PT  - JOURNAL ARTICLE
AU  - FERREIRA, MARIA-JOSÉ U.
AU  - DUARTE, NOÉLIA
AU  - GYÉMÁNT, NORA
AU  - RADICS, RITA
AU  - CHEREPNEV, GEORGY
AU  - VARGA, ANDRAS
AU  - MOLNÁR, JOSEPH
TI  - Interaction between Doxorubicin and the Resistance Modifier Stilbene on Multidrug Resistant Mouse Lymphoma and Human Breast Cancer Cells
DP  - 2006 Sep 01
TA  - Anticancer Research
PG  - 3541--3546
VI  - 26
IP  - 5A
4099  - http://ar.iiarjournals.org/content/26/5A/3541.short
4100  - http://ar.iiarjournals.org/content/26/5A/3541.full
SO  - Anticancer Res2006 Sep 01; 26
AB  - 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 1 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. Copyright© 2006 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved