BCRP/ABCG2 inhibition sensitizes hepatocellular carcinoma cells to sorafenib

Wei-Chien Huang; Yi-Ling Hsieh; Chao-Ming Hung; Pei-Hsuan Chien; Yu-Fong Chien; Lei-Chin Chen; Chih-Yen Tu; Chia-Hung Chen; Sheng-Chieh Hsu; Yueh-Ming Lin; Yun-Ju Chen

doi:10.1371/journal.pone.0083627

BCRP/ABCG2 inhibition sensitizes hepatocellular carcinoma cells to sorafenib

PLoS One. 2013 Dec 31;8(12):e83627. doi: 10.1371/journal.pone.0083627. eCollection 2013.

Authors

Affiliations

¹ 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.
² Department of Biological Science & Technology, I-Shou University, Kaohsiung, Taiwan.
³ School of Medicine for International Students, I-Shou University, Kaohsiung, Taiwan ; Department of General Surgery, E-Da Hospital, Kaohsiung, Taiwan.
⁴ Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan.
⁵ Department of Nutrition, I-Shou University, Kaohsiung, Taiwan.
⁶ 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.
⁷ 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.
⁸ Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
⁹ Division of Colorectal Surgery, Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
¹⁰ Department of Biological Science & Technology, I-Shou University, Kaohsiung, Taiwan ; Department of Medical Research, E-Da Hospital, Kaohsiung, Taiwan.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters / antagonists & inhibitors*
ATP-Binding Cassette Transporters / genetics
Antineoplastic Agents / administration & dosage
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Biological Transport, Active
Carcinoma, Hepatocellular / drug therapy*
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism*
Cell Line, Tumor
Drug Resistance, Multiple
Drug Resistance, Neoplasm
Drug Synergism
Gefitinib
Hep G2 Cells
Humans
Liver Neoplasms / drug therapy*
Liver Neoplasms / genetics
Liver Neoplasms / metabolism*
MAP Kinase Signaling System
Neoplasm Proteins / antagonists & inhibitors*
Neoplasm Proteins / genetics
Niacinamide / administration & dosage
Niacinamide / analogs & derivatives*
Niacinamide / pharmacokinetics
Niacinamide / pharmacology
Phenylurea Compounds / administration & dosage
Phenylurea Compounds / pharmacokinetics
Phenylurea Compounds / pharmacology*
Protein Kinase Inhibitors / administration & dosage
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology
Quinazolines / administration & dosage
Quinazolines / pharmacology
RNA, Small Interfering / genetics
Sorafenib

Substances

ABCG2 protein, human
ATP Binding Cassette Transporter, Subfamily G, Member 2
ATP-Binding Cassette Transporters
Antineoplastic Agents
Neoplasm Proteins
Phenylurea Compounds
Protein Kinase Inhibitors
Quinazolines
RNA, Small Interfering
Niacinamide
Sorafenib
Gefitinib

Grants and funding

This work was supported by grants from the National Science Council of Taiwan (NSC-101-2911-I-002-303, NSC-101-2320-B-214-005, NSC-102-2320-B-039-054-MY3, NSC-102-2320-B-039-052), E-Da Hospital, Taiwan (EDAHT100026, EDPJ101039), I-Shou University, Taiwan (ISU101-S-06), the National Health Research Institutes of Taiwan (NHRI-EX-101-9812BC) and China Medical University and Hospital (CMU101-S-28). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.