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

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

doi:10.18632/oncotarget.5813

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.

Highlights

multidrug resistance (MDR) is a well characterized broad pattern of cross resistance to various structurally unrelated drugs after exposure to a single drug, which is a formidable barrier to the successful cancer chemotherapy
Western blot analysis confirmed that ABCB1 was overexpression in KBv200, MCF-7/adr and HEK293/ ABCB1 cells, while undetectable expression levels were exhibited in their parental drug sensitive KB, MCF-7 and HEK293/pcDNA3.1 cells; and ABCC1 and ABCG2 were overexpression in HL60/adr and S1-MI-80 cells, but not in their parental sensitive HL60 and S1 cells, respectively (Figure 1)
We investigated the cytotoxicity of cetuximabin different cancer cells by MTT assay

Summary

Introduction

MDR is a well characterized broad pattern of cross resistance to various structurally unrelated drugs after exposure to a single drug, which is a formidable barrier to the successful cancer chemotherapy. The mechanism associated with efflux of drugs has focused on the overexpression of the superfamily of ABC transporters that function as active drug efflux pump leading to extrude a wide range of structurally and mechanistically diverse anticancer drugs against a concentration gradient, thereby resulting in chemo therapy failure [1]. ABCB1, ABCC1, and ABCG2 play major roles in the development of MDR in cancer cells [3]. Overexpression of ABCB1 on the surface of cancer cells is considered as the most common explanation of MDR. A lot of MDR inhibitors have been developed to reverse MDR, some of which are being evaluated in clinical trials for their potential circumvention of anticancer drug resistance [6,7,8,9,10,11]. No transporter inhibitors have been put into use in the clinic because of insufficient efficacy, unacceptable toxicity or unpredictable pharmacokinetic interactions [12, 13]

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Conclusion