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

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

Master & PhD Program in Biotechnology Industry

Research output: Contribution to journal › Journal Article › peer-review

71 Scopus citations

Abstract

The multikinase inhibitor, sorafenib (Nexavar (R), 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.

Original language	American English
Journal	PLoS ONE
Volume	8
Issue number	12
DOIs	https://doi.org/10.1371/journal.pone.0083627
State	Published - 2013

Keywords

CANCER RESISTANCE PROTEIN
COMBINATION
GEFITINIB
GROWTH-FACTOR RECEPTOR
LUNG-CANCER
MEDIATED DRUG-RESISTANCE
MODULATION
MULTIDRUG-RESISTANCE
TRANSPORTERS
TYROSINE KINASE INHIBITOR

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1371/journal.pone.0083627

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title = "BCRP/ABCG2 Inhibition Sensitizes Hepatocellular Carcinoma Cells to Sorafenib",

abstract = "The multikinase inhibitor, sorafenib (Nexavar (R), 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.",

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

year = "2013",

doi = "10.1371/journal.pone.0083627",

language = "American English",

volume = "8",

journal = "PLoS ONE",

issn = "1932-6203",

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number = "12",

}

TY - JOUR

T1 - BCRP/ABCG2 Inhibition Sensitizes Hepatocellular Carcinoma Cells to Sorafenib

AU - Huang, Wei-Chien

AU - Hsieh, Yi-Ling

AU - Hung, Chao-Ming

AU - Chien, Pei-Hsuan

AU - Chien, Yu-Fong

AU - Chen, Lei-Chin

AU - Tu, Chih-Yen

AU - Chen, Chia-Hung

AU - Hsu, Sheng-Chieh

AU - Lin, Yueh-Ming

AU - Chen, Yun-Ju

PY - 2013

Y1 - 2013

N2 - The multikinase inhibitor, sorafenib (Nexavar (R), 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.

AB - The multikinase inhibitor, sorafenib (Nexavar (R), 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.

KW - CANCER RESISTANCE PROTEIN

KW - COMBINATION

KW - GEFITINIB

KW - GROWTH-FACTOR RECEPTOR

KW - LUNG-CANCER

KW - MEDIATED DRUG-RESISTANCE

KW - MODULATION

KW - MULTIDRUG-RESISTANCE

KW - TRANSPORTERS

KW - TYROSINE KINASE INHIBITOR

U2 - 10.1371/journal.pone.0083627

DO - 10.1371/journal.pone.0083627

M3 - Journal Article

C2 - 24391798

SN - 1932-6203

VL - 8

JO - PLoS ONE

JF - PLoS ONE

IS - 12

ER -

BCRP/ABCG2 Inhibition Sensitizes Hepatocellular Carcinoma Cells to Sorafenib

Abstract

Keywords

UN SDGs

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