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Dicoumarol impairs mitochondrial electron transport and pyrimidine biosynthesis in human myeloid leukemia HL-60 cells

David González-Aragón1, Julia Ariza, José M Villalba

  • 1Departamento de Biología Celular, Fisiología e Inmunología, Facultad de Ciencias, Universidad de Córdoba, Campus Rabanales, Edificio Severo Ochoa, 3(a) planta, 14014 Córdoba, Spain.

Biochemical Pharmacology
|November 25, 2006
PubMed

Insights

Dicoumarol increases superoxide and alters cell cycle by inhibiting mitochondrial electron transport and pyrimidine biosynthesis, not primarily through NAD(P)H:quinone oxidoreductase 1 (NQO1) inhibition. These mechanisms impact tumor cell growth.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Pharmacology

Background:

  • Dicoumarol is known to inhibit NAD(P)H:quinone oxidoreductase 1 (NQO1) and increase intracellular superoxide, affecting tumor cell growth.
  • The precise mechanisms linking dicoumarol, superoxide generation, and cell cycle changes remain incompletely understood.

Purpose of the Study:

  • To establish a mechanistic link between dicoumarol, superoxide production, and cell cycle alterations in HL-60 cells.
  • To investigate the role of NQO1 inhibition versus direct mitochondrial effects in dicoumarol-induced superoxide generation.

Main Methods:

  • Utilized ES936, an irreversible NQO1 inhibitor, to assess NQO1's role.
  • Investigated direct effects of dicoumarol on mitochondrial Complexes II, III, and IV.
  • Employed succinate and thenoyltrifluoroacetone to probe mechanisms of superoxide generation.
  • Assessed pyrimidine biosynthesis impairment and rescue strategies.

Main Results:

  • Dicoumarol directly inhibited mitochondrial Complexes II, III, and IV.
  • Succinate addition significantly decreased dicoumarol-induced superoxide boost, implicating reversed electron flow in Complex II.
  • Blocking Complex II's quinone site potentiated superoxide generation, suggesting cytochrome b560 involvement.
  • Dicoumarol induced S-phase arrest by inhibiting pyrimidine biosynthesis at dihydroorotate dehydrogenase, reversible with uridine or orotate.

Conclusions:

  • Dicoumarol inhibits mitochondrial electron transport and induces superoxide release via reversed electron flow in Complex II.
  • Dicoumarol impairs pyrimidine biosynthesis, contributing to cell cycle arrest.
  • The primary mechanisms of dicoumarol's cellular effects involve direct mitochondrial inhibition and metabolic disruption, rather than solely NQO1 inhibition.

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