1: Apoptosis.  2004 Mar;9(2):223-33.  

Ascorbate potentiates the cytotoxicity of menadione leading to an oxidative
stress that kills cancer cells by a non-apoptotic caspase-3 independent form of
cell death.

Verrax J, Cadrobbi J, Marques C, Taper H, Habraken Y, Piette J, Calderon PB.

Unite de Pharmacocinetique, Metabolisme, Nutrition et Toxicologie, Departement
des Sciences Pharmaceutiques, Universite Catholique de Louvain, Belgium.

Hepatocarcinoma cells (TLT) were incubated in the presence of ascorbate and
menadione, either alone or in combination. Cell death was only observed when
such compounds were added simultaneously, most probably due to hydrogen peroxide
(H(2)O(2)) generated by ascorbate-driven menadione redox cycling. TLT cells were
particularly sensitive to such an oxidative stress due to its poor antioxidant
status. DNA strand breaks were induced by this association but this process did
not correspond to oligosomal DNA fragmentation (a hallmark of cell death by
apoptosis). Neither caspase-3-like DEVDase activity, nor processing of
procaspase-3 and cleavage of poly(ADP-ribose) polymerase (PARP) were observed in
the presence of ascorbate and menadione. Cell death induced by such an
association was actively dependent on protein phosphorylation since it was
totally prevented by preincubating cells with sodium orthovanadate, a tyrosine
phosphatase inhibitor. Finally, while H(2)O(2), when administered as a bolus,
strongly enhances a constitutive basal NF-kappaB activity in TLT cells, their
incubation in the presence of ascorbate and menadione results in a total
abolition of such a constitutive activity.

PMID: 15004519 [PubMed - in process]