Summary
Numerous studies suggest that generation of oxidative stress could be useful in cancer treatment. In this study, we evaluated, in vitro and in vivo, the antitumor potential of oxidative stress induced by ascorbate/menadione (asc/men). This combination of a reducing agent (ascorbate) and a redox active quinone (menadione) generates redox cycling leading to formation of reactive oxygen species (ROS). Asc/men was tested in several cell types including K562 cells (a stable human-derived leukemia cell line), freshly isolated leukocytes from patients with chronic myeloid leukemia, BaF3 cells (a murine pro-B cell line) transfected with Bcr-Abl and peripheral blood leukocytes derived from healthy donors. Although these latter cells were resistant to asc/men, survival of all the other cell lines was markedly reduced, including the BaF3 cells expressing either wild-type or mutated Bcr-Abl. In a standard in vivo model of subcutaneous tumor transplantation, asc/men provoked a significant delay in the proliferation of K562 and BaF3 cells expressing the T315I mutated form of Bcr-Abl. No effect of asc/men was observed when these latter cells were injected into blood of mice most probably because of the high antioxidant potential of red blood cells, as shown by in vitro experiments. We postulate that cancer cells are more sensitive to asc/men than healthy cells because of their lack of antioxidant enzymes, mainly catalase. The mechanism underlying this cytotoxicity involves the oxidative cleavage of Hsp90 with a subsequent loss of its chaperone function thus leading to degradation of wild-type and mutated Bcr-Abl protein.
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Acknowledgments
The authors thank Isabelle Blave and Véronique Allaeys for their excellent technical assistance. They also thank Pr. Roger Verbeeck for his careful reading and corrections of the manuscript. This work was supported by grants from the Belgian Fonds National de la Recherche Scientifique (3.4594.04) and by the Fonds Spéciaux de Recherche (FSR) Université Catholique de Louvain. Raphaël Beck is an FRIA recipient, Julien Verrax is an FNRS post-doctoral researcher, Nicolas Dejeans is an FNRS-Télévie post-doctoral researcher and Christophe Glorieux is an FNRS-Télévie recipient.
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Raphaël Beck is an FRIA recipient.
Nicolas Dejeans is an FNRS-Télévie Postdoctoral Researcher.
Christophe Glorieux is an FNRS-Télévie recipient.
Julien Verrax is an FNRS Postdoctoral Researcher.
Henryk Taper in memoriam (died 24/04/2009)
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Beck, R., Pedrosa, R.C., Dejeans, N. et al. Ascorbate/menadione-induced oxidative stress kills cancer cells that express normal or mutated forms of the oncogenic protein Bcr-Abl. An in vitro and in vivo mechanistic study. Invest New Drugs 29, 891–900 (2011). https://doi.org/10.1007/s10637-010-9441-3
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DOI: https://doi.org/10.1007/s10637-010-9441-3