Evaluation of cellular uptake, cytotoxicity and cellular ultrastructural effects of heteroleptic oxidovanadium(IV) complexes of salicylaldimines and polypyridyl ligands.

Searching for prospective vanadium-based drugs for cancer treatment, a new series of structurally related [VIVO(L-2H)(NN)] compounds (1-8) was developed. They include a double deprotonated salicylaldimine Schiff base ligand (L-2H) and different NN-polypyridyl co-ligands having DNA intercalating capacity. Compounds were characterized in solid state and in solution. EPR spectroscopy suggests that the NN ligands act as bidentate and bind through both nitrogen donor atoms in an axial-equatorial mode. The cytotoxicity was evaluated in human tumoral cells (ovarian A2780, breast MCF7, prostate PC3). The cytotoxic activity was dependent on type of cell and incubation time. At 24h PC3 cells presented low sensitivity, but at 72h all complexes showed high cytotoxic activity in all cells. Human kidney HEK293 and ovarian cisplatin resistant A2780cisR cells were also included to evaluate selectivity towards cancer cells and potency to overcome cisplatin resistance, respectively. Most complexes showed no detectable interaction with plasmid DNA, except 2 and 7 which depicted low ability to induce single strand breaks in supercoiled DNA. Based on the overall cytotoxic profile, complexes with 2,2´-bipyridine and 1,10-phenanthroline ligands (1 and 2) were selected for further studies, which consisted on cellular distribution and ultrastructural analyses. In the A2780 cells both depicted different distribution profiles; the former accumulates mostly at the membrane and the latter in the cytoskeleton. Morphology of treated cells showed nuclear atypia and membrane alterations, more severe for 1. Complexes induce different cell death pathways, predominantly necrosis for 1 and apoptosis for 2. Complexes alternative mode of cell death motivates the possibility for further developments.

Hypoglycemic, lipid-lowering and metabolic regulation activities of metforminium decavanadate (H2Metf)3 [V10O28]·8H2O using hypercaloric-induced carbohydrate and lipid deregulation in Wistar rats as biological model.

Because of the increasing global spread of type 2 diabetes mellitus, there is a need to develop new antidiabetic agents. Recently we have synthesized new decavanadates using metformin as counterion. In particular, the compound containing three metforminium dications has been obtained in high yield and has been completely characterized. Biological studies using Wistar rats that have been fed with a high caloric diet inducing insulin resistance and metabolic syndrome were carried out. Results of the impact on key biochemical parameters mediated by metformin alone and the new compound are here presented. The metforminium decavanadate (H2Metf)3[V10O28]·8H2O, abbreviated as Metf-V10O28, was shown to have pharmacological potential as a hypoglycemic, lipid-lowering and metabolic regulator, since the resulting compound made of the two components with antidiabetic activities, reduces both dosage and time of administration (twice a week). Hence, due to the beneficial effects induced by the metforminium decavanadate we recommend to continue the exploration into the mechanism and toxicology of this new compound.

Astrogliosis and HSP 70 activation in neonate rats' brain exposed to sodium metavanadate through lactation.

The effect of sodium metavanadate (NaVO3) exposure on lipid oxidative damage in the CNS of suckling rats was studied. Using histological markers of cellular injury, we also studied the morphological alterations of neurons and astroglial cells in different regions of neonate rats CNS after NaVO3 exposure. Dams of treated litters were intraperitoneally injected with 3mgNaVO3/kgbody weight/day during 12days starting on post-natal day (PND) 10. On the 21st PND, four pups of each litter were sacrificed by decapitation and six brain areas were removed for lipid peroxidation assay by the thiobarbituric acid (TBA) reaction, the other four were transcardially perfused-fixed and their brains were removed and cut with a cryostat. Brain sections were processed for: NADPHd histochemistry and anti-HSP70, anti-GFAP and anti-S100 immunohistochemistry. The relative optical density of the NADPHd stained layers and of S100 (+) astrocytes and the GFAP (+) astrocyte surface area in Cer and Hc were measured. Although MDA levels, S100 immunostaining and NADPHd activity didn't show differences between experimental and control groups, both astrogliosis and HSP70 activation were detected in Cer, while only the former was detected in Hc of V-exposed pups.

Spectroscopic characterization of a VO2+ complex of oxodiacetic acid and its bioactivity on osteoblast-like cells in culture.

The oxovanadium(IV) complex of oxodiacetic acid (H2oda) of stoichiometry [VO(oda)(H2O)2], which presents an unprecedented tridentate OOO coordination, was thoroughly characterized by infrared, Raman, electronic, and electron paramagnetic resonance spectroscopies. The biological activity of the complex on the cell proliferation and differentiation was tested on osteoblast-like cells (MC3T3E1 osteoblastic mouse calvaria-derived cells and UMR106 rat osteosarcoma-derived cells) in culture. The complex caused inhibition of cellular proliferation in both osteoblast-like cells in culture, but the cytotoxicity was stronger in the normal (MC3T3E1) than in the tumoral (UMR106) osteoblasts. The effect of the complex in cell differentiation was tested through the specific activity of alkaline phosphatase of the UMR106 cells because they expressed a high activity of this enzyme. What occurs with other vanadium compounds [VO(oda)(H2O)2] is an inhibitory agent of osteoblast differentiation.

Mechanisms of vanadate-induced cellular toxicity: role of cellular glutathione and NADPH.

Besides its insulin-mimetic effects, vanadate is also known to have a variety of physiological and pharmacological properties, varying from induction of cell growth to cell death and is also a modulator of the multidrug resistance phenotype. However, the mechanisms underlying these effects are still not understood. The present report analyzes the mechanisms of vanadate toxicity in two cell lines previously found to have different susceptibilities to this compound. It was shown that catalase and GSH reversed the sensitivity of a vanadate-sensitive cell line and NADPH sensitized vanadate-resistant cells. NADPH also increased the residues of P-Tyr and the induction of Ras protein expression in vanadate-resistant cells, while GSH avoided these effects in vanadate-sensitive cells. Thus, it seems that the effects of vanadate in signal transduction are dependent on NADPH and are related to cell death. Based on the effects observed in the present study it was suggested that once inside the cell, vanadate is reduced to vanadyl in a process dependent on NADPH. Vanadyl then may react with H2O2 generating primarily peroxovanadium species (PV) rather than following the Fenton reaction. The PV compounds formed would be responsible for P-Tyr increase, Ras induction, and cell death. The results obtained also point to vanadate as a possible chemotherapic in the use of multidrug-resistant tumors.