Browsing by Author "Varga, Andras"
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- Apoptosis induction and modulation of P-glycoprotein mediated multidrug resistance by new macrocyclic lathyrane-type diterpenoidsPublication . Duarte, Noelia; Varga, Andras; Cherepnev, Georg; Radics, Rita; Molnar, Joseph; Ferreira, Maria-Jose U.The macrocyclic lathyrane diterpenes, latilagascenes D-F (1-3) and jolkinol B (4), were isolated from the methanol extract of Euphorbia lagascae, and evaluated for multidrug resistance reversing activity on mouse lymphoma cells. All compounds displayed very strong activity compared with that of the positive control, verapamil. The structure-activity relationship is discussed. The evaluation of compounds 1 and 4, and of latigascenes A-C (5-7), isolated from the same species, as apoptosis-inducers was also carried out. Compound I was the most active. Furthermore, in the model of combination chemotherapy, the interaction between the doxorubicine and latilagascene B (6) was studied in vitro, on human MDR1 gene transfected mouse lymphoma cells, showing that the type of interaction was synergistic. Latilagascenes D-F (1-3) are new compounds whose structures were established on the basis of spectroscopic methods, including 2D NMR experiments (COSY, HMQC, HMBC and NOESY). (c) 2006 Elsevier Ltd. All rights reserved.
- Interaction between doxorubicin and the resistance modifier stilbene on multidrug resistant mouse lymphoma and human breast cancer cellsPublication . Ferreira, Maria-Jose U.; Duarte, Noelia; Gyemant, Nora; Radics, Rita; Cherepnev, Georgy; Varga, Andras; Molnar, JosephThe 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'-trihydroxy4'-methoxystilbene (4). The structures of the compounds were assigned by spectroscopic methods (IR, H-1-NMR, C-13-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.
- Multidrug Resistance Modulation and Apoptosis Induction of Cancer Cells by Terpenic Compounds Isolated from Euphorbia SpeciesPublication . Duarte, Noelia; Ramalhete, Catia; Varga, Andras; Molnar, Joseph; Ferreira, Maria-Jose U.Background: One of the most promising strategies to overcome multidrug resistance (MDR) is to use compounds that can modulate P-glycoprotein and restore the cytotoxicity of anticancer drugs. Furthermore, the search for compounds that regulate and overcome apoptosis deficiency of cancer cells is also of great therapeutic importance. Materials and Methods: Seven known pentacyclic triterpenes and one steroid were isolated from Euphorbia lagascae methanolic extracts and identified by physical and spectroscopic methods. These compounds, together with eleven terpenoids previously isolated from Euphorbia lagascae and E. tuckeyana were tested for their MDR-reversing and/or apoptosis induction activities by flow cytometry on L5178 human MDR1 gene-transfected mouse lymphoma cells. Results: Four taraxastane-type triterpenes: 21 alpha-hydroxytaraxasterol, 21 alpha-hydroxytaraxasterol acetate, 3 beta,30-dihydroxy-20(21)-taraxastene and 3 beta-hydroxy-20-taraxasten-30-al, and two steroids: stigmastane-3,6-dione and ergosterol peroxide exhibited a significant MDR-Pgp modulation activity. Some aspects of structure-activity relationships are discussed. Regarding apoptosis induction, the most significant results were obtained for the polycyclic diterpenes ent-16 alpha, 17-dihydroxykauran-3-one and ent-16 alpha,17-dihydroxyatisan-3-one.