Browsing by Author "Molnar, Joseph"
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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.
- Cucurbitane-Type Triterpenoids from the African Plant Momordica balsaminaPublication . Ramalhete, Catia; Mansoor, Tayyab A.; Mulhovo, Silva; Molnar, Joseph; Ferreira, Maria-Jose U.Phytochemical investigation of the aerial parts of Momordica balsamina led to the isolation of five new cucurbitane-type triterpenoids (1-5) and two known analogues (6, 7). Their structures were elucidated on the basis of spectroscopic methods including 2D NMR experiments (COSY, HMQC, HMBC, and NOESY). The new compounds feature unusual oxidation patterns in the cucurbitane skeleton, such as at C-29 (1-3) and C-12 (4, 5). Compounds 1-4, 6, and 7 were evaluated for in vitro cytotoxicity against human breast cancer cells (MCF-7), using the MTT assay.
- Euphoportlandols A and B, tetracylic diterpene polyesters from Euphorbia portlandica and their anti-MDR effects in cancer cellsPublication . Madureira, Ana M.; Gyemant, Nora; Ascenso, Jose R.; Abreu, Pedro M.; Molnar, Joseph; Ferreira, Maria-Jose U.Two new tetracyclic diterpene polyesters, euphoportlandols A (1) and B (2), have been isolated along with 12 known tetracyclic triterpenes from an acetone extract of Euphorbia portlandica. Their structures were established as 5 alpha, 11 alpha,-14 alpha, 17-tetraacetoxy-3 beta-benzoyloxy-6 beta, 15 beta-dihydroxy-9-oxoseget-8(12)-ene (1) and 5 alpha,11 alpha,14 alpha,17-tetraacetoxy-3 beta-benzoyloxy- 6 beta, 15 beta- dihydroxy-9-oxosegetane (2), respectively, by spectroscopic data interpretation. Compounds 1 and 2 were evaluated for their ability to inhibit multidrug resistance in cancer cells. Both compounds were found to be inhibitors of P-glycoprotein activity.
- Evaluation of Cucurbitane-type Triterpenoids from Momordica balsamina on P-Glycoprotein (ABCB1) by Flow Cytometry and Real-time FluorometryPublication . Spengler, Gabriella; Ramalhete, Catia; Martins, Marta; Martins, Ana; Serly, Julianna; Viveiros, Miguel; Molnar, Joseph; Duarte, Noelia; Mulhovo, Silva; Ferreira, Maria-Jose U.; Amaral, LeonardBackground: Cancer cells become refractory to chemotherapy as a consequence of their overexpressing ABC transporters that extrude not only the therapeutic agent but other unrelated compounds such as chemotoxins and biocides before they can reach their intended targets. A compound that can inhibit the activity of these transporters may find use as an adjunct to chemotherapy that had been rendered ineffective. Materials and Methods: Four curcubitane-type triterpenes isolated from Momordica balsamina Linn. (Cucurbitaceae), a plant from Mozambique were evaluated for their inhibition of the ABC transporter P-glycoprotein coded by the human ABCB1 gene transfected into mouse lymphoma cells. The evaluation was conducted by flow cytometry using rhodamine 123 and real-time fluorometry assessing accumulation of ethidium bromide (EB) on a real-time basis. Results: Among the compounds isolated, the most active was 7-methoxycucurbita-5,24-diene-3 beta,23(R)-diol, which inhibited the efflux of ethidium bromide (EB) and rhodamine 123 from the ABCB1-transfected mouse lymphoma cell. Conclusion: Real-time fluorometry replicated the flow cytometric results with significant advantages for the evaluation of efflux pump inhibitors. The substitution of side groups on the cucurbitane skeleton appears to be significant in the inhibition of ABCB1 activity.. - Fundacao para a Ciencia e a Tecnologia [FCT], Portugal [SFRH/BPD/34578/2007, SFRH/BD/22321/2005, SFRH/BD/19445/2004]; Luso-Hungarian Cooperation [FCT/DREBM 00542, OMFB-00389/2008, PT-13/2007]. - G. Spengler, C. Ramalhete and A. Martins were supported by grants SFRH/BPD/34578/2007, SFRH/BD/22321/2005 and SFRH/BD/19445/2004 (Fundacao para a Ciencia e a Tecnologia [FCT], Portugal), respectively and by Luso-Hungarian Cooperation FCT/DREBM 00542, OMFB-00389/2008, PT-13/2007.
- INHIBITION OF P-GLYCOPROTEIN TRANSPORT ACTIVITY IN A RESISTANT MOUSE LYMPHOMA CELL LINE BY DITERPENIC LACTONESPublication . Ferreira, Maria-Jose U.; Gyemant, Nora; Madureira, Ana M.; Molnar, Joseph
- 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.
- MACROCYCLIC DITERPENES AS LEAD COMPOUNDS FOR THE DEVELOPMENT OF P-GLYCOPROTEIN MODULATORS IN MULTIDRUG-RESISTANT CANCER CELLSPublication . Ferreira, Maria-Jose U.; Duarte, Noelia; Jardanhazy, Anett; Madureira, Ana-Margarida; Ramalhete, Catia; Ocsovszki, Imre; Molnar, Joseph
- Macrocyclic lathyrane and jatrophane diterpenes as P-glycoprotein modulators in multi-drug-resistant cancer cellsPublication . Ferreira, MJU; Duarte, Noélia; Járdánházy, Anett; Madureira, AM; Ramalhete, C; Molnar, Joseph
- Macrocyclic lathyrane diterpenes as antitumor promotersPublication . Pusztai, Rozalia; Ferreira, Maria-Jose U.; Duarte, Notlia; Engi, Helga; Molnar, JosephHuman cytomegalovirus (CMV) preferentially infects tumor tissues and the accumulated CMV immediate-early (IE) antigen may lead to tumor promotion and progression. The development of strategies to inhibit human CMV IE antigen expression and/or function is an important goal to prevent and treat certain forms of cancers associated with human CMV. The aim of this study was to search for antitumor promoters from plant sources. The effect of six macrocyclic lathyrane-type diterpenoids, latilagascenes A-E (1-5) and jolkinol B (6), isolated from the methanol extract of Euphorbia lagascae, on the expression of IE antigen in lung cancer cells (A549) infected by CMV was studied. All the compounds, except latilagascene D (4), decreased IE antigen expression of CMV.
- 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.