Interaction between doxorubicin and the resistance modifier stilbene on multidrug resistant mouse lymphoma and human breast cancer cells.
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.
Ferreira
Maria-José U
MJ
CECF, Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.
Duarte
Noélia
N
Gyémánt
Nora
N
Radics
Rita
R
Cherepnev
Georgy
G
Varga
Andras
A
Molnár
Joseph
J
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D004347:Drug Interactions; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology; D028481:Euphorbia / Q000737:chemistry; D005456:Fluorescent Dyes / Q000493:pharmacokinetics; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D012639:Seeds / Q000737:chemistry; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D002121:Calcium Channel Blockers; D005456:Fluorescent Dyes; D013267:Stilbenes; D020112:Rhodamine 123; C041525:3,3',4,5'-tetrahydroxystilbene; D004317:Doxorubicin; D014700:Verapamil