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

[摘要] 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 µM) 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.

[学科分类] 分子生物学，细胞生物学和基因

[关键词] Pharmacologic Ascorbate;H2O2;Ferritin;Lactate;Neuroblastoma;Warburg Effect