Interaction between Doxorubicin and the Resistance Modifier Stilbene on Multidrug Resistant Mouse Lymphoma and Human Breast Cancer Cells

• Published in: Anticancer research Vol. 26; no. 5A; pp. 3541 - 3546
• Main Authors: FERREIRA, Maria-José U, DUARTE, Noélia, GYEMANT, Nora, RADICS, Rita, CHEREPNEV, Georgy, VARGA, Andras, MOLNAR, Joseph
• Format: Journal Article
• Language: English
• Published: Attiki International Institute of Anticancer Research 01-09-2006
• Subjects: Animals; Antibiotics, Antineoplastic - pharmacology; Apoptosis - drug effects; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Biological and medical sciences; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Calcium Channel Blockers - pharmacology; Cell Line, Tumor; Doxorubicin - pharmacology; Drug Interactions; Drug Resistance, Multiple - drug effects; Drug Resistance, Multiple - physiology; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - physiology; Euphorbia - chemistry; Fluorescent Dyes - pharmacokinetics; Hematologic and hematopoietic diseases; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma - drug therapy; Lymphoma - genetics; Lymphoma - metabolism; Medical sciences; Mice; Rhodamine 123 - pharmacokinetics; Seeds - chemistry; Stilbenes - chemistry; Stilbenes - pharmacology; Tumors; Verapamil - pharmacology; Antineoplastic agent; multidrug resistance; Doxorubicin; Isomerases; Cancerology; Stilbenes; Lymphoproliferative syndrome; Multiple resistance; Tumor cell; Human; DNA topoisomerase (ATP-hydrolysing); Treatment resistance; Enzyme; Rodentia; Enzyme inhibitor; Malignant hemopathy; Breast cancer; Malignant tumor; Lymphoid neoplasm; Lymphoma; Mammary gland diseases; Vertebrata; Mammalia; Euphorbia lagascae; Mouse; Cell death; Animal; Anthracyclins; Apoptosis
• ISSN: 0250-7005; 1791-7530

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, 1 H-NMR, 13 C-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.