Oncotarget

Research Papers:

Cetuximab enhanced the efficacy of chemotherapeutic agent in ABCB1/P-glycoprotein-overexpressing cancer cells

Fang Wang, Yifan Chen, Lihua Huang, Tao Liu, Yue Huang, Jianming Zhao, Xiaokun Wang, Ke Yang, Shaolin Ma, Liyan Huang, Kenneth Kin Wah To, Yong Gu and Liwu Fu _

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Oncotarget. 2015; 6:40850-40865. https://doi.org/10.18632/oncotarget.5813

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Abstract

Fang Wang1,2,*, Yifan Chen1,2,*, Lihua Huang1,*, Tao Liu1, Yue Huang1, Jianming Zhao1, Xiaokun Wang1,2, Ke Yang1, Shaolin Ma1, Liyan Huang1, Kenneth Kin Wah To3, Yong Gu4, Liwu Fu1,2

1Collaborative Innovation Center for Cancer Medicine, State Key Laboratory of Oncology in South China, Sun Yat-Sen University Cancer Center, Guangzhou, China

2Guangdong Esophageal Cancer Institute, Guangzhou, China

3School of Pharmacy, the Chinese University of Hong Kong, Hong Kong, China

4Department of Thoracic Surgery, the First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong Province, China

*These authors have contributed equally to this work

Correspondence to:

Liwu Fu, e-mail: Fulw@mail.sysu.edu.cn

Yong Gu, e-mail: gugong64@163.com

Keywords: cetuximab, EGFR, multidrug resistance, ABCB1/P-glycoprotein, chemotherapeutic agent

Received: March 21, 2015     Accepted: September 23, 2015     Published: October 19, 2015

ABSTRACT

The overexpression of ATP-binding cassette (ABC) transporters is closely associated with the development of multidrug resistance (MDR) in certain types of cancer, which represents a formidable obstacle to the successful cancer chemotherapy. Here, we investigated that cetuximab, an EGFR monoclonal antibody, reversed the chemoresistance mediated by ABCB1, ABCG2 or ABCC1. Our results showed that cetuximab significantly enhanced the cytotoxicity of ABCB1 substrate agent in ABCB1-overexpressing MDR cells but had no effect in their parental drug sensitive cells and ABCC1, ABCG2 overexpressing cells. Furthermore, cetuximab markedly increased intracellular accumulation of doxorubicin (DOX) and rhodamine 123 (Rho 123) in ABCB1-overexpressing MDR cancer cells in a concentration-dependent manner. Cetuximab stimulated the ATPase activity but did not alter the expression level of ABCB1 or block phosphorylation of AKT and ERK. Interestingly, cetuximab decreased the cell membrane fluidity which was known to decrease the function of ABCB1. Our findings advocate further clinical investigation of combination chemotherapy of cetuximab and conventional chemotherapeutic drugs in ABCB1 overexpressing cancer patients.


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