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Effect of Citrus Bioactive Compounds on Targeting Human Colorectal Cancer Stem Cells
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Recently, there has been an increase in the interest of the application of natural extract for cancer prevention and treatment, where phenolic compounds are associated with a high effectiveness in prevention and treatment of the disease. One of the promising targets for cancer therapy is the cancer stem cells population, which has been recognized as responsible for tumor initiating, relapse and chemo-resistance.
The main goal of this thesis was to evaluate the chemotherapeutical potential of polymethoxylated flavones (PMFs) from orange peel extracts, using HT29 3D colorectal cancer model. This model was characterized in terms of stemness and self-renewal properties.
HT29 cell spheroids were characterized along the culture time showing resemblances to the in vivo tumors, reflecting highly rich stem population where high expression of CD44, CD133 and ALDH1 biomarkers was associated to high self-renewal capacity. Moreover, this model showed partial EMT characteristics.
Orange peel extract showed anticancer potential in HT29 cell aggregates by inhibiting cell proliferation and inducing cell cycle arrest and apoptosis. Self-renewal ability was also affected with association to decreasing of the expression of stemness markers. The bioactive molecules in the extract were identified as nobiletin, sinensetin, tangeretin and scutellarein tetramethylether. Among all PMFs, tangeretin exhibited the highest capability in affecting self-renewal, inducing apoptosis and cell cycle arrest and reducing the expression of mesenchymal and stemness markers. The mixture of PMFs
showed similarities with the activity of orange extract although in a less effective way, suggesting the presence of other compounds that might potentiate the effect. Additionally, orange peel extract showed to interact synergistically with 5-fluorouracil decreasing the drug dosage to inhibit HT29 cell spheroids proliferation.
Results of this thesis revealed that orange bioactive compounds, including PMFs, are able to target cancer cells with stemness and self-renewal characteristics and thus can be considered as promising natural chemotherapeutic agents for colorectal cancer treatment.
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Colorectal cancer Cancer stem cells Phytochemicals Polymethoxylated flavones Orange peel extracts 3D cell models