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Apoptosis-Inducing Effect of 5-Fluorouracil Combined with Resveratrol on Tumor Cells in Vitro and in Vivo

??OBJECTIVE To study the effects of 5-Fu combined with resveratrol (Res) on the growth and apoptosis of A431 and TE-1 cell lines and the underlying mechanism.To study the therapeutic effects of 5-Fu/Res combination on mouse skin papilloma chemically induced by DMBA/TPA. METHODS The effects of 5-Fu/Res combination on the viability of cancer cells were evaluated by MTT assay, growth curves assay and LDH releasing assay. The inhibitory effect of combination of the two drugs was analyzed by the method of Chou and Talalay. Apoptoses of A431 and TE-1 were determined by inverted microscope and gel electrophoresis of DNA fragment analysis. Intracellular Ca²⁺ concentration was determined to study the underlying mechanisms of 5-Fu and Res on the apoptosis of cancer cells. The mouse skin papilloma model was established by DMBA and TPA,the expression of actived-caspase-3 in mouse skin was examined by immunohistochemistry. RESULTS Combination of 5-Fu and Res decreased the median inhibitory concentration (IC₅₀) to cancer cells remarkably. 5-Fu/Res combination showed a synergistic effect on apoptosis of A431 and TE-1 cells. Much more typical morphological changes of apoptosis and amount of fragmented DNA were observed in the cells treated with 5-Fu and resveratrol in combination than that in the cells treated with the agents alone. The increase of [Ca²⁺]_i induced by 5-Fu/Res combination might be involved in the apoptotic induction. There was a significant decrease of the number of tumors after treatment with 5-Fu and Res in the tumor-bearing mice model. Active caspase-3 in the cells of mice skin was generated by 5-Fu in combination resveratrol was more effective than either alone. CONCLUSION The 5-Fu/Res combination shows synergistic anti-tumor effects both in vitro and in vivo.