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

Oncotarget. 2015 Dec 1;6(38):40850-65. 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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Blotting, Western
  • Cell Proliferation / drug effects
  • Cetuximab / pharmacology*
  • Drug Resistance, Multiple / drug effects*
  • Drug Resistance, Neoplasm / drug effects*
  • ErbB Receptors / antagonists & inhibitors
  • ErbB Receptors / metabolism
  • Humans
  • Immunoenzyme Techniques
  • Immunoprecipitation
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • RNA, Messenger
  • EGFR protein, human
  • ErbB Receptors
  • Cetuximab