Dihydroartemisinin enhances antitumor effect of 5-fluorouracil against gastric cancer by down-regulating SIRT1 expression |
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Authors: | WAN Bin CAO Heng-bin YU Gen-hua |
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Affiliation: | 1. Department of Pharmacy, Huzhou Central Hospital, Huzhou 313000, China;2. Department of Interventional Radiology, Huzhou Central Hospital, Huzhou 313000, China |
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Abstract: | AIM: To investigate the effect of dihydroartemisinin (DHA) adjuvant treatment on enhancing the antitumor effect of 5-fluorouracil (5-FU) against gastric cancer. METHODS: The gastric cancer BGC-823 cells were divided into control group, DHA group, 5-FU group, 5-FU+DHA group and 5-FU+DHA+SIRT1 plasmid group. The viability of BGC-823 cells treated with DHA and 5-FU was measured by MTT assay. The expression of SIRT1 and NADPH oxidase, activation of caspase-9 and caspase-3, and phosphorylation of ASK1 and JNK in the BGC-823 cells treated with DHA and 5-FU were determined by Western blot. The production of ROS and the apoptosis of the BGC-823 cells treated with DHA and 5-FU were analyzed by flow cytometry. RESULTS: Dihydroartemisinin significantly inhibited the expression of SIRT1 and increased NADPH oxidase protein level (P<0.05). DHA increased the sensitivity of BGC-823 cells to 5-FU, thus decreasing the IC50 of 5-FU to the gastric cancer cells. However, transfection with SIRT1 plasmid decreased the cytotoxicity of DHA and 5-FU co-treatment to the BGC-823 cells. DHA promoted the production of ROS and phosphorylation of ASK1 and JNK induced by 5-FU in the BGC-823 cells (P<0.05). However, ROS scavenger N-acetylcysteine (NAC) or JNK specific inhibitor SP600125 inhibited the cell death and activation of caspase-9 and caspase-3 induced by DHA and 5-FU co-treatment (P<0.05). In addition, NAC significantly inhibited the phosphorylation of JNK in the BGC-823 cells co-treated with DHA and 5-FU. However, treatment with SP600125 did not influence the ROS production in the BGC-823 cells, indicating that JNK was the downstream target of ROS pathway. CONCLUSION: Combination of DHA with 5-FU induces caspase-dependent apoptosis in gastric cancer cells through the SIRT1/NADPH oxidase/ROS/JNK signaling pathway. |
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Keywords: | Dihydroartemisinin SIRT1 protein 5-fluorouracil BGC-823 cells Reactive oxygen species JNK signaling pathway |
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