1: Biochem Pharmacol. 2006 Sep 14;72(6):671-80. Epub 2006 Jul 7.

Oxidative stress by ascorbate/menadione association kills K562 human chronic
myelogenous leukaemia cells and inhibits its tumour growth in nude mice.

Verrax J, Stockis J, Tison A, Taper HS, Calderon PB.

Unite de Pharmacocinetique, Metabolisme, Nutrition et Toxicologie, Departement
des sciences pharmaceutiques, Universite Catholique de Louvain, Belgium.
julien.verrax@uclouvain.be

The effect of oxidative stress induced by the ascorbate/menadione-redox
association was examined in K562 cells, a human erythromyeloid leukaemia cell
line. Our results show that ascorbate enhances menadione redox cycling, leading
to the formation of intracellular reactive oxygen species (as shown by
dihydrorhodamine 123 oxidation). The incubation of cells in the presence of both
ascorbate/menadione and aminotriazole, a catalase inhibitor, resulted in a
strong decrease of cell survival, reinforcing the role of H(2)O(2) as the main
oxidizing agent killing K562 cells. This cell death was not caspase-3-dependent.
Indeed, neither procaspase-3 and PARP were processed and only a weak cytochrome
c release was observed. Moreover, we observed only 23% of cells with depolarized
mitochondria. In ascorbate/menadione-treated cells, DNA fragmentation was
observed without any sign of chromatin condensation (DAPI and TUNEL tests). The
cell demise by ascorbate/menadione is consistent with a necrosis-like cell death
confirmed by both cytometric profile of annexin-V/propidium iodide labeled cells
and by light microscopy examination. Finally, we showed that a single i.p.
administration of the association of ascorbate and menadione is able to inhibit
the growth of K562 cells by about 60% (in both tumour size and volume) in an
immune-deficient mice model. Taken together, these results reinforced our
previous claims about a potential application of the ascorbate/menadione
association in cancer therapy.

PMID: 16828058 [PubMed - indexed for MEDLINE]

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