Multidrug resistance reversal in mouse lymphoma cells by heterocyclic compounds

Joseph Molnár, Diana Szabo, Yvette Mándi, Ilona Mucsi, János Fischer, Andreas Varga, Sigrid König, Noboru Motohashi

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Abstract

Due to the close homology between bacterial and tumor cell transporter proteins, some antiplasmid and anticancer compounds were tested for their ability to reserve the multidrug resistance (mdr) of lymphoma cells. Some known anticancer medicines such as platidiam, novantron, fluorouracil, bleomycin and methotrexate were ineffective/while vinca alkaloids exerted a strong reversal effect on the mdr of lymphoma cells. The structurally related reserpine and yohimbine do not affect the activity of efflux pump. Some selected antitumor phenothiazines and benzo[a]phenothiazines, including trifluoperazine inhibit the P-glycoprotein (pgp) function. This fact is independent from the antiproliferative- or differentiation inducing effects. Since the polylactosamine specific tomato lectin prevents the action of the chemosensitizers tested, it is supposed that the site of action of phenothiazines can be at the 1st loop in the transmembrane glycoprotein. The efflux pump activity of the pgp in brain capillary endothel which is responsible for blood brain barrier (BBB) was also inhibited by some phenothiazines. However, the tomato lectin sensitivity of pgp was different in mouse lymphoma and human brain capillary endothelial cells. The mdr-gene expression of the mouse lymphoma cells (which were transfected with the human mdr-1 gene) could be reduced by phenothiazines such as promethazine and trifluoperazine, when the cells were cultured in the presence of 0.5 μg/mL phenothiazines. Further synergism was found between two resistance modifiers i.e. verapamil and trifluoperazine on the inhibition of mdr-glycoprotein.

Original languageEnglish
Pages (from-to)3033-3038
Number of pages6
JournalAnticancer research
Volume18
Issue number4 C
Publication statusPublished - Jul 1 1998

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Keywords

  • Blood brain barrier
  • Multidrug resistance
  • Phenothiazines
  • Tomato lectin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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