The efficacy of the ribonucleotide reductase inhibitor Didox in preclinical models of AML

PLoS One. 2014 Nov 17;9(11):e112619. doi: 10.1371/journal.pone.0112619. eCollection 2014.

Abstract

Acute Myeloid Leukemia (AML) is an aggressive malignancy which leads to marrow failure, and ultimately death. There is a desperate need for new therapeutics for these patients. Ribonucleotide reductase (RR) is the rate limiting enzyme in DNA synthesis. Didox (3,4-Dihydroxybenzohydroxamic acid) is a novel RR inhibitor noted to be more potent than hydroxyurea. In this report we detail the activity and toxicity of Didox in preclinical models of AML. RR was present in all AML cell lines and primary patient samples tested. Didox was active against all human and murine AML lines tested with IC50 values in the low micromolar range (mean IC50 37 µM [range 25.89-52.70 µM]). It was active against primary patient samples at concentrations that did not affect normal hematopoietic stem cells (HSCs). Didox exposure resulted in DNA damage and p53 induction culminating in apoptosis. In syngeneic, therapy-resistant AML models, single agent Didox treatment resulted in a significant reduction in leukemia burden and a survival benefit. Didox was well tolerated, as marrow from treated animals was morphologically indistinguishable from controls. Didox exposure at levels that impaired leukemia growth did not inhibit normal HSC engraftment. In summary, Didox was well tolerated and effective against preclinical models of AML.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • DNA Damage / drug effects
  • Disease Models, Animal
  • Drug Evaluation, Preclinical
  • Drug Resistance, Neoplasm
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Hydroxamic Acids / administration & dosage
  • Hydroxamic Acids / pharmacology*
  • Karyotype
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / mortality
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Ribonucleotide Reductases / antagonists & inhibitors
  • Signal Transduction / drug effects
  • Tumor Stem Cell Assay
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Hydroxamic Acids
  • Tumor Suppressor Protein p53
  • Ribonucleotide Reductases
  • 3,4-dihydroxybenzohydroxamic acid