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.