Inhibition of the multidrug resistance protein 1 (MRP1) by peptidomimetic glutathione-conjugate analogs.

Danny Burg, Pieter Wielinga, Noam Zelcer, Tohru Saeki, Gerard J. Mulder, Piet Borst

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Inhibition of multidrug resistance protein 1 (MRP1) mediated cytostatic drug efflux might be useful in the treatment of drug resistant tumors. Because the glutathione (GSH) conjugate of ethacrynic acid (EA), GS-EA, is a good substrate of MRP1, GS-EA derivatives are expected to be good inhibitors of MRP1. To study structure-activity relationships of MRP1 inhibition, a series of novel GS-EA analogs was synthesized in which peptide bonds of the GSH backbone were replaced by isosteric groups (Bioorg Med Chem 10:195-205, 2002). Several of these compounds were effective inhibitors of MRP1-mediated (3H)GS-EA and (3H)E217betaG transport, as studied in membrane vesicles prepared from MRP1-overproducing Sf9 cells. The modifications of the peptide backbone have distinct implications for recognition by MRP1: the gamma-glutamyl-cysteine peptide bond is important for binding, whereas the cysteinyl-glycine amide does not seem essential. When the gamma-glutamyl-cysteine peptide bond (C-CO-N) is replaced by a urethane isostere (O-CO-N), an effective competitive MRP1-inhibitor (Ki = 11 muM) is obtained. After esterification of this compound to improve its cellular uptake, it inhibited MRP1-mediated efflux of calcein from 2008 ovarian carcinoma cells overexpressing MRP1. This compound also partially reversed the resistance of these cells to methotrexate. Because the urethane isostere is stable toward gamma-glutamyl transpeptidase-mediated breakdown, it is an interesting lead-compound for the development of in vivo active MRP1 inhibitors.
Original languageEnglish
JournalMolecular Pharmacology
Volume62
Issue number5
Pages (from-to)1160-1166
ISSN0026-895x
Publication statusPublished - 2002
Externally publishedYes

Keywords

  • drug resistance
  • ovarian carcinoma Ovarian Neoplasms (MeSH) Carcinoma (MeSH) neoplastic disease, reproductive system disease/female
  • Insecta Arthropoda Invertebrata Animalia (Animals, Arthropods, Insects, Invertebrates) - Lepidoptera [75330] Sf9 cell line cell line
  • Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] 2008 cell line cell line ovarian carcinoma
  • ethacrynic acid glutathione conjugate
  • methotrexate 59-05-2 antineoplastic-drug resistance
  • multidrug resistance protein 1 MRP1 inhibition
  • 10060, Biochemistry studies - General
  • 12512, Pathology - Therapy
  • 16506, Reproductive system - Pathology
  • 22002, Pharmacology - General
  • 22005, Pharmacology - Clinical pharmacology
  • 24004, Neoplasms - Pathology, clinical aspects and systemic effects
  • 24008, Neoplasms - Therapeutic agents and therapy
  • 64076, Invertebrata: comparative, experimental morphology, physiology and pathology - Insecta: physiology
  • Pharmacology
  • Tumor Biology

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