Differential modulation of oxidative stress in normal and cancer cells by mangafodipir improves the therapeutic index of anticancer drugs

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Intracellular H2O2 accumulation is a determining event for the cytotoxicity of anticancer agents independently of their molecular targets. Compounds that increase H2O2 levels enhance both the efficacy and toxicity of anticancer agents. Mangafodipir, a contrast agent for magnetic resonance imaging, increases both H2O2 synthesis through superoxide dismutase activity and H2O2 catabolism through catalase and glutathione-reductase activities. Therefore, we explored the ability of mangafodipir to modulate paclitaxel (PCX), 5FU and oxaliplatin (OXA) cytotoxicity in cancer and normal cells. Human leucocytes were exposed to either PCX, OXA or 5FU for 24h at IC50. Concomitant exposure to 400 μM mangafopidir decreased PCX, OXA and 5FU cytotoxicity by 50, 30 and 15%, respectively, as evaluated by MTT assay. The protective effect of mangafodipir on the hematologic toxicity of PCX was studied in BALB/c mice. Severe neutropenia and bone marrow hypoplasia observed in all animals at day 10 of PCX treatment (20 mg/kg ip x3/w) were abrogated by concomitant treatment with mangafodipir (10 mg/kg ip x3/w). Sublethal intraperitoneal administration of pathogen Staphyloccus aureus induced the early death of 14/17 mice with PCX-induced neutropenia and of 3/17 mangafodipir + PCX-treated mice. In contrast, mangafodipir enhanced the efficacy of anticancer agents in cancer cells, both in vitro and in vivo. Indeed, in CT26 mouse colon cancer cells, mangafodipir increased the cytotoxicity of PCX, OXA and 5FU by 5, 40 and 6%, respectively. Similar results were observed using Hepa1.6 mouse hepatoma and A549 human lung cancer cells. In mice with implanted syngenics CT26 cells, mangafodipir, PCX or their combination induced 40, 40 and 55% tumor reduction, respectively. To determine whether the differential effect of mangafodpir in normal and cancer cells was related to oxidative stress modulation, intracellular H2O2 levels were monitored in vitro by oxidation of the fluorescent probe H2DCFDA. Co-exposure of mangafodipir resulted in a 10 to 30% reduction of H2O2 accumulation induced by anticancer agents in leucocytes, but in a 4-fold increase in CT26 cells. Hence, mangafodipir protects against the toxicity of anticancer agents in normal cells, and increases their efficacy in cancer cells, both in vitro and in vivo. The resulting increased therapeutic index seems related to a differential modulation of H2O2 levels in normal and cancer cells and will be explored in an ongoing clinical trial.