title: BCRP/ABCG2 inhibition sensitizes hepatocellular carcinoma cells to sorafenib.
abstract: The multikinase inhibitor, sorafenib (Nexavar®, BAY43-9006), which inhibits both the Raf/MEK/ERK pathway and several receptor tyrosine kinases (RTKs), has shown significantly therapeutic benefits in advanced hepatocellular carcinoma (HCC). However, not all HCC patients respond to sorafenib well and new therapeutic strategies to optimize the efficacy of sorafenib are urgently required. Overexpression of breast cancer resistance protein (BCRP/ABCG2) mediates the drug-efflux of several tyrosine kinase inhibitors (TKIs) to attenuate their efficacy. This study aimed to investigate the role of BCRP/ABCG2 in the sensitivity of HCC to sorafenib. Our data showed that BCRP/ABCG2 mediated the efflux of sorafenib. Co-treatment with a BCRP/ABCG2 inhibitor greatly augmented the cytotoxicity of sorafenib in HCC cells. Similar results were also achieved by the competitive inhibitor of BCRP/ABCG2, gefitinib, in combination with sorafenib. These results suggest not only that BCRP/ABCG2 is a potential predictor for the sorafenib sensitivity in HCC, but also that blockage of BCRP/ABCG2 may be a potential strategy to increase the response of HCC cells to sorafenib.
authors.affiliation: Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan ; Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan ; The Ph.D. program for Cancer Biology and Drug Discovery, China Medical University, Taichung, Taiwan ; Department of Biotechnology, Asia University, Taichung, Taiwan.
authors.forename: Wei-Chien
authors.initials: WC
authors.lastname: Huang
authors.affiliation: Department of Biological Science & Technology, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Hsieh
authors.affiliation: School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan ; Department of General Surgery, E-Da Hospital, Kaohsiung, Taiwan.
authors.forename: Chao-Ming
authors.initials: CM
authors.lastname: Hung
authors.affiliation: Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan.
authors.forename: Pei-Hsuan
authors.initials: PH
authors.lastname: Chien
authors.affiliation: Department of Biological Science & Technology, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Yu-Fong
authors.initials: YF
authors.lastname: Chien
authors.affiliation: Department of Nutrition, I-Shou University, Kaohsiung, Taiwan.
authors.forename: Lei-Chin
authors.initials: LC
authors.lastname: Chen
authors.affiliation: Division of Pulmonary and Critical Care Medicine, China Medical University Hospital, Taichung, Taiwan ; Department of Internal Medicine, China Medical University, Taichung, Taiwan ; Department of Life Science, National Chung-Hsing University, Taichung, Taiwan.
authors.forename: Chih-Yen
authors.initials: CY
authors.lastname: Tu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, China Medical University Hospital, Taichung, Taiwan ; Department of Respiratory Therapy, China Medical University, Taichung, Taiwan ; Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Chia-Hung
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Sheng-Chieh
authors.initials: SC
authors.lastname: Hsu
authors.affiliation: Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Yueh-Ming
authors.initials: YM
authors.lastname: Lin
authors.affiliation: Department of Biological Science & Technology, I-Shou University, Kaohsiung, Taiwan ; Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan.
authors.forename: Yun-Ju
authors.initials: YJ
authors.lastname: Chen
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D001693:Biological Transport, Active; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D000077156:Gefitinib; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D000077157:Sorafenib
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D034741:RNA, Small Interfering; D009536:Niacinamide; D000077157:Sorafenib; D000077156:Gefitinib