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Regulation of equilibrative nucleoside uptake by protein kinase inhibitors

Min Huang1, Yanhong Wang, Beverly S Mitchell

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

Nucleosides, Nucleotides & Nucleic Acids
|December 2, 2004
PubMed

Insights

Protein kinase inhibitors unexpectedly target nucleoside transporters like ENT1 and ENT2 in leukemia cells. This finding impacts the combined use of nucleoside analogs and kinase inhibitors in cancer therapy.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Nucleoside transporters, specifically equilibrative nucleoside transporters 1 and 2 (ENT1 and ENT2), mediate the uptake of nucleosides and their analogs into human leukemia K562 cells.
  • Protein kinase inhibitors are widely used in cancer therapy, but their potential interactions with nucleoside transport mechanisms are not well understood.

Purpose of the Study:

  • To investigate the effect of various protein kinase inhibitors on the transport of nucleoside analogs in human leukemia K562 cells.
  • To identify potential off-target effects of kinase inhibitors on nucleoside transporters.

Main Methods:

  • K562 cells were incubated with different protein kinase inhibitors.
  • The transport of uridine (ARA-C) and cytidine (CPEC) analogs was measured in the presence of these inhibitors.

Main Results:

  • A broad range of protein kinase inhibitors, including those targeting p38 MAPK, EGF receptor kinase, protein kinase C, and TOR, significantly inhibited the transport of both ARA-C and CPEC analogs.
  • These inhibitory effects suggest that nucleoside transporters are susceptible to modulation by diverse kinase inhibitors.

Conclusions:

  • Nucleoside transporters (ENT1 and ENT2) represent unexpected targets for protein kinase inhibitors.
  • The interaction between kinase inhibitors and nucleoside transporters may necessitate adjustments in the design and application of combination therapies involving nucleoside analogs and kinase inhibitors in clinical settings.

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