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

• Published in: Investigational new drugs 2012-08, Vol.30 (4), p.1302-1310
• Main Authors: Delwar, Zahid M., Avramidis, Dimitrios, Follin, Elna, Hua, Yan, Siden, Åke, Cruz, Mabel, Paulsson, Kajsa M., Yakisich, Juan Sebastian
• Format: Article
• Language: English
• Subjects: Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Brain cancer; Brain Neoplasms - drug therapy; Brain Neoplasms - pathology; Cancer and Oncology; Cancer och onkologi; Cancer therapies; Cell culture; Cell cycle; Cell Death - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Cells; Clinical Medicine; Clinical outcomes; Cytotoxicity; Dithiothreitol - pharmacology; Drug Screening Assays, Antitumor; Drug therapy; Drugs; DTT; Genistein; Genistein - pharmacology; Glioma; Glioma - drug therapy; Glioma - pathology; Gliomas; Humans; Immunology; Kinases; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Medicine; Medicine & Public Health; Menadione; Oncology; Oxidative stress; Pharmacology/Toxicology; Phosphatase; Preclinical Studies; Proliferation; Protective Agents - pharmacology; Protective Agents - therapeutic use; Proteins; Sodium; Sodium orthovanadate; Studies; Time Factors; Toxicity; Tumors; Vanadates - pharmacology; Vanadates - therapeutic use; Vitamin K 3 - pharmacology; Vitamin K 3 - therapeutic use
• ISSN: 0167-6997; 1573-0646; 1573-0646
• DOI: 10.1007/s10637-011-9680-y

Summary 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.