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.

• Authors: Owen Clark, Inhye Park, Alessia Di Florio, Ann-Christin Cichon, Sarah Rustin, Roman Jugov, Ruhina Maeshima, Andrew W Stoker
• Journal: Cancer letters (Cancer Lett) Vol. 357 Issue 1 Pg. 316-327 (Feb 01 2015) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 25444896 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Chemical References

• Pyrones
• bis(maltolato)oxovanadium(IV)
• Vanadates
• Buthionine Sulfoximine

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Buthionine Sulfoximine (administration & dosage, pharmacology)
• Cell Line, Tumor
• Drug Synergism
• Fibroblasts (drug effects)
• Humans
• Mice
• Neuroblastoma (drug therapy, metabolism)
• Oxidation-Reduction
• Pyrones (administration & dosage, pharmacology)
• Signal Transduction
• Transfection
• Vanadates (administration & dosage, pharmacology)