| 20203294 |
Ranzato E, Biffo S, Burlando B: Selective Ascorbate Toxicity to Malignant Mesothelioma: A Redox Trojan Mechanism. Am J Respir Cell Mol Biol. 2010 Mar 4.
We have studied the mechanism of ascorbate toxicity to malignant mesothelioma cells. Neutral red uptake (NRU) showed that ascorbate, but not dehydroascorbate, was highly toxic to the mesothelioma cell lines REN and MM98, while it was significantly less toxic to immortalized (HMC-htert) and primary mesothelial cells. Ascorbate transport inhibitors phloretin, sodium azide and ouabain did not reduce ascorbate toxicity . Toxicity was markedly reduced by the H2O2-degrading enzyme catalase. Confocal imaging of cells loaded with the dihydrhodamine 123 ROS probe showed that ascorbate caused a strong increase of rhodamine fluorescence in mesothelioma, but not in mesothelial cells. Mesothelioma cells showed much higher superoxide production (revealed by cytochrome c reduction assay) and NOX4 expression (revealed by Western blot) than mesothelial cells. Two inhibitors of cellular superoxide sources, apocynin and rotenone, reduced ascorbate cytotoxicity and the ascorbate-induced rise in rhodamine fluorescence. Taken together, data indicate that ascorbate-induced extracellular H2O2 production induces a strong oxidative stress in mesothelioma cells due to the higher superoxide production rate of these tumor cells. This can explain the selective toxicity of ascorbate to mesothelioma cells, and suggests its possible use in the clinical treatment of malignant mesothelioma. |
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