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In the present study, the effects of apigenin on intensifying the chemosensitivity of HCC cells and an HCC xenograft model in response to 5\u2010fluorouracil (5\u2010FU) were investigated. Sub\u2010toxic concentrations of apigenin (4\u00a0<jats:italic>\u03bc<\/jats:italic>mol\/L) significantly enhanced the cytotoxicity of 5\u2010FU (100\u00a0<jats:italic>\u03bc<\/jats:italic>g\/mL) in HCC cells. <jats:italic>In vivo<\/jats:italic>, combined treatment with apigenin (20\u00a0mg\/kg, five times\/week for 3\u00a0weeks) and 5\u2010FU (20\u00a0mg\/kg for 5 consecutive days) significantly inhibited the growth of HCC xenograft tumours. Annexin V\u2013propidium iodide dual staining assays, terminal deoxyribonucleotidyl transferase\u2010mediated dUTP\u2013digoxigenin nick end\u2010labelling assays and western blotting analysis were used to confirm the synergistic effects of apigenin and 5\u2010FU on HCC apoptosis. Coincubation of HCC cells with apigenin and 5\u2010FU increased levels of reactive oxygen species (ROS), which was followed by a decrease in the mitochondrial membrane potential (\u0394\u03a8m). In addition, combined triggered the mitochondrial apoptotic pathway, as indicated by decreased Bcl\u20102 expression and loss of \u0394\u03a8m, with significant activation of caspase 3 and poly(ADP\u2010ribose) polymerase. The present study is the first to demonstrate that apigenin may potentiate the cytotoxicity of 5\u2010FU in HCC via inhibition of ROS\u2010mediated drug resistance and concurrent activation of the mitochondrial pathways of apoptosis.<\/jats:p>","DOI":"10.1111\/1440-1681.12333","type":"journal-article","created":{"date-parts":[[2014,11,1]],"date-time":"2014-11-01T02:49:35Z","timestamp":1414810175000},"page":"146-153","source":"Crossref","is-referenced-by-count":61,"title":["5\u2010Fluorouracil combined with apigenin enhances anticancer activity through mitochondrial membrane potential (\u0394\u03a8m)\u2010mediated apoptosis in hepatocellular carcinoma"],"prefix":"10.1111","volume":"42","author":[{"given":"Xiao\u2010Yun","family":"Hu","sequence":"first","affiliation":[{"name":"State Key Laboratory of Organ Failure Research Guangdong Provincial Key Laboratory of Viral Hepatitis Research Department of Infectious Diseases Nanfang Hospital Southern Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji\u2010Yun","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Nanfang Hospital Southern Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue\u2010Jun","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology Nanfang Hospital Southern Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Liu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research Guangdong Provincial Key Laboratory of Viral Hepatitis Research Department of Infectious Diseases Nanfang Hospital Southern Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya\u2010Bing","family":"Guo","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Organ Failure Research Guangdong Provincial Key Laboratory of Viral Hepatitis Research Department of Infectious Diseases Nanfang Hospital Southern Medical University Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,1,12]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.3322\/canjclin.55.2.74"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2008.01.022"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2007.04.061"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2011.12.001"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.510250201"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.44.5643"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/COC.0b013e318219863b"},{"key":"e_1_2_7_9_1","first-page":"1379","article-title":"Improved chemotherapy for hepatocellular carcinoma","volume":"32","author":"Cao H","year":"2012","journal-title":"Anticancer Res."},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.11-7-790"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/mnfr.201200424"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.3164\/jcbn.08-230"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2011.04.015"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.2741\/3735"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1089\/jmf.2010.0208"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2001.5672"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2012.04.013"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2007.09.015"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-002-0503-x"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-11-0343"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0625.2010.01091.x"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.fct.2013.07.036"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-010-0089-7"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2004.01.004"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2011.4414"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1089\/acm.2012.0295"},{"key":"e_1_2_7_27_1","first-page":"282570","article-title":"Chemotherapy and dietary phytochemical agents","volume":"2012","author":"Sak K","year":"2012","journal-title":"Chemother. 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