title: Cytotoxic effect of menadione and sodium orthovanadate in combination on human glioma cells.
abstract: Gliomas are the most common primary brain tumor, and their treatment is still a challenge. Here, we evaluated the antiproliferative effect of a novel combination of two potent oxidative stress enhancers: menadione (M) and sodium orthovanadate (SO). We observed both short-term and prolonged growth inhibitory effects of M or SO alone as well as in combination (M:SO) on DBTRG.05MG human glioma cells. A stronger antiproliferative effect was observed in the short-term proliferation assay with the M:SO combination compared to either investigated agent alone. In the long-term proliferation assay, a 10-day exposure to M:SO at concentrations of 10 μM:17.5 μM or 17.5 μM:10 μM was enough to kill 100% of the cells; no cell regrowth was observed after re-incubation in drug-free media. When used in combination, the single concentration of M and SO could be decreased by 2.5- to 5-fold of those used for each experimental drug alone and still obtain a similar antiproliferative effect. The underlying molecular mechanism was investigated by co-incubating M:SO with dithiothreitol (DTT) and genistein. Both substances partially neutralized the effects of the M:SO combination, showing additive effects. This observation suggests a role of oxidative stress and tyrosine kinase stimulation in the M:SO cytotoxic effect. Our results indicate that M:SO combination is an attractive alternative for glioma treatment that encourages further study. The neutralizing effects of genistein and DTT reveal a possibility for their use in the minimization of potential M:SO systemic toxicity.
authors.affiliation: Department of Clinical Neuroscience R54, Karolinska Institute, Karolinska University Hospital, Huddinge, S-141 86 Stockholm, Sweden.
authors.forename: Zahid M
authors.initials: ZM
authors.lastname: Delwar
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Avramidis
authors.forename: Elna
authors.initials: E
authors.lastname: Follin
authors.forename: Yan
authors.initials: Y
authors.lastname: Hua
authors.forename: Åke
authors.initials: Å
authors.lastname: Siden
authors.forename: Mabel
authors.initials: M
authors.lastname: Cruz
authors.forename: Kajsa M
authors.initials: KM
authors.lastname: Paulsson
authors.forename: Juan Sebastian
authors.initials: JS
authors.lastname: Yakisich
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004229:Dithiothreitol / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D019833:Genistein / Q000494:pharmacology; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology*; D006801:Humans; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D014638:Vanadates / Q000494:pharmacology / Q000627:therapeutic use*; D024483:Vitamin K 3 / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D020011:Protective Agents; D014638:Vanadates; D024483:Vitamin K 3; D019833:Genistein; D004229:Dithiothreitol