Huanli Xu1, Tao Yang2, Xiaohui Liu3, Ye Tian3, Xiaoliang Chen3, Ru Yuan3, Shuonan Su3, Xiukun Lin3, Guanhua Du4. 1. Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China; National Center for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, PR China. 2. National Center for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, PR China. 3. Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China. 4. National Center for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100050, PR China. Electronic address: xhl_52china@163.com.
Abstract
AIMS: Some compounds derived from Chinese medicine have demonstrated great prospective roles in sensitization to chemotherapy. This study aimed to investigate the combination of luteolin and 5-fluorouracil on proliferations of hepatocellular carcinoma cells and the potential mechanisms. MAIN METHODS: The antitumor effects of luteolin, 5-fluorouracil, and their combinations were detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium/phenazine methosulfate assay, and isobole method was used to evaluate drug combinations. CellTiter-Blue and Caspase-Glo 3/7 assay were used for assessment of cell viability and apoptosis after treatment with luteolin, 5-fluorouracil and their combinations. Cell cycle distributions and apoptosis were detected by PI staining, Hoechst 33342 staining and FITC-Annexin V/PI staining. Bcl-2, bax, p53 and PARP expressions were determined by Western blot. Furthermore, mRNA levels of 5-fluorouracil metabolism related enzymes were detected by RT-PCR. KEY FINDINGS: Drug combination study showed that luteolin could synergize the antitumor effects of 5-fluorouracil at different dose ratios (luteolin: 5-fluorouracil=10:1, 20:1, 40:1) against HepG2 and Bel7402 cells. Cell viability and cell apoptosis analysis showed that the synergistic growth inhibition caused by combined luteolin and 5-fluorouracil was closely related to apoptosis. Further mechanism studies showed that the synergistic effects of drug combinations were related with enhanced bax/bcl-2 ratios and p53 expressions, and induced PARP cleavage. Also, combined luteolin and 5-fluorouracil could significantly decrease the dihydropyrimidine dehydrogenase. SIGNIFICANCE: These results showed that luteolin could synergize the antitumor effects of 5-fluorouracil on HepG2 and Bel7402 cells, which might be related with apoptosis and regulation of 5-fluorouracil metabolism.
AIMS: Some compounds derived from Chinese medicine have demonstrated great prospective roles in sensitization to chemotherapy. This study aimed to investigate the combination of luteolin and 5-fluorouracil on proliferations of hepatocellular carcinoma cells and the potential mechanisms. MAIN METHODS: The antitumor effects of luteolin, 5-fluorouracil, and their combinations were detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium/phenazine methosulfate assay, and isobole method was used to evaluate drug combinations. CellTiter-Blue and Caspase-Glo 3/7 assay were used for assessment of cell viability and apoptosis after treatment with luteolin, 5-fluorouracil and their combinations. Cell cycle distributions and apoptosis were detected by PI staining, Hoechst 33342 staining and FITC-Annexin V/PI staining. Bcl-2, bax, p53 and PARP expressions were determined by Western blot. Furthermore, mRNA levels of 5-fluorouracil metabolism related enzymes were detected by RT-PCR. KEY FINDINGS: Drug combination study showed that luteolin could synergize the antitumor effects of 5-fluorouracil at different dose ratios (luteolin: 5-fluorouracil=10:1, 20:1, 40:1) against HepG2 and Bel7402 cells. Cell viability and cell apoptosis analysis showed that the synergistic growth inhibition caused by combined luteolin and 5-fluorouracil was closely related to apoptosis. Further mechanism studies showed that the synergistic effects of drug combinations were related with enhanced bax/bcl-2 ratios and p53 expressions, and induced PARP cleavage. Also, combined luteolin and 5-fluorouracil could significantly decrease the dihydropyrimidine dehydrogenase. SIGNIFICANCE: These results showed that luteolin could synergize the antitumor effects of 5-fluorouracil on HepG2 and Bel7402 cells, which might be related with apoptosis and regulation of 5-fluorouracil metabolism.
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