Oxovanadium-based inhibitors can drive redox-sensitive cytotoxicity in neuroblastoma cells and synergise strongly with buthionine sulfoximine

Abstract

In a wide range of neuroblastoma-derived lines oxovanadium compounds such as bis(maltolato)oxovanadium(IV) (BMOV) are cytotoxic. This is not explained by oxidative stress or inhibition of ion channels. Genotoxicity is unlikely given that a p53 response is absent and p53-mutant lines are also sensitive. Cytotoxicity is inhibited by N-acetyl cysteine and glutathione ester, indicating that BMOV action is sensitive to cytoplasmic redox and thiol status. Significantly, combining BMOV with glutathione synthesis inhibition greatly enhances BMOV-induced cell death. This combination treatment triggers high AKT pathway activation, highlighting the potential functional importance of PTP inhibition by BMOV. AKT activation itself, however, is not required for cytotoxicity. Oxovanadium compounds may thus represent novel leads as p53-independent therapeutics for neuroblastoma.

Stabilities and Biological Activities of Vanadium Drugs: What is the Nature of the Active Species?

“…Inorganic V salts, e.g., Na 3 VO 4 or VOSO 4 ⋅5 H 2 O, and anti‐diabetic V IV complexes, e.g., 1 , undergo complex speciation in biological media, as discussed earlier in the review, but the products of this speciation are often assumed to be relatively non‐toxic, although they were highly cytotoxic in some cell lines (Table S1) . Both Na 3 VO 4 and 1 converge within 24 h at 310 K into the same mixture of decomposition products (≈75 % V V and ≈25 % V IV complexes with protein and carbohydrate ligands), which were probably mostly responsible for the observed biological activity.…”

“…Anti‐cancer activity studies of 1 (or more likely of its reaction products with cell culture media) in human neuroblastoma cells showed that V cytotoxicity varies by at least an order of magnitude, even in closely related cell lines. In agreement with data from V V salts (Section 2.1), the cytotoxicity of 1 strongly correlated with cellular thiol levels …”

“…Both Na 3 VO 4 and 1 converge within 24 h at 310 K into the same mixture of decomposition products (≈75 % V V and ≈25 % V IV complexes with protein and carbohydrate ligands), which were probably mostly responsible for the observed biological activity. Notably, the effects of V compounds in cultured cells varied widely not only between cell lines (Table S1) and measurement techniques, but also within the same cell line studied using the same technique by different researchers. For instance, the reported IC 50 values for Na 3 VO 4 in A549 (human lung cancer) cells, determined after 72 h treatments using the well‐established MTT assay (based on mitochondrial respiration as a measure of cell metabolic activity) were 9.5 μ m , 24 μ m , or >50 μ m .…”

“…[18,27] XANESd ata [24] showed equilibration of 1 in typical cell culture media within about 24 ha t3 10 Kt hat led to am ixture of V V ( % 75 %) and V IV ( % 25 %) complexes with proteins and carbohydrates (same as for Na 3 VO 4 ). Anti-cancer activity studies of 1 (or more likely of its reaction products with cell culture media) in human neuroblastoma cells [47] showed that Vc ytotoxicityv aries by at least an order of magnitude, even in closely relatedc ell lines. In agreement with data from V V salts (Section 2.1), [38] the cytotoxicity of 1 strongly correlated with cellular thiol levels.…”

“…In agreement with data from V V salts (Section 2.1), [38] the cytotoxicity of 1 strongly correlated with cellular thiol levels. [47] Due to commercial availability and stabilityu nder ambient conditions, [V IV O(acac) 2 ]( 2;a cac = acetylacetonato(À) = 2,4- pentanedionato(À)) is ac ommon reference drug in studies of Ve fficacy (Table S1). [48][49][50][51] Makinen and co-workers [52] argued that 2 is superior to 1 as an anti-diabetic due to its highers tability in extracellular media and increased cellular uptake.…”