Sodium Orthovanadate Inhibits p53-Mediated Apoptosis

Abstract

Sodium orthovanadate (vanadate) inhibits the DNA-binding activity of p53, but its precise effects on p53 function have not been examined. Here, we show that vanadate exerts a potent antiapoptotic activity through both transcription-dependent and transcription-independent mechanisms relative to other p53 inhibitors, including pifithrin (PFT) α. We compared the effects of vanadate to PFTα and PFTµ, an inhibitor of transcriptionindependent apoptosis by p53. Vanadate suppressed p53-associated apoptotic events at the mitochondria, including the loss of mitochondrial membrane potential, the conformational change of Bax and Bak, the mitochondrial translocation of p53, and the interaction of p53 with Bcl-2. Similarly, vanadate suppressed the apoptosis-inducing activity of a mitochondrially targeted temperature-sensitive p53 in stable transfectants of SaOS-2 cells. In radioprotection assays, which rely on p53, vanadate completely protected mice from a sublethal dose of 8 Gy and partially from a lethal dose of 12 Gy. Together, our findings indicated that vanadate effectively suppresses p53-mediated apoptosis by both transcription-dependent and transcriptionindependent pathways, and suggested that both pathways must be inhibited to completely block p53-mediated apoptosis. Cancer Res; 70(1); 257-65. ©2010 AACR.

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

“…On the other hand, SO can induce apoptosis or necrosis [30], but it was also found to protect p53-dependent apoptosis [57,58]. We anticipate that the type of cell death induced by M:SO will largely depend on the concentration of each compound (e.g., M (10 μM):SO (17:5 μM) vs. M (17.5 μM):SO (10 μM)), exposure time and cell phenotype (e.g., p53 activity).…”

Bax, Bcl2, and p53 Differentially Regulate Neomycin- and Gentamicin-Induced Hair Cell Death in the Zebrafish Lateral Line

“…PFTμ is hypothesized to inhibit p53 mitochondrial activity by disrupting binding of p53 to Bcl2 or Bcl-xL, which then allows them to bind and inhibit Bax and thereby promote cell survival (Strom et al 2006;Morita et al 2010). We therefore asked if overexpressing Bcl2 would protect hair cells from aminoglycoside damage.…”

Orthovanadate-Induced Vasoconstriction of Rat Mesenteric Arteries Is Mediated by Rho Kinase-Dependent Inhibition of Myosin Light Chain Phosphatase

“…1) Because of its structural similarity to phosphate, vanadate possesses various biochemical and pharmacological properties, such as the ability to inhibit ATPases 2) and protein tyrosine phosphatases (PTPases), 3) epidermal growth factor (EGF)-like mitogenic activity, 4) insulin-mimetic properties, 5) anti-apoptotic activities, 6) and antitumor or carcinogenic properties. 7,8) Vanadium compounds exert contractile effects on vascular and non-vascular smooth muscle, such as the guinea pig taenia coli, trachea, and gallbladder smooth muscle.…”