DNA-PK, ATM and MDR proteins inhibitors in overcoming fludarabine resistance in CLL cells.
| Autor: | Svirnovski AI; Republican Scientific and Practical Center for Hematology and Transfusiology, 160 Dolginovski Tract, Minsk 220053, Belarus. asvirnov@yandex.ru, Serhiyenka TF, Kustanovich AM, Khlebko PV, Fedosenko VV, Taras IB, Bakun AV |
|---|---|
| Jazyk: | angličtina |
| Zdroj: | Experimental oncology [Exp Oncol] 2010 Dec; Vol. 32 (4), pp. 258-62. |
| Abstrakt: | 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. |
| Databáze: | MEDLINE |
| Externí odkaz: |
|