Redox and decomposition analysis of anticancer oxido-vanadium(V) complexes in the presence of antioxidants

Abstract

Because ascorbic acid and glutathione are important extra- and intracellular reductants, their chemical reactions, including redox activities, with the vanadium(V) anti-cancer agent, [VO(HSHED)(DTB)], were investigated in aqueous and non-aqueous solutions. The reactivity in organic solvents mimic extracellular conditions during drug delivery in DMSO solutions and more lipophilic cellular environments, whilst the aqueous chemistry mimics the extracellular environment after diffusion from the DMSO delivery medium and the cytosolic intracellular environment. Reactivities were monitored using 51V NMR, EPR, and UV/Vis/NIR spectroscopies, electrospray mass spectrometry and cyclic voltammetry, which showed that ascorbic acid, but not glutathione (or its mimic) reduced V(V) to V(IV) in both aqueous and non-aqueous environments. The proposed mechanism of reduction involved a ligand-exchange reaction of the DTB ligand with ascorbate, followed by intramolecular redox reactions to form V(IV) and dehydroascorbate as the ultimate products. While 5 mM ascorbate added to the extracellular matrix reduced the anti-proliferative activity by an order of magnitude in T98G glioblastoma cells, this is more than an order of magnitude higher than the typical extracellular concentrations of 30-150 M. By contrast, pre-saturation of the T98G cells with ascorbic acid to more typical values found in vivo (1-2-mM in the cytosol) caused a five-fold increase in anti-proliferative activity, which demonstrated that these complexes have an even higher activity than deduced from standard cell assays. This high activity is due, in part, to reduction to V(IV) and subsequent redox activity. These results provide pathways to improve the efficacy of these drugs in intratumoral injections, by pre-saturating the tumor via intracellular injection of dehydroascorbic acid, which is reduced intracellularly to ascorbate, followed by an intratumoral injection of the V(V) anti-cancer agent.