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• W3165011036 abstract "Colorectal cancer tissues comprise a subpopulation of cells, the so-called cancer stem cells (CSCs), that are believed to be responsible for therapy resistance and cancer relapse. Targeting specifically this small population of cells remain a great challenge in colorectal cancer therapy since the available drugs are attacking the bulk of the tumor, leaving intact the stem cell which are tumorigenic and capable to self-renew. Therefore, CSCs represent an attractive target, since it is also known that these cells escape the first line therapy, 5-Fluorouracil (5-FU). In this PhD work, we present how a novel hybridization approach deriving from the combination of the conventional drug 5-FU with the natural compound Thymoquinone (TQ), can produce a unique hybrid molecule that specifically target this rare subpopulation of cancer cells. Here we have designed, synthesized and evaluated the anti-cancer properties of different hybrid molecules consisting on three different linkers. In parallel, we compared the cytotoxic effects of the hybrid agents with their parental compounds, as well as with the combination of the individual compounds. The 5-FU/TQ combination therapy and 5-FU/TQ hybridization strategy (SARB hybrid) displayed increased cytotoxicity against colorectal cancer cells, without being toxic to non-malignant HCEC cell or to organoids obtained from normal murine small intestine. NanoString gene expression analysis allowed us to explore the affected genes and pathways upon all the treatments. We could identify overlapping gene signatures but also deregulated pathways exclusively in SARB or in Combi treatment. Notably, two key stem cell controlling pathways, such as WNT/s-Catenin and PI3K/AKT were simultaneously downregulated after Combi and SARB treatment. In relationship to the individual drug treatments, we found other targets beyond the recognized mechanisms of action of 5-FU and TQ. Additional evidence on proving the capacity of these two combination approaches on targeting stem cell related markers, was the massive downregulation of CD133+ CSC population, which was also accompanied by the striking reduction of self-renewal capacity. The possibility to propagate long-term 3D tumor cell spheres was lost upon SARB treatment, even at sub-toxic doses. In order to validate our findings also in vivo, the chicken egg model was used. When inoculating the treated HCT116 cells onto the chorioallantoic membrane (CAM) and let them grow into a tumor, we indeed, observed a significant reduction on tumor growth upon SARB administration. The immunohistochemical staining's of CAM-derived xenografts displayed a concomitant nuclear s-Catenin and E-cadherin staining, data that were in line with the reduced transcriptional activity of s-Catenin and weakened cell adhesion upon SARB exposure. In comparison to 5-FU, both, Combi and SARB treatment reduced the angiogenic capacity of the residual resistant tumor cells. Taken together, our results strongly encourage the combination or hybridization of the clinical drug 5-FU and the plant-derived compound TQ as potential candidates that simultaneously target a broader spectrum of oncogenic pathways, eventually leading to a successful eradication of colorectal cancer stem cells." @default.
• W3165011036 created "2021-06-07" @default.
• W3165011036 creator A5083489137 @default.
• W3165011036 date "2019-01-01" @default.
• W3165011036 modified "2023-09-24" @default.
• W3165011036 title "Combination therapy as a promising strategy to overcome drug resistance in colorectal cancer" @default.
• W3165011036 hasPublicationYear "2019" @default.
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