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

A I Svirnovski1, T F Serhiyenka, A M Kustanovich

  • 1Republican Scientific and Practical Center for Hematology and Transfusiology, 160 Dolginovski Tract, Minsk 220053, Belarus. asvirnov@yandex.ru

Experimental Oncology
|January 29, 2011
PubMed
Abstract

Insights

Inhibitors like caffeine and vanillin enhanced fludarabine

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Chronic lymphocytic leukemia (CLL) often develops resistance to fludarabine, a common chemotherapeutic agent.
  • Understanding the mechanisms of drug resistance is crucial for developing effective treatment strategies.

Purpose of the Study:

  • To investigate the effects of DNA-dependent protein kinase (DNA-PK) inhibitors (vanillin, NU7026), an ATM/ATR inhibitor (caffeine), and a multidrug resistance (MDR) modulator (cyclosporine A) on fludarabine-resistant and sensitive CLL cells.
  • To evaluate the potential of these agents in overcoming fludarabine resistance in CLL.

Main Methods:

  • Cell viability was assessed using the MTT assay.
  • Expression of DNA-PKs and ATM was analyzed by Western blotting.
  • Multidrug transporter expression and function were evaluated using flow cytometry.
  • The expression of pro- and anti-apoptotic genes was measured at the mRNA level.

Main Results:

  • Caffeine, vanillin, NU7026, and CsA increased fludarabine cytotoxicity in resistant CLL cells, though sensitive cells showed greater sensitization.
  • Increased ATM expression was observed in resistant CLL samples, but no clear correlation with DNA-PKs levels or inhibitor effects was found.
  • Resistant CLL cells exhibited reduced MDR efflux and lower BCL-XS mRNA levels.

Conclusions:

  • The study suggests that drug synergy can be achieved with fludarabine and inhibitors in fludarabine-resistant CLL cells.
  • These combinations may offer a strategy to overcome resistance to nucleoside analogs in CLL.
  • Further research is needed to fully elucidate the molecular pathways involved in this synergistic effect.

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