Biomedical subjects

Nóra Gyémánt

Publications and source records attributed to Nóra Gyémánt.

9 recordsLinked to original sources

PubMed2006

P-glycoprotein effects of cyclic urea HIV protease inhibitor DMP 323 in competitional absorption studies.

Cyclic ureas form a perspective class of non-peptidic HIV-1 protease inhibitors with major bioavailability problems. Low absorption rates of DMP 323 as one of the first representatives led to investigations whether transport efflux pump P-glycoprotein (P-gp) within the intestine may be partly responsible for the low absorption rates. DMP 323 proved to be a P-gp substrate in competition studies with P-gp inhibitor ritonavir and H17 as a representative of another class of non-peptidic HIV-1 protease inhibitors. Intestinal DMP 323 absorption was mainly increased under co-application of both ritonavir and H17. DMP 323 used as a membrane efflux pump inhibitor itself showed little affinities to P-gp compared to H17 as strong P-gp inhibitor. So P-gp proved to play a decisive role in the low intestinal absorption of the cyclic urea representative DMP 323.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2006

Inhibition of multidrug resistance of cancer cells by natural diterpenes, triterpenes and carotenoids.

The multidrug resistance (MDR) proteins are member of the ATP-binding cassette superfamily and are present in a majority of human tumors. Their activity is a crucial factor leading to therapeutic failure. It is likely that compounds which inhibit the function of the MDR-efflux proteins such as MDR1 will improve the cytotoxic action of anticancer chemotherapy. Therefore, a search for MDR reversing compounds was conducted among three classes of plant derived compounds such as diterpenes, triterpenes and carotenoids in a hope to find inhibitors without adverse effects in these natural compounds. The inhibition of efflux activity was determined by measuring the accumulation of substrate analogues such as rhodamine in tumor cells in the presence of potential inhibitors. Thus we determined the effect of structurally unrelated diterpenes, triterpenes and carotenoids on reversal of multidrug resistance in MDR-1 gene-transfected L1210 mouse lymphoma cells and MDR mediated multidrug resistance of human breast cancer cells MDA-MB-231 (HTB-26) and MCF-7. The majority of diterpenes, cycloartane triterpenes and carotenoids isolated from vegetables and medicinal plants were able to enhance rhodamine 123 accumulations of MDR-cells. Synergistic interaction was found between epirubicine and resistance modifier terpenoids in vitro. It is supposed that these MDR modulators bind into transmembrane domains and the action of ABC transporters is inhibited by induced conformational changes.

Animals↗

PubMed2005

Biological activity of carotenoids in red paprika, Valencia orange and Golden delicious apple.

Carotenoid fractions were extracted from red paprika, Valencia orange peel and the peel of Golden delicious apple. Thus, hypophasic carotenoids of paprika (PM1), orange (PM3) and apple (PM4), and epiphasic extractions of paprika (PM2) and apple (PM5) were obtained by extraction, saponification and partition between MeOH-H(2)O (9:1) (hypophasic) and hexane (epiphasic). A high content of capsanthin was quantified in hypophasic carotenoids (PM1) from red spice paprika, whereas the hypophasic fractions from orange (PM3) and apple (PM4) were mainly composed of violaxanthin, zeaxanthin and lutein. On the other hand, a high content of beta,beta-carotene and beta-cryptoxanthin was found in epiphasic fractions (PM2 and PM5). The extracts were studied for their anti-Helicobacter pylori (H. pylori), anti-human immunodeficiency virus (HIV), cytotoxic, multidrug resistance (MDR) reversal and radical scavenging activity. Among five PM extracts and beta,betacarotene, PM4 showed potent anti-H. pylori activity (MIC(50) = 36 microg/mL), comparable to metronidazole (MIC(50) = 45 microg/mL). The extracts were inactive against HIV. PM3 and PM4 showed slightly higher cytotoxic activity against three human tumor cell lines (squamous cell carcinoma HSC-2, HSC-3, submandibular gland carcinoma HSG) and human promyelocytic leukemic HL-60 cells than against three normal human oral cells (gingival fibroblast HGF, pulp cell HPC, periodontal ligament fibroblast HPLF), suggesting a tumor-specific cytotoxic activity. PM1, PM3 and PM4 displayed much higher MDR-reversing activity than (+/-)-verapamil. ESR spectroscopy demonstrated that PM1-5 and beta,beta-carotene produced little or no detectable radical under alkaline conditions and did not scavenge the O(2) (-) produced by the hypoxanthine and xanthine oxidase reaction. On the other hand, PM1 and PM2 scavenged efficiently 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, whereas singlet oxygen was also quenched efficiently by PM5 and PM2. The data suggest the potential importance of carotenoids as possible anti-H. pylori and MDR reversal agents. The active principles in the carotenoid extract might differ, depending upon the types of fruits and vegetables.

