Vanadate-induced cell death is dissociated from H2O2 generation

Abstract

Vanadium is an environmentally toxic metal with peculiar and sometimes contradictory cellular effects. It is insulin-mimetic, it can either stimulate cell growth or induce cell death, and it has both mutagenic and antineoplastic properties. However, the mechanisms involved in those effects are poorly understood. Several studies suggest that H(2)O(2) is involved in vanadate-induced cell death, but it is not known whether cellular sensitivity to vanadate is indeed related to H(2)O(2) generation. In the present study, the sensitivity of four cell lines from different origins (K562, K562-Lucena 1, MDCK, and Ma104) to vanadate and H(2)O(2) was evaluated and the production of H(2)O(2) by vanadate was analyzed by flow cytometry. We show that cell lines very resistant to H(2)O(2) (K562, K562-Lucena 1, and Ma104 cells) are much more sensitive to vanadate than MDCK, a cell line relatively susceptible to H(2)O(2), suggesting that vanadate-induced cytotoxicity is not directly related to H(2)O(2) responsiveness. In accordance, vanadate concentrations that reduced cellular viability to approximately 60-70% of the control (10 mumol/L) did not induce H(2)O(2) formation. A second hypothesis, that peroxovanadium (PV) compounds, produced once vanadate enters into the cells, are responsible for the cytotoxicity, was only partially confirmed because MDCK cells were resistant to both vanadate and PV compounds (10 micromol/L each). Therefore, our results suggest that vanadate toxicity occurs by two distinct pathways, one dependent on and one independent of H(2)O(2) production.

Cytotoxic effect of menadione and sodium orthovanadate in combination on human glioma cells

“…Stock solutions of genistein (50 mM) and M (100 mM) were prepared in DMSO and stored at −20°C. SO stock solution was prepared in distilled sterile water (1 mM, pH 10) according to previous study guidelines [32,38] and stored at −80°C. Final dilutions of the investigated drugs were prepared in cell culture media prior to use.…”

“…They also exhibit antineoplastic activity against multidrug-resistant tumor cells [31]. The particular cytotoxic mechanism of action for vanadium salts has not been elucidated, but several possibilities, such as inhibition of protein phosphatases, protein kinases involvement, DNA damage, changes in cytosolic calcium, generation of ROS and oxidative stress, have been proposed [30,32]. On the other hand, vanadium salts as dietary microelements [30] have high biological significance.…”

“…Several investigators found that vanadate is clinically significant for diabetes treatment [30,32,33,35,37] and that it could also be a useful chemotherapeutic candidate in combination with other antineoplastic agents to treat multidrugresistant tumors. According to previous studies in animal and human models, vanadium compound toxicity is relatively low [32], producing mainly gastrointestinal discomfort, diarrhea, dehydration, and loss of weight. Most of these effects were corrected with the addition of NaCl to drinking water [35].…”

Vanadium compounds induced mitochondria permeability transition pore (PTP) opening related to oxidative stress

“…Many studies suggested a close relationship between vanadium toxicity and ROS [9,[20][21][22]. Vanadium induced apoptosis of cells associated with elevated ROS levels and ROS-related signal transduction [23,24], while antioxidants, either as complex ligands [25] or co-administration [26,27], significantly reduced vanadium toxicity.…”

Chemical, Biochemical, and Biological Behaviors of Vanadate and Its Oligomers

“…It is reported that vanadate induced cell cycle arrest at the G2/M phase by H 2 O 2 -activated ERK and p38 pathways (Zhang et al 2003). But, there might be another mechanism leading to vanadate-induced cytotoxicity independent on H 2 O 2 generation (Capella et al 2002(Capella et al , 2007. Our group also demonstrated that vanadate can induce cell cycle arrest in HepG2 cells via an ROS-independent pathway (Fu et al 2008), and by using antioxidants as synergistic agents, the damage to normal liver cells may be avoided (Wang et al 2010).…”