting self-renewal capacity of colon CSCs enriched from the sensitive and resistant cell lines in 3D cultures over several generations in comparison to 2D monolayers. In addition, xenotransplantation experiments were used to assess for the tumor initiation of 2D vs. 3D cells.
Results: Our results of TQ efficacy in 2D cell culture system showed that it reduced the viability of both cell lines. Importantly, our 3D results showed that TQ inhibits HCT116 colonosphere growth at 10-fold lower concentrations than those required to inhibit the growth of 2D monolayer cells. Interestingly, the injection of 100 spheres derived from HCT116 sensitive cell line and not the 2D equivalent cell density into NOD-SCID immunocompromised mice resulted in tumor development, suggesting that spheres are rich in cells with stem-like properties.
Conclusion: In summary, our data suggests that TQ might be an effective treatment strategy and may prevent colorectal cancer recurrence by targeting CSCs.
Citation Format: Farah R. Ballout, Maamoun Fatfat, Rana Abdel-Samad, Nadine Darwiche, Regine Schneider-Stock, Wassim Abou-Kheir, Hala-Gali Muhtasib. Targeting colorectal cancer stem cells with the anticancer molecule thymoquinone [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 170.
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