Enhancement of quinone redox cycling by ascorbate induces a caspase-3 independent cell death in human leukaemia cells. Anin vitrocomparative study

Abstract

Since the higher redox potential of quinone molecules has been correlated with enhanced cellular deleterious effects, we studied the ability of the association of ascorbate with several quinones derivatives (having different redox potentials) to cause cell death in K562 human leukaemia cell line. The rationale is that the reduction of quinone by ascorbate should be dependent of the quinone half-redox potential thus determining if reactive oxygen species (ROS) are formed or not, leading ultimately to cell death or cell survival. Among different ROS that may be formed during redox cycling between ascorbate and the quinone, the use of different antioxidant compounds (mannitol, desferal, N-acetylcysteine, catalase and superoxide dismutase) led to support H2O2 as the main oxidizing agent. We observed that standard redox potentials, oxygen uptake, free ascorbyl radical formation and cell survival were linked. The oxidative stress induced by the mixture of ascorbate and the different quinones decreases cellular contents of ATP and GSH while caspase-3-like activity remains unchanged. Again, we observed that quinones having higher values of half-redox potential provoke a severe depletion of ATP and GSH when they were associated with ascorbate. Such a drop in ATP content may explain the lack of activation of caspase-3. In conclusion, our results indicate that the cytotoxicity of the association quinone/ascorbate on K562 cancer cells may be predicted on the basis of half-redox potentials of quinones.

α-Tocopheryl succinate promotes selective cell death induced by vitamin K3 in combination with ascorbate

“…Figure 6). A caspase-3 independent cell death was previously observed in leukaemia cells after VK3 -AA treatment (Verrax et al, 2005). This can be reconciled with the notion that peroxidation of the plasma membrane of cells may favour unregulated increase in intracellular levels of calcium as previously observed (Sakagami and Satoh, 1997), which, along with thiol oxidation, may result in mitochondrial destabilisation.…”

“…An antagonistic interaction was found for the combination of a-TOS and VK3, whereas AA did not exert any effect when combined with a-TOS. As previously described (De Loecker et al, 1993;Jamison et al, 1996;Verrax et al, 2005;Tareen et al, 2008;Beck et al, 2009) and also observed in this study, an efficient synergistic effect on cell viability was observed for the pro-oxidant mixture containing pharmacological doses of AA and a redox-active compound such as menadione (VK3), (c.f. Figure 2).…”

“…Figures 6 and 7). This reinforces the concept that mitochondrial destabilisation constitutes a central event in the programmed cell death such as apoptosis and autoschizis (Verrax et al, 2005). Again, this evokes the possibility that primary thiol oxidation of mitochondrial proteins, derived from an oxidative shift in the cellular redox potential , can induce mitochondrial membrane permeabilisation (Zamzami et al, 1998).…”

“…The combined action of ascorbic acid (AA) and vitamin K3 (VK3) has been reported to synergistically induce cell death in different cancers (De loecker et al, 1993;Verrax et al, 2005;Tareen et al, 2008). Oxidative stress generated by the ascorbate-driven quinone redox cycling kills tumour cells by a mechanism including glycolysis inhibition, loss of calcium homoeostasis, DNA damage, and altered activity of mitogen-activated protein kinases (MAPK).…”

Endoplasmic reticulum calcium release potentiates the ER stress and cell death caused by an oxidative stress in MCF-7 cells

“…In summary, ER homeostasis is a fragile equilibrium, which can be modulated by dysregulation of calcium or oxidative/reductive balance, features previously associated with oxidative stress. However, studies of the links between these factors are scarce.We and others have shown that the association of ascorbate and menadione is an H 2 O 2 -generating system that results in necrosis-like cell death in a wide variety of cancer cell types [29][30][31][32][33][34][35] including MCF-7 cells (a human breast derived cell line), and that loss of calcium homeostasis appeared to be a major factor in the cytotoxicity [36]. The aim of the present study was to investigate the role of disruption of calcium homeostasis and a potential involvement of ER stress in the mechanisms leading to cancer cell death from an oxidative …”