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The purine analog fludarabine acts as a cytosolic 5'-nucleotidase II inhibitor

F Cividini1, R Pesi1, L Chaloin2

  • 1University of Pisa, Department of Biology, Biochemistry Unit, Pisa, Italy.

Biochemical Pharmacology
|February 7, 2015
PubMed

Insights

Fludarabine inhibits cytosolic 5'-nucleotidase II (cN-II), an enzyme linked to anticancer drug resistance. This finding suggests that cN-II inhibitors could enhance chemotherapy efficacy and overcome resistance in hematologic malignancies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Cytosolic 5 -nucleotidase II (cN-II) is implicated in anticancer drug resistance, particularly in hematologic malignancies.
  • cN-II's role as a therapeutic target in oncology has been explored due to its association with treatment resistance.

Purpose of the Study:

  • To investigate fludarabine as a potential inhibitor of cN-II.
  • To elucidate the mechanism of fludarabine's interaction with cN-II.
  • To assess the synergistic or antagonistic effects of fludarabine and 6-mercaptopurine in cancer cells with varying cN-II expression levels.

Main Methods:

  • In vitro enzymatic assays using wild-type and mutant recombinant cN-II.
  • In silico molecular docking studies.
  • Synergy experiments in human follicular lymphoma and acute promyelocytic leukemia cell lines with altered cN-II expression via shRNA.

Main Results:

  • Fludarabine demonstrated mixed-type inhibition of cN-II enzymatic activity (Ki 0.5 mM, Ki' 9 mM).
  • Cliofarabine and cladribine did not inhibit cN-II.
  • Molecular docking and mutant studies indicated inhibition via interaction with a regulatory site.
  • Synergy between fludarabine and 6-mercaptopurine was observed in control cells but antagonism in cells with reduced cN-II expression.

Conclusions:

  • Fludarabine acts as a cN-II inhibitor, interacting with its regulatory site.
  • The findings support the hypothesis that cN-II inhibition can modulate drug response.
  • Combining cN-II inhibitors with other anticancer drugs may enhance therapeutic effects and overcome resistance in hematologic cancers.
Keywords:
Adenosine analogsCancer pharmacologyChemoresistanceCytosolic 5′-nucleotidase IIFludarabine

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