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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

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Abstract

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 (H2O2) 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 H2O2, when administered as a bolus, strongly enhances a constitutive basal NF-κB activity in TLT cells, their incubation in the presence of ascorbate and menadione results in a total abolition of such a constitutive activity.

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Authors and Affiliations

  1. Unité de Pharmacocinétique, Métabolisme, Nutrition et Toxicologie, Département des Sciences Pharmaceutiques, Université Catholique de Louvain, Belgium

    Julien Verrax, Julie Cadrobbi, Carole Marques, Henryk Taper & Pedro Buc Calderon

  2. Laboratoire de Virologie, Université de Liége, Belgium

    Yvette Habraken & Jacques Piette

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  1. Julien Verrax
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  2. Julie Cadrobbi
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  7. Pedro Buc Calderon
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Correspondence to Pedro Buc Calderon.

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Verrax, J., Cadrobbi, J., Marques, C. et al. 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. Apoptosis 9, 223–233 (2004). https://doi.org/10.1023/B:APPT.0000018804.26026.1a

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  • DOI: https://doi.org/10.1023/B:APPT.0000018804.26026.1a

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