Application of 5-fluorouracil (5-FU) in cholangiocarcinoma (CCA) is limited by adverse side effects and chemoresistance. Therefore, the combination therapy of 5-FU with other substances, especially natural products may provide a new strategy for CCA treatment. The aim of this study was to evaluate the combination effects of 5-FU and two ethanolic extracts of Thai noni juice (TNJ) products on CCA cell lines and nude mice xenografts. The results of antiproliferative assay showed the combination treatment of 5-FU and each TNJ ethanolic extract exerted more cytotoxicity on CCA cells than either single agent treatment. Synergistic effects of drug combinations can enable the dose reduction of 5-FU. The mechanism underlying a combination treatment was apoptosis induction through an activation of p53 and Bax proteins. In the nude mouse xenograft model, combination treatments of 5-FU with each TNJ ethanolic extract suppressed the growth of CCA cells implanted mice more than single agent treatments with no effects on mouse body weight, kidney, and spleen. Moreover, low doses of TNJ ethanolic extracts reduced the hepatotoxicity of 5-FU in nude mice. Taken together, these data suggested that the ethanolic extracts of TNJ products can enhance the anti-CCA effect and reduce toxicity of 5-FU.

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Background and Objectives: The treatments of cholangiocarcinoma (CCA) with Cisplatin (Cis) and Gemcitabine (Gem) often cause side effects and drug resistance. This study aimed to investigate the combined effects of Tiliacora triandra leaf powder ethanolic extract (TLPE) and Cis or Gem on CCA cells in vitro and in nude mouse xenografts. Materials and Methods: Antiproliferative activity was evaluated using MTT assay. Drug interaction was studied by Chou-Talalay method. Apoptosis induction and cell cycle arrest were analyzed by flow cytometry. Cell cycle and apoptosis regulating proteins were evaluated by western blot analysis. Results:Treatments with Cis or Gem in combination with TLPE significantly inhibited the growth of KKU-M213B and KKU-100 cells compared with single drug treatments. Synergistic drug interactions were observed with the dose reduction of Cis and Gem treatments. The safety of TLPE was demonstrated in vitro by the hemolytic assay. Synergistic combination treatments down-regulated Bcl2 and reduced the ratio of Bcl2/Bax in both CCA cells. TLPE enhanced tumor suppression of both Cis and Gem in nude mouse xenograft models. Combination treatments with Cis and TLPE reduced Cis toxicity, as demonstrated by the enhanced body weight change of the treated mice compared with the treatment with Cis alone. Furthermore, TLPE reduced hepatotoxicity caused by Gem treatment and reduced kidney and spleen toxicities caused by Cis treatment. Conclusion: These findings suggest that TLPE enhances the anticancer activity of Cis and Gem and reduces their toxicity both in vitro and in nude mouse xenograft models.

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