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Imatinib-resistant CML cells have low ENT activity but maintain sensitivity to gemcitabine

Andrea V Leisewitz1, Eric I Zimmerman, Shannon Z Jones

  • 1Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, North Carolina 27599, USA.

Nucleosides, Nucleotides & Nucleic Acids
|July 5, 2008
PubMed

Insights

Imatinib treatment reduces nucleoside transporter activity in chronic myeloid leukemia (CML) cells. However, gemcitabine remains effective, suggesting nucleoside analogs can be used alongside imatinib to overcome resistance.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Philadelphia chromosome-positive chronic myeloid leukemia (CML) is primarily treated with imatinib, a Bcr-Abl tyrosine kinase inhibitor.
  • Resistance to imatinib is a significant clinical challenge in CML treatment.
  • Nucleoside analogs like gemcitabine are explored as combination therapies, requiring equilibrative nucleoside transporters (ENTs) for cellular uptake.

Purpose of the Study:

  • To investigate the impact of imatinib treatment on equilibrative nucleoside transporter (ENT) expression and activity in CML cells.
  • To determine the sensitivity of imatinib-resistant CML cells to gemcitabine.
  • To evaluate the potential of nucleoside analogs as adjunctive therapy for imatinib-resistant CML.

Main Methods:

  • Assessing ENT1-dependent activity and mRNA expression following imatinib treatment.
  • Analyzing ENT1 and ENT2 activity and expression in imatinib-resistant CML cell lines.
  • Evaluating gemcitabine sensitivity in imatinib-resistant CML cells.

Main Results:

  • Imatinib treatment led to decreased ENT1 activity and mRNA expression.
  • Imatinib-resistant CML cells exhibited reduced levels of both ENT1 and ENT2 activity and expression.
  • Despite decreased ENT expression, imatinib-resistant cells remained sensitive to gemcitabine.

Conclusions:

  • Imatinib therapy negatively affects ENT1-mediated nucleoside uptake.
  • Nucleoside analogs like gemcitabine retain efficacy in imatinib-resistant CML cells.
  • Nucleoside analogs represent a viable adjunctive therapeutic strategy for overcoming imatinib resistance in CML.

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