Anti-Bacterial Agents↗

PubMed2004

Biological activity of barbados cherry (acerola fruits, fruit of Malpighia emarginata DC) extracts and fractions.

Fractionation of barbados cherry (acerola fruit, a fruit of Malpighia emarginata DC.) extracts were performed by organic solvent extractions and column chromatographies, using two extraction methods. Higher cytotoxic activity was concentrated in fractions A4 and A6 (acetone extract), and H3 and HE3 (hexane extract). These four fractions showed higher cytotoxic activity against tumor cell lines such as human oral squamous cell carcinoma (HSC-2) and human submandibular gland carcinoma (HSG), when compared with that against normal cells such as human periodontal ligament fibroblasts (HPLF) and human gingival fibroblasts (HGF). HE2 (hexane extract), AE2 (ethyl acetate extract), AE3, AE4, AE5, A8, A9 and A10 showed some relatively higher anti-bacterial activity on the Gram-positive Staphylococcus epidermidis ATCC 1228 but were ineffective on the representative Gram-negative species E. coli and Ps. aeruginosa. The fractions were inactive against Helicobacter pylori, two representative Candida species, and human immunodeficiency virus (HIV). H3, H4 and HE3, which displayed higher tumor-specific cytotoxicity also showed higher multidrug resistance (MDR) reversal activity, than (+/-)-verapamil as positive control. ESR spectroscopy shows that the radical-mediated oxidation is not involved in the induction of tumor-specific cytotoxic activity. The tumor specific cytotoxic activity and MDR reversal activity of barbados cherry may suggest its possible application for cancer therapy.

Anti-Infective Agents↗

PubMed2004

Comparative effects on intestinal absorption in situ by P-glycoprotein-modifying HIV protease inhibitors.

PURPOSE: P-glycoprotein (P-gp) is made responsible for the limited oral bioavailability of P-gp substrates like peptidic HIV protease inhibitors (PIs). With respect to combined application of two PIs in antiretroviral regimes, we first investigated the influences on intestinal saquinavir uptake using different PIs in in situ perfusion studies. METHODS: Perfusion experiments were carried out in three intestinal segments with P-gp substrates talinolol and saquinavir using fixed concentrations of PIs and with each varying concentrations in the jejunum and ileum. Furthermore, cellular uptake of fluorescent P-gp substrate rhodamine-123 and MRP-substrate carboxyfluorescein has each been quantified in P-gp and MRP-expressing cells by flow cytometry under co-administration of PIs. RESULTS: Increase of calculated permeabilities of P-gp-specific substrate talinolol was found under co-administration of both PIs, ritonavir and H17, with highest absorption rates in the ileal and colon segment. H17 proved to be a better P-gp inhibitor than ritonavir by resulting IC50 values and also in the cellular uptake of rhodamine. Similar increases of permeabilities in ileum and colon have also been found for saquinavir as P-gp as well as MRP-substrate with differences in the jejunal uptake, which was found higher for H17. Additional MRP-inhibitory activities of H17 were proved by increasing cellular uptake rates of carboxyfluorescein in MRP-expressing cells. CONCLUSIONS: The investigated PIs were characterized as effective P-gp inhibitors in the intestinal absorption of P-gp substrates. H17 showed MRP-inhibitory effects that also favor intestinal drug absorption of corresponding substrates. With respect to combined therapeutic application of PIs, compounds like H17 raise hopes for improved bioavailability of poorly absorbed compounds.

ATP Binding Cassette Transporter, Subfamily B↗

PubMed2004

Bacterial models for tumor development. Mini-review.

UNLABELLED: The tumor-inducing effects of Agrobacterium, Bartonella and Helicobacter bacterial species are compared step by step. An analogy for the existence of these individual steps is considered in connection with the development of cancer. The transformations of eukaryotic cells occur in particular in the type IV secretion system, i.e. involving the simultaneous transmission of DNA and protein from bacterial cells to eukaryotic cells. Thus, transfected cells facilitate the indefinite growth of tissue cells and additionally produce growth factors, triggering further bacterial multiplication. The higher numbers of bacteria then produce more transfection and the cycle repeats as long as the host lives. The main limiting factor is the frequency of bacterial infection, while the secondary rate-limiting factors are the levels of transforming growth factors and factors triggering bacteria growth. CONCLUSIONS: Analogous processes are probably responsible for the tumor induction by the three different bacterial species; however, the critical points for eradication are different. The early eradication or limitation of B. henselae or H. pylori can prevent hemangiomas, stomach cancer and malignant cell proliferation. The crown gall formation by A. tumefaciens can only be avoided by prevention of the transforming activity of a single bacterial infection. Questions arise as to what is common in the three processes, and the nature of the rate-limiting step in the three different models. The frequency of transformation is the rate-limiting step, but the co-transmission of the DNA-protein complex is common in the three systems.

