5-Fluorouracil combined with apigenin enhances anticancer activity through mitochondrial membrane potential (ΔΨm)-mediated apoptosis in hepatocellular carcinoma

被引:66
作者
Hu, Xiao-Yun [1 ]
Liang, Ji-Yun [2 ]
Guo, Xue-Jun [2 ]
Liu, Li [1 ]
Guo, Ya-Bing [1 ]
机构
[1] Southern Med Univ, Nanfang Hosp, Dept Infect Dis, State Key Lab Organ Failure Res,Guangdong Prov Ke, Guangzhou 510515, Guangdong, Peoples R China
[2] Southern Med Univ, Nanfang Hosp, Dept Radiat Oncol, Guangzhou 510515, Guangdong, Peoples R China
关键词
5-fluorouracil; apigenin; apoptosis; chemosensitivity; hepatocellular carcinoma; CANCER-CELLS; PATHWAY; CHEMOTHERAPY; STRESS; GEMCITABINE; MECHANISM; NECROSIS; RECEPTOR; THERAPY; HEAD;
D O I
10.1111/1440-1681.12333
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The development of chemoresistance may reduce the efficacy of chemotherapeutic drugs for treating hepatocellular carcinoma (HCC). In the present study, the effects of apigenin on intensifying the chemosensitivity of HCC cells and an HCC xenograft model in response to 5-fluorouracil (5-FU) were investigated. Sub-toxic concentrations of apigenin (4mol/L) significantly enhanced the cytotoxicity of 5-FU (100g/mL) in HCC cells. In vivo, combined treatment with apigenin (20mg/kg, five times/week for 3weeks) and 5-FU (20mg/kg for 5 consecutive days) significantly inhibited the growth of HCC xenograft tumours. Annexin V-propidium iodide dual staining assays, terminal deoxyribonucleotidyl transferase-mediated dUTP-digoxigenin nick end-labelling assays and western blotting analysis were used to confirm the synergistic effects of apigenin and 5-FU on HCC apoptosis. Coincubation of HCC cells with apigenin and 5-FU increased levels of reactive oxygen species (ROS), which was followed by a decrease in the mitochondrial membrane potential (m). In addition, combined triggered the mitochondrial apoptotic pathway, as indicated by decreased Bcl-2 expression and loss of m, with significant activation of caspase 3 and poly(ADP-ribose) polymerase. The present study is the first to demonstrate that apigenin may potentiate the cytotoxicity of 5-FU in HCC via inhibition of ROS-mediated drug resistance and concurrent activation of the mitochondrial pathways of apoptosis.
引用
收藏
页码:146 / 153
页数:8
相关论文
共 36 条
[1]   Gemcitabine and Docetaxel for Hepatocellular Carcinoma A Phase II North Central Cancer Treatment Group Clinical Trial [J].
Alberts, Steven R. ;
Reid, Joel M. ;
Morlan, Bruce W. ;
Farr, Gist H., Jr. ;
Camoriano, John K. ;
Johnson, David B. ;
Enger, James R. ;
Seay, Thomas E. ;
Kim, George P. .
AMERICAN JOURNAL OF CLINICAL ONCOLOGY-CANCER CLINICAL TRIALS, 2012, 35 (05) :418-423
[2]   Dangerous Combinations: Ingestible CAM Supplement Use During Chemotherapy in Patients with Ovarian Cancer [J].
Andersen, M. Robyn ;
Sweet, Erin ;
Lowe, Kimberly A. ;
Standish, Leanna J. ;
Drescher, Charles W. ;
Goff, Barbara A. .
JOURNAL OF ALTERNATIVE AND COMPLEMENTARY MEDICINE, 2013, 19 (08) :714-720
[3]   Treatment of hepatocellular carcinoma (HCC) with systemic chemotherapy combining epirubicin, cisplatinum and infusional 5-fluorouracil (ECF regimen) [J].
Boucher, E ;
Corbinais, S ;
Brissot, P ;
Boudjema, K ;
Raoul, JL .
CANCER CHEMOTHERAPY AND PHARMACOLOGY, 2002, 50 (04) :305-308
[4]  
Bruix J, 1997, HEPATOLOGY, V25, P259
[5]   Apigenin Induces Apoptosis in Human Leukemia Cells and Exhibits Anti-Leukemic Activity In Vivo [J].
Budhraja, Amit ;
Gao, Ning ;
Zhang, Zhuo ;
Son, Young-Ok ;
Cheng, Senping ;
Wang, Xin ;
Ding, Songze ;
Hitron, Andrew ;
Chen, Gang ;
Luo, Jia ;
Shi, Xianglin .
MOLECULAR CANCER THERAPEUTICS, 2012, 11 (01) :132-142
[6]   Apigenin induces apoptosis via tumor necrosis factor receptor- and Bcl-2-mediated pathway and enhances susceptibility of head and neck squamous cell carcinoma to 5-fluorouracil and cisplatin [J].
Chan, Leong-Perng ;
Chou, Tzung-Han ;
Ding, Hsiou-Yu ;
Chen, Pin-Ru ;
Chiang, Feng-Yu ;
Kuo, Po-Lin ;
Liang, Chia-Hua .
BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, 2012, 1820 (07) :1081-1091
[7]   Apigenin Induces Apoptosis through a Mitochondria/Caspase-Pathway in Human Breast Cancer MDA-MB-453 Cells [J].
Choi, Eun Jeong ;
Kim, Gun-Hee .
JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION, 2009, 44 (03) :260-265
[8]   Antioxidative characteristics and inhibition of α-melanocyte-stimulating hormone-stimulated melanogenesis of vanillin and vanillic acid from Origanum vulgare [J].
Chou, Tzung-Han ;
Ding, Hsiou-Yu ;
Hung, Wei Jing ;
Liang, Chia-Hua .
EXPERIMENTAL DERMATOLOGY, 2010, 19 (08) :742-750
[9]   Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis [J].
El-Serag, Hashem B. ;
Rudolph, Lenhard .
GASTROENTEROLOGY, 2007, 132 (07) :2557-2576
[10]  
European Assoc Study Liver, 2012, EUR J CANCER, V48, P599, DOI [10.1016/j.ejca.2011.12.021, 10.1016/j.jhep.2011.12.001]