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.