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Tamashevski A.V.,National Academy of Sciences of Belarus | Kozlova N.M.,National Academy of Sciences of Belarus | Goncharova N.V.,Republican Scientific and Practical Center for Hematology and Transfusiology | Zubritskaya G.P.,National Academy of Sciences of Belarus | Slobozhanina E.I.,National Academy of Sciences of Belarus
Biophysics | Year: 2011

The influence of agents modifying cholesterol in plasma membranes on the functional activity of transporter proteins (P-glycoprotein (P-gp) and multidrug resistance protein 1 (MRP1)) in human lymphocytes has been studied. It was shown that changes in the lateral distribution of cholesterol using the polyene antibiotic filipin, which disturbs the structure and function of glycolipid microdomains in plasma membranes of lymphocytes lead to a decrease in the transport activity of both P-gp and MRP1. It was found that the treatment of human lymphocytes with the cyclic oligosaccharide methyl-β-cyclodextrin, which leads to cholesterol depletion and reduction of lipid bilayer microviscosity in membranes of these cells, also decreases the functional activity of these proteins. It was concluded that the transport activity of P-gp and MRP1 depends on the modification of cholesterol in the membranes of human lymphocytes, i.e., is closely associated with the level of cholesterol and its lateral distribution. © 2011 Pleiades Publishing, Ltd. Source

Svirnovski A.I.,Republican Scientific and Practical Center for Hematology and Transfusiology | Serhiyenka T.F.,Republican Scientific and Practical Center for Hematology and Transfusiology | Kustanovich A.M.,Republican Scientific and Practical Center for Pediatric Oncology and Hematology | Khlebko P.V.,Republican Scientific and Practical Center for Hematology and Transfusiology | And 3 more authors.
Experimental Oncology | Year: 2010

Aim: To perform the comparative study of the effects of DNA-dependent protein kinase (DNA-PK) inhibitors vanillin and NU7026, ataxia telangiectasia mutated kinase (ATM)/ ATM and Rad3 related (ATR) kinase inhibitor caffeine and multidrug resistance (MDR) protein modulator cyclosporine A (CsA) on fludarabine resistant and sensitive lymphocytes from chronic lymphocytic leukemia (CLL) patients. Methods: Cells sensitivity in vitro was determined with 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT). DNA-PKs and ATM expression in CLL cells was evaluated using Western blotting. Multidrug tansporter protein expression and function was assessed by flow cytometry. Pro- or anti-apoptotic genes (BAX, LICE BCL-2, BCL-XS FLICE, FAS, TRAIL) expression on mRNA level was evaluated. Results: Caffeine, vanillin, NU7026 and CsA increased fludarabine cytotoxicity against fludarabine-resistant CLL cells samples in comparison with sensitive cell samples. However, fludarabine- sensitive CLL samples were sensitized with inhibitors to a greater extent compared with resistant CLL samples. ATM expression increased in fludarabine-resistant CLL samples, but no apparent correlation between DNA-PKs level and fludarabine sensitivity in vitro or sensitization effect of DNA-PK inhibitors were observed. Fludarabine-resistant CLL lymphocytes showed tendency for depressed MDR efflux and decreased level of mRNA of pro-apoptotic gene BCL-XS. Conclusion: Absence of any definite conformity between fludarabine-resistant cell susceptibility to combined action of fludarabine and inhibitors, and molecular pathways that might be involved in this process does not exclude drugs synergy in fludarabine-resistant cells that could be used for overcoming resistance to nucleoside analogs in CLL. Copyright © Experimental Oncology, 2010. Source

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