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

Abstract

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.

Suppression of Cytosolic NADPH Pool by Thionicotinamide Increases Oxidative Stress and Synergizes with Chemotherapy

“…To further explore the ability of thionicotinamide to potentiate oxidative stressors, we treated C85 cells with menadione, a vitamin K analog and known generator of ROS (Beck et al, 2011), then examined the ROS levels. Cells treated with a combination thionicotinamide and menadione exhibited significantly higher levels of ROS in a dose-dependent manner (Fig.…”

A stronger reversal effect of the combination of dasatinib and menadione on P-gp-mediated multidrug resistance in human leukemia K562/Adr cell line

“…25 It has been reported that the imatinib resistant cell line shows overexpression of both Bcr-Abl and P-gp protein. 26 The inhibition of DA and MQ to oncogenic protein Bcr-Abl has already been reported, and there is a possibility that the haemorrhage side effect of DA, which is partly due to the inhibition of PDGFR, may be improved by MQ through inducing phosphorylation of PDGFR, 18,19 thus in this study, we aimed at investigating the combined effect of DA and MQ on P-gp-mediated MDR in P-gpoverexpressing K562/Adr cells.…”

Inhibitory Effect of Vitamin C in Combination With Vitamin K3 on Tumor Growth and Metastasis of Lewis Lung Carcinoma Xenografted in C57BL/6 Mice

“…Although vit CK3 treatment has been shown to inhibit tumor development and lung metastasis in several models of tumorbearing mice (20,21,25), its mechanism of action is poorly understood. In this study, we implanted (s.c.) LLC cells into C57BL/6 mice to imitate the lung metastasis and investigated the possible mechanisms of antimetastatic and antitumor effects of vit CK3.…”

“…Vit C in combination with vit K3 (vit CK3) has been shown to change morphology and cause DNA degeneration in bladder carcinoma T24 cells (18). Vit CK3 can reactivate DNases to cause autoschizis in human prostate tumors (DU145)-bearing mice (19) and inhibited tumor volume and metastasis in hepatoma-bearing C3H mice (20,21).…”