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.
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.
Beck
Raphaël
R
Toxicology and Cancer Biology Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, avenue E. Mounier 73, 1200 Bruxelles, Belgium.
Pedrosa
Rozangela Curi
RC
Dejeans
Nicolas
N
Glorieux
Christophe
C
Levêque
Philippe
P
Gallez
Bernard
B
Taper
Henryk
H
Eeckhoudt
Stéphane
S
Knoops
Laurent
L
Calderon
Pedro Buc
PB
Verrax
Julien
J
D000818:Animals; D001205:Ascorbic Acid / Q000737:chemistry / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000187:drug effects; D004912:Erythrocytes / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D020014:K562 Cells; D051379:Mice; D008819:Mice, Nude; D050505:Mutant Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress / Q000187:drug effects*; D024483:Vitamin K 3 / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D050505:Mutant Proteins; D024483:Vitamin K 3; D006861:Hydrogen Peroxide; D016044:Fusion Proteins, bcr-abl; D001205:Ascorbic Acid
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