H2O2-mediated Cytotoxicity of Pharmacologic Ascorbate Concentrations to Neuroblastoma Cells: Potential Role of Lactate and Ferritin

By intravenous (but not oral) application of ascorbate, millimolar serum concentrations can be reached, which are preferentially cytotoxic to cancer cells. Cytotoxicity is mediated by transition metal-dependent generation of H2O2 in the interstitial space. In this study, the sensitivity of neuroblastoma cells (Kelly, SK-N-SH) to ascorbate and H2O2 and their defense mechanisms against H2O2 were investigated. Since aerobic glycolysis (the Warburg effect) is a feature of many tumour cells, their glucose consumption and lactate production were monitored. Furthermore, synthesis and release of ferritin by neuroblastoma cells were analysed in order to examine whether ferritin is possibly an iron source for H2O2 generation. Ascorbate (0.6-5.0 mM) and H2O2 (25-100 mu M) were found to be similarly cytotoxic to Kelly and SK-N-SH cells. In each case, cytotoxicity increased if cell concentrations decreased, in accordance with low cell concentrations having lower capacities to detoxify H2O2. Kelly and SK-N-SH cells produced and released remarkable amounts of lactate and ferritin. We propose the selective cytotoxicity of high dose ascorbate to tumour cells to be due to the preferential generation of H2O2 in the acidic and ferritin-rich tumour microenvironment, combined with reduced defense systems against H2O2 as a consequence of aerobic glycolysis. Copyright (C) 2010 S. Karger AG, Basel