Reversing ABCB1-mediated multi-drug resistance from within cells using translocating immune conjugates

J Drug Target. 2012 Jun;20(5):445-52. doi: 10.3109/1061186X.2012.685473.

Abstract

Multi-drug resistance (MDR) is still a major cause of the eventual failure of chemotherapy in cancer treatment. Different approaches have been taken to render these cells drug sensitive. Here, we attempted sensitizing drug-resistant cells from within, using a translocating immune conjugate approach. To that effect, a monoclonal antibody, C219, directed against the intracellular ATP-binding site of the membrane-anchored MDR transporter ABCB1 [P-glycoprotein (P-gp), MDR1], was conjugated to human immunodeficiency virus [HIV(37-72)Tat] translocator peptide through a disulfide bridge. Fluorescence-labelled IgG-Tat conjugates accumulated in drug resistant Chinese hamster ovary (CHO) cells within less than 20 min. Preincubation with C219-S-S-(37-72)Tat conjugate augmented calcein accumulation in drug-resistant CHO and mouse lymphoma cells, indicating reduction in ABCB1 transporter activity. A thioether conjugate C219-S-(37-72)Tat was ineffective, as were disulfide and thioether conjugates of an irrelevant antibody. Furthermore, in the presence of C219-S-S-(37-72)Tat, drug resistant cells were sensitized to colchicine and doxorubicin. Taken together, these findings demonstrate, as proof of principle, a novel approach for the reversal of MDR from within cells, by delivery of translocating immune conjugates as sensitizing agents towards chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / immunology*
  • Adenosine Triphosphate / metabolism
  • Animals
  • Antibodies, Monoclonal / immunology*
  • CHO Cells
  • Cell Line, Tumor
  • Colchicine / pharmacology
  • Cricetinae
  • Cricetulus
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple
  • Humans
  • Immunoconjugates
  • Immunoglobulin G / immunology*
  • Lymphoma / drug therapy
  • Lymphoma / pathology
  • Mice
  • Time Factors
  • tat Gene Products, Human Immunodeficiency Virus / immunology*

Substances

  • ABCB1 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antibodies, Monoclonal
  • Immunoconjugates
  • Immunoglobulin G
  • tat Gene Products, Human Immunodeficiency Virus
  • Doxorubicin
  • Adenosine Triphosphate
  • Colchicine