DNA-PK, ATM and MDR proteins inhibitors in overcoming fludarabine resistance in CLL cells.

Abstract

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.

• Authors: A I Svirnovski, T F Serhiyenka, A M Kustanovich, P V Khlebko, V V Fedosenko, I B Taras, A V Bakun
• Journal: Experimental oncology (Exp Oncol) Vol. 32 Issue 4 Pg. 258-62 (Dec 2010) ISSN: 1812-9269 [Print] Ukraine
• PMID: 21270755 (Publication Type: Journal Article)

Chemical References

• 2-(morpholin-4-yl)benzo(h)chromen-4-one
• ATP Binding Cassette Transporter, Subfamily B
• Antineoplastic Agents
• Benzaldehydes
• Cell Cycle Proteins
• Chromones
• DNA-Binding Proteins
• Morpholines
• Protein Kinase Inhibitors
• Tumor Suppressor Proteins
• Caffeine
• Cyclosporine
• vanillin
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• DNA-Activated Protein Kinase
• Protein Serine-Threonine Kinases
• Vidarabine
• fludarabine

Topics

• ATP Binding Cassette Transporter, Subfamily B (antagonists & inhibitors)
• Antineoplastic Agents (pharmacology)
• Ataxia Telangiectasia Mutated Proteins
• Benzaldehydes (pharmacology)
• Blotting, Western
• Caffeine (pharmacology)
• Cell Cycle Proteins (antagonists & inhibitors)
• Cell Line, Tumor
• Chromones (pharmacology)
• Cyclosporine (pharmacology)
• DNA-Activated Protein Kinase (antagonists & inhibitors)
• DNA-Binding Proteins (antagonists & inhibitors)
• Drug Resistance, Neoplasm (drug effects)
• Flow Cytometry
• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell (metabolism)
• Morpholines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Tumor Suppressor Proteins (antagonists & inhibitors)
• Vidarabine (analogs & derivatives, pharmacology)