Interaction between doxorubicin and the resistance modifier stilbene on multidrug resistant mouse lymphoma and human breast cancer cells

Maria José U. Ferreira, Noélia Duarte, Nora Gyémánt, Rita Radics, Georgy Cherepnev, Andras Varga, Joseph Molnár

Research output: Article

44 Citations (Scopus)

Abstract

The hydroxystilbene trans-3,5,3′,4′-tetrahydroxystilbene (piceatannol) (1), isolated from the methanol extract of Euphorbia lagascae defatted seeds, was methylated to yield the derivatives trans-3,5,3′, 4′-tetramethoxystilbene (2), (trans-3,5-dihydroxy-3′,4′- dimethoxystilbene) (3) and trans-3,5,3′-trihydroxy-4′- methoxystilbene (4). The structures of the compounds were assigned by spectroscopic methods (IR, 1H-NMR, 13C-NMR and MS), The ability of piceatannol (1) and the three methylated derivatives to modulate the transport activity of P-glycoprotein (P-gp) and apoptosis induction on the L5178 mouse lymphoma cell line containing the human MDR1 gene was studied by flow cytometry. The reversal of multidrug-resistance (MDR) was investigated by measuring the accumulation of rhodamine-123, a fluorescent substrate analog of doxorubicin, in cancer cells. Verapamil was applied as a positive control. For the evaluation of the compounds as apoptosis inducers, tumor cells were stained with FITC-labelled annexin-V and propidium iodide. The tetramethylated derivative (2) was found to be a powerful inhibitor of P-gp activity. Compounds I and 2 showed an increased apoptotic effect in the MDR subline, the most active being piceatannol (1). Furthermore, in the combination chemotherapy model, the interaction between doxorubicin and the resistance modifier 2 was studied in vitro. The results of checkerboard experiments indicated that the type of interaction was additive between doxorubicin and compound 2 on the human MDR1 gene-transfected mouse lymphoma cells. However, in the MCF7/dox human breast cancer cells, the interaction was non-additive. The degree of additive and non-additive interactions were close to the borderline of the FIX values corresponding to the two types of interactions.

Original languageEnglish
Pages (from-to)3541-3546
Number of pages6
JournalAnticancer research
Volume26
Issue number5 A
Publication statusPublished - szept. 2006

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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