Objective: Canceris known as one of the most challenging diseases in management and therapy, especially in developing countries. In Iran, for instance, high mortality of gastrointestinal malignancies, including Esophageal Squamous Cell Carcinoma (ESCC), is mainly due to their poor diagnosis and inefficacy of current therapeutic strategies.Paclitaxel and 5-fluorouracil are two anticancer agents commonly prescribed for ESCC. To investigate whether natural compounds such as coumarins could enhance the efficacy of chemical drugs, the synergic effects of auraptene has been examined in present study in vitro. Materials and Methods: Auraptene was isolated from Citrus species using column chromatography. KYSE30 cells, an ESCC cell line, and HFF3 cells, human normal fibroblasts, were treated with increasing concentrations of auraptene, paclitaxel and 5-fluorouracil, and their viability was assessed by MTT test. After determining the IC50 of auraptene and both drugs, KYSE30 cells were treated with combining concentrations, including 5, 10 and 20 μg/ml auraptene with 1, 2 and 4 μg/ml paclitaxel or 2.5, 5 and 10 μg/ml 5-fluorouracil. Then, effects of each combinationwere assessed on cells‟ morphology and viability after 24, 48, 72 and 96 h. Moreover, induced apoptosis was studied by flow cytometry based on the detection of FITC annexin V and propidium iodide. Results: After auraptene treatment, the IC50 of this coumarin was determined >40 μg/ml in KYSE30 and HFF3 cells. However, 72 h after drug administration, the IC50 values of paclitaxel and 5-fluorouracil were measured as <4 μg/ml and <20 μg/ml, respectively. Studying KYSE30 cells treated with combining concentrations revealed that combination of 20 μg/ml auraptene with 1 μg/ml paclitaxel increased the toxicity of paclitaxel up to 35.5%. Furthermore, after combination of 20 μg/ml auraptene with 5 μg/ml 5-fluorouracil, the cytotoxicity of 5-fluorouracil was increased up to 24%. Further studying auraptene effects on 5-fluorouracil toxicity confirmed other results since apoptosis induced by 5-fluorouracil in KYSE30 cells was enhanced by 26.8% when used in combination with auraptene. Conclusion: Asauraptene enhances the cytotoxicity of paclitaxel and 5-fluorouracil without any toxic effects on cancerous and normal cells, it is worth to study its synergic effects on other anticancer drugs.

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