nu-7026 has been researched along with Leukemia--Lymphocytic--Chronic--B-Cell* in 2 studies
2 other study(ies) available for nu-7026 and Leukemia--Lymphocytic--Chronic--B-Cell
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DNA-PK, ATM and MDR proteins inhibitors in overcoming fludarabine resistance in CLL cells.
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.. 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.. 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.. 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. Topics: Antineoplastic Agents; Ataxia Telangiectasia Mutated Proteins; ATP Binding Cassette Transporter, Subfamily B; Benzaldehydes; Blotting, Western; Caffeine; Cell Cycle Proteins; Cell Line, Tumor; Chromones; Cyclosporine; DNA-Activated Protein Kinase; DNA-Binding Proteins; Drug Resistance, Neoplasm; Flow Cytometry; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Morpholines; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Tumor Suppressor Proteins; Vidarabine | 2010 |
Human chronic lymphocytic leukemia B cells can escape DNA damage-induced apoptosis through the nonhomologous end-joining DNA repair pathway.
Nonhomologous end-joining (NHEJ) DNA factors maintain genomic stability through their DNA double-strand break (DSB) repair and telomere-associated activities. Unrepaired or misrepaired DSBs can lead to apoptotic death or chromosomal damage. The B cells of some B-chronic lymphocytic leukemia (B-CLL) patients are resistant to radiation-induced apoptosis in vitro. We show here that the novel DNA-dependent protein kinase (DNA-PK) inhibitor, NU7026 (2-(morpholin-4-yl)-benzo[h]chomen-4-one), and the phosphatidylinositol 3 (PI-3) kinase inhibitor, wortmannin, restored sensitivity to DNA damage-induced apoptosis of otherwise resistant cells. These resistant malignant B cells also escaped DSB-induced apoptosis following exposure to etoposide or neocarzinostatin. We found that at 15 minutes after irradiation, the levels of NHEJ (as measured by an in vitro DSB end-ligation assay) and DNA-PK catalytic subunit (DNA-PKcs) activity were, respectively, 2-fold and 4-fold higher in radio-resistant than in radio-sensitive B-CLL cells or Epstein-Barr virus (EBV)-transformed B cells. Ku70/Ku80 heterodimer DNA end-binding activity was also 2- to 3-fold higher in the resistant B-CLL cell subset compared with the sensitive B-CLL cell subset. Our results provide the first evidence that overactivating the NHEJ DNA repair pathway impairs DNA damage-induced apoptosis in malignant B cells and that this may contribute to their resistance to current chemotherapy. Topics: Androstadienes; Antibiotics, Antineoplastic; Antigens, Nuclear; Antineoplastic Agents, Phytogenic; Apoptosis; B-Lymphocytes; Blotting, Western; Cell Line, Transformed; Cell Line, Tumor; Cell-Free System; Chromones; Dimerization; DNA; DNA Damage; DNA Repair; DNA-Binding Proteins; Dose-Response Relationship, Drug; Enzyme Inhibitors; Etoposide; Gamma Rays; Humans; Ku Autoantigen; Leukemia, Lymphocytic, Chronic, B-Cell; Morpholines; Okadaic Acid; Phosphatidylinositol 3-Kinases; Protein Binding; Telomere; Time Factors; Wortmannin; Zinostatin | 2005 |