Enhancement of quinone redox cycling by ascorbate induces a caspase-3
independent cell death in human leukaemia cells. An in vitro
comparative study
JULIEN VERRAX1,†, MARIANNE DELVAUX1, NELSON BEGHEIN2, HENRYK TAPER1,
BERNARD GALLEZ2, & PEDRO BUC CALDERON
1Unite de Pharmacocinetique, Me´tabolisme, Nutrition et
Toxicologie, Departement des sciences pharmaceutiques, Universite
Catholique de Louvain, Brussels, Belgium, and 2Unite de Chimie
pharmaceutique et de radiopharmacie, Unite de Resonance
magne´tique biomedicale, Departement des sciences
pharmaceutiques, Universite Catholique de Louvain, Brussels, Belgium
Accepted by Dr T. Grune
(Received 9 November 2004; in revised form 18 January 2005)
Abstract
Since the higher redox potential of quinone molecules has been
correlated with enhanced cellular deleterious effects, we
studied the ability of the association of ascorbate with several
quinones derivatives (having different redox potentials) to cause
cell death in K562 human leukaemia cell line. The rationale is that the
reduction of quinone by ascorbate should be dependent
of the quinone half-redox potential thus determining if reactive oxygen
species (ROS) are formed or not, leading ultimately to
cell death or cell survival. Among different ROS that may be formed
during redox cycling between ascorbate and the quinone,
the use of different antioxidant compounds (mannitol, desferal,
N-acetylcysteine, catalase and superoxide dismutase) led to
support H2O2 as the main oxidizing agent. We observed that standard
redox potentials, oxygen uptake, free ascorbyl radical
formation and cell survival were linked. The oxidative stress induced
by the mixture of ascorbate and the different quinones
decreases cellular contents of ATP and GSH while caspase-3-like
activity remains unchanged. Again, we observed that
quinones having higher values of half-redox potential provoke a severe
depletion of ATP and GSH when they were associated
with ascorbate. Such a drop in ATP content may explain the lack of
activation of caspase-3. In conclusion, our results indicate
that the cytotoxicity of the association quinone/ascorbate on K562
cancer cells may be predicted on the basis of half-redox
potentials of quinones.
Keywords: Ascorbate, quinone, redox cycling, reactive oxygen species,
cancer