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Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and the Cancer Stem Cells (CSC) are the responsible of CRC persistence. Aloysia polystachya (AP) is an aromatic native plant of Verbenaceae family which is widely distributed and consumed in infusions in subtropical regions of South America. Its effects include diuretic, sedative, antispasmodic activities. We have previously demonstrated that AP extract has a cytotoxic effect in several human tumor cell lines, including apoptosis. The aim of this work was to investigate the cytotoxic effects of AP in vitro and in vivo in a CRC model. Therefore, CRC cell lines CT26 (murine) and HCT116 (human), were stimulated with AP extract or vehicle, with or without 5-fluorouracyle (5-FURA) and the survival and CSC properties were determined. The survival was measured after crystal violet staining at 570nm and CSC phenotype was determined by measuring the plurytpotency markers (CD133, OCT4 and Nanog by PCR and IFI), colony formation by clonogenic assay and HOESCHT efflux capacity (chemotherapeutic drugs efflux via ABCG2-transporters). In vivo experiments involved male BALB/c mice that were subcutaneously inoculated with murine CRC CT26 cell line. Once the tumor was detected, animals were treated twice a week (days 14, 17, 21, 24 and 28) with an intraperitoneal injection with AP and the sub-effective dose of 5-FURA (5mg/kg). Normal animals, not inoculated with CT26 cells were also used as control for histological analysis.The tumor size was determined twice a week. After 30 days, the mice were sacrificed and necropsied and the histopathology of tumors and the liver sections was performed by staining with hematoxylin and eosin. We found that AP extract decreased significantly the expression level of pluripotency markers, the colony formation and the efflux capacity of chemotherapeutic drugs respect to control cells and increased the cell death induced by 5-FURA treatment respect to cells stimulated with 5-FURA alone (P<0.05; Tukey test). We found that tumor growth was significantly inhibited by AP or AP plus 5-FURA respect to control animals without treatment or treated with 5-FURA alone (p<0.05; Tukey test). Histopathological analysis of tumor sections shown some necrosis area only in animals treated with AP or AP plus 5-FURA while the hepatic parenchyma shown a preserved architecture, confirming non-toxic effects of AP in vivo. Our results demonstrate that AP is capable to induce the cell death of CRC, resulted effective in vivo, non-toxic and has the ability to reduce the CSC side population. Being CSC the most resistant to chemotherapeutic drugs, responsible of cancer progression and perpetuation, the autochthonous plant derivatives could be attractive tools to be investigated as future oncologic therapeutics. Citation Format: Mileni Soares-Machado, Alejandra Palma, Laura Panelo, Leonardo Paz, Francisco Rosa, Cecilia Lira, Pablo Azurmendi, Fernanda Rubio, Guido Lenz, Alejandro Urtreger, Monica Costas. Effect of Aloysia polystachya in cancer stem cells of colorectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 494.