期刊
JOURNAL OF CANCER
卷 8, 期 18, 页码 3697-3706出版社
IVYSPRING INT PUBL
DOI: 10.7150/jca.20196
关键词
5-fluorouracil; curcumin; gastric cancer; MKN45 cell; COX-2; NF-kappa B
类别
资金
- National Natural Science Foundation of China [81341124, 81101678]
- Science and Technology Support Project of Sichuan Province [2017JQ0013]
- Sichuan Provincial Human Resource and Social Security Department [2016-183]
- Sichuan Province [14JC0134, 14ZC0026, 14ZC0066]
- Southwest Medical University [14JC0134, 14ZC0026, 14ZC0066, 2015LZCYD-S09 (4/8)]
Background: 5-fluorouracil (5-FU) is one of the most commonly used first-line anticancer drugs to treat gastric cancer in clinical practice. However, severe adverse events such as gastrointestinal toxicity and bone marrow suppression limit its clinical application. Combination chemotherapy to combine two or more anticancer drugs with different mechanistic action is an effective anticancer strategy against gastric cancer. Therefore, we studied the anticancer effect of the combination of 5-FU with curcumin against gastric cancer MKN45 and AGS cells (normal gastric mucosal GES-1 cells as control) and associated molecular mechanisms. Methods: Cytotoxicity of 5-FU and curcumin alone or in combination was evaluated in MKN45, AGS and GES cells by MTT assay. The protein expressions of COX-2 and NF-kappa B were evaluated in MKN45 cells by Western blotting analysis. In addition, antitumor activity of 5-FU and curcumin alone or in combination was evaluated in nude mice bearing MKN45 tumor xenografts in vivo. Results: The combination of 5-FU and curcumin (2: 1, mol/mol) showed 2.2-, 3.5-fold and 2.3-, 3.9-fold enhanced cytotoxic effect compared to 5-FU or curcumin alone and generated synergistic effect at the concentration of 5-FU (>4.09 and >5.71 mu mol/l) and curcumin (>2.05 and >2.86 mu mol/l) in MKN45 cells for 48 h and 72 h exposures, respectively. The combination of 5-FU and curcumin also potentiated cytotoxicity in AGS cells compared to 5-FU or curcumin alone but the effect was moderate. However, the cytotoxicity of 5-FU and curcumin alone or in combination was much less in GES-1 cells. Furthermore, the protein expressions of COX-2 and NF-kappa B in MKN45 cells were decreased by 44.79% and 37.67%, 47.17% and 48.21%, 60.21% and 62.44%, respectively, after treatment of curcumin (25 mu mol/l) and 5-FU (50 mu mol/l) alone or in combination for 48 h. Curcumin also enhanced the anticancer activity of 5-FU without increasing toxicity in nude mice bearing MKN45 tumor xenografts in vivo. Conclusions: Curcumin enhances the anticancer effect of 5-FU against gastric cancer in vitro and in vivo. The possible molecular mechanism may be, at least in part, related to down-regulation of COX-2 and NF-kappa B pathways.
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