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

Hans Wellhöner, Aryeh Weiss, Axel Schulz, Knut Adermann, Ori Braitbard, Allan Bar-Sinai, Jacob Hochman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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(3772)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-(3772)Tat conjugate augmented calcein accumulation in drug-resistant CHO and mouse lymphoma cells, indicating reduction in ABCB1 transporter activity. A thioether conjugate C219-S-(3772)Tat was ineffective, as were disulfide and thioether conjugates of an irrelevant antibody. Furthermore, in the presence of C219-S-S-(3772)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.

Original languageEnglish
Pages (from-to)445-452
Number of pages8
JournalJournal of Drug Targeting
Volume20
Issue number5
DOIs
StatePublished - Jun 2012

Keywords

  • C219 antibody
  • HIV-Tat
  • Immune conjugates
  • MDR

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