Agrobacterium tumefaciens↗

PubMedDate not supplied

Modulation of multidrug resistance and apoptosis of cancer cells by selected carotenoids.

The multidrug resistance (MDR) proteins that belong to the ATP-binding casette superfamily are present in a majority of human tumors and are an important final cause of therapeutic failure. Therefore, compounds which inhibit the function of the MDR-efflux proteins may improve the cytotoxic action of anticancer chemotherapy. The effects of carotenoids were studied on the activity of the MDR-1 gene-encoded efflux pump system. The carotenoids, isolated from paprika and other vegetables, were tested on the rhodamine 123 accumulation of human MDR-1 gene-transfected L1210 mouse lymphoma cells and human breast cancer cells MDA-MB-231 (HTB-26). Capsanthin and capsorubin enhanced the rhodamine 123 accumulation 30-fold relative to nontreated lymphoma cells. Lycopene, lutein, antheraxanthin and violaxanthin had moderate effects, while alfa- and beta-carotene had no effect on the reversal of MDR in the tumor cells. Apoptosis was induced in human MDR1 transfected mouse lymphoma cells and human breast cancer MDA-MB-231 (HTB-26) cell lines in the presence of lycopene, zeaxanthin and capsanthin. The data suggest the potential of carotenoids as possible resistance modifiers in cancer chemotherapy.

Animals↗

PubMedDate not supplied

Cinnamylidene ketones as potential modulators of multidrug resistance in mouse lymphoma and human colon cancer cell lines.

The resistance to chemotherapy of cancer cells is mediated by the overexpression of P-glycoprotein, as an ATP-dependent membrane efflux pump. Two families of compounds have been screened, the cinnamylidenecycloalkanones and cinnamylidenebenzocycloalkanones, as promising multidrug resistance (MDR) reversal agents on mouse lymphoma and human colon cancer (COL0320) cell lines. The antiproliferative effects of the cinnamylidene derivatives were tested with the MTT method The MDR effect on drug accumulation was tested by flow cytometry. Combinations of resistance modifiers and cytostatics were tested on the two cell lines to obtain evidence for additive or synergistic interactions. Verapamil was applied as a resistance-modifying positive control. The best effects in the reversal of MDR in both cell lines were exhibited by the methoxy derivatives 2-(2-methaoxycinnamylidene)indan-1-one, 2-(2-methoxycinnamylidene)-3,4-dihydro-2H-naphthalen-1-one, 6-(2-methoxycinnamylidene)-6,7,8,9-tetrahydrocyclohepten-5-one), 2-cinnamylidene-3,4-dihydro-2H-naphthalen-1-one and 6-cinnamylidene-6,7,8,9-tetrahydrobenzocyclohepten-5-one. 2-(2-methoxycinnamylidene) indan-1-one and 2-(2-methoxy-cinnamylidene)-3,4-dihydro-2H-naphthalen-1-one were able to enhance the antiproliferative activity of doxorubicin in a synergistic way.

Animals↗

PubMedDate not supplied

Reversal of multidrug resistance of cancer cells in vitro: modification of drug resistance by selected carotenoids.

The development of multidrug resistance (MDR) causes difficulties in the chemotherapy of of human cancer. Investigation of the possibility of reversal of MDR has been greatly aided by the use of cell lines with acquired resitance to anticancer agents in vitro or transfected with the mdrl gene. The aim of this study was to examine new perspectives of chemotherapy focused on natural, carotenoid compounds, in connection with the modification of MDR. The function of the MDR protein was examined via the R123 drug accumulation of both cell lines in the presence of carotenoids. The fluorescence of the cell population was measured by flow cytometry. The most effective resistance modifiers Monoepoxy-beta-carotene, (SS, 8S)-capsochrome, (8'S) Luteoxanthin, (9Z)-Violaxanthin, (9Z)-Zeaxanthin, (13Z)-Zeaxanthin were assayed for their antiproliferative effects in combination with the anti-cancer drug epirubicin. (13Z)-Zeaxanthin was able to enhance the antiproliferative effect on human mdrl gene transfected mouse lymphoma and anthracycline resistant human breast cancer cell line MCF7. (8'S)-luteoxanthin, (5S, 8S)-capsochrome and (9Z)-zeaxanthin treatment revealed synergism with epirubicin on resistant mouse lymphoma. The enhanced antiproliferative activity of epirubicin combinated with (9Z)-Violaxanthin was more significant on MCF7 cells resistant to anthracycline.

ATP Binding Cassette Transporter, Subfamily B, Mem↗