Hyperforin inhibits P-gp and BCRP activities in chronic lymphocytic leukaemia cells and myeloid cells.
ABSTRACT We showed previously that hyperforin (HF), a natural phloroglucinol, stimulated apoptosis in B cell chronic lymphocytic leukaemia cells (CLL) and displayed anti-angiogenic properties. In the present work, we investigated the effects of hyperforin on the activity of P-gp/MDR1, an ABC (ATP-binding cassette) transporter putatively involved in multidrug resistance (MDR). Ex vivo treatment of CLL cells with HF markedly impaired the activity of P-gp, as measured by the inhibition of the capacity of the treated cells to efflux the rhodamine 123 probe. In addition, most CLL cells expressed breast cancer resistance protein (BCRP), another ABC transporter. The activity of BCRP was also inhibited by HF, as assessed by the impaired capacity of HF-treated CLL cells to efflux the specific probe mitoxantrone. The capacity of HF to reverse P-gp and BCRP activity was confirmed in myeloid leukaemia cell lines, notably in HL-60/DNR cells selected for their resistance to daunorubicine and overexpressing P-gp. Our results therefore suggest that HF might be of interest in the therapy of CLL and other haematological malignancies through its potential capacity to revert MDR in addition to its pro-apoptotic properties.
SourceAvailable from: Sonja Gadzovska Simic[Show abstract] [Hide abstract]
ABSTRACT: The effects of polysaccharide elicitors such as chitin, pectin, and dextran on the production of phenylpropanoids (phenolics and flavonoids) and naphtodianthrones (hypericin and pseudohypericin) in Hypericum perforatum shoot cultures were studied. Nonenzymatic antioxidant properties (NEAOP) and peroxidase (POD) activity were also observed in shoot extracts. The activities of phenylalanine ammonia lyase (PAL) and chalcone-flavanone isomerase (CHFI) were monitored to estimate channeling in phenylpropanoid/flavonoid pathways of elicited shoot cultures. A significant suppression of the production of total phenolics and flavonoids was observed in elicited shoots from day 14 to day 21 of postelicitation. This inhibition of phenylpropanoid production was probably due to the decrease in CHFI activity in elicited shoots. Pectin and dextran promoted accumulation of naphtodianthrones, particularly pseudohypericin, within 21 days of postelicitation.The enhanced accumulation of naphtodianthrones was positively correlated with an increase of PAL activity in elicited shoots. All tested elicitors induced NEAOP at day 7, while chitin and pectin showed increase in POD activity within the entire period of postelicitation.The POD activity was in significantly positive correlation with flavonoid and hypericin contents, suggesting a strong perturbation of the cell redox system and activation of defense responses in polysaccharide-elicited H. perforatum shoot cultures.The Scientific World Journal 12/2014; 2014(Article ID 609649):10 pages. DOI:10.1155/2014/609649 · 1.73 Impact Factor
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ABSTRACT: Side-population (SP) analysis identifies precursor cells in normal and malignant tissues. Cells with this phenotype have increased resistance to many cytotoxic agents, and may represent a primary drug-resistant population in malignant diseases. To discover whether drug-resistant malignant SP cells are nonetheless sensitive to immune-mediated killing, we first established the presence of a malignant CD5+CD19+ SP subset in the blood of 18/21 subjects with B-cell chronic lymphocytic leukemia (B-CLL). We examined the fate of these cells in six of these individuals who received autologous human CD40 ligand and interleukin-2 (hCD40L/IL-2) gene-modified tumor cells as part of a tumor vaccine study. Vaccinated patients showed an increase in B-CLL-reactive T cells followed by a corresponding decline in circulating CD5+CD19+ SP cells. T-cell lines and clones generated from vaccinated patients specifically recognized B-CLL SP tumor cells. Elimination of SP cells is likely triggered by their increased expression of target antigens, such as receptor for hyaluronan-mediated motility (RHAMM), after stimulation of the malignant cells by hCD40L, as CD8+ RHAMM-specific T cells could be detected in the peripheral blood of immunized patients and were associated with the decline in B-CLL SP cells. Hence, malignant B cells with a primary drug-resistant phenotype can be targeted by T- cell-mediated effector activity after immunization of human subjects.Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2010; 24(3):563-572. DOI:10.1038/leu.2009.281 · 9.38 Impact Factor
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ABSTRACT: Irradiation of hyperforin in acetonitrile gave a single degradation product with a first order kinetics (k = 3.23 M h(-1)). The degradation product was a 1:1 tautomeric mixture of 2-methyl-3-hydroxy-4-(1-oxo-2-methyl-1-propyl)-1,5dioxo-6-(3-methyl-1-but-2-enyl)-2-cyclohexene and 2-methyl-1,3,5-trioxo-4-(1-hydroxy-2-methyl-1-propylene)-6-(3-methyl-1-but-2-enyl)-cyclohexane. The product can also be obtained through three Norrish II reactions, followed by a fragmentation reaction.Letters in Organic Chemistry 10/2008; 5(7):583-586. DOI:10.2174/157017808785982112 · 0.65 Impact Factor