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Pharmacological Ascorbate Induces Sustained Mitochondrial Dysfunction
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8 01 2023
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Source: Free Radic Biol Med. 204:108-117
[PDF-4.78 MB]
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Alternative Title:Free Radic Biol Med
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Description:Pharmacological ascorbate (P-AscH|; high dose given intravenously) generates H|O| that is selectively cytotoxic to cancer compared to normal cells. The RAS-RAF-ERK1/2 is a major signaling pathway in cancers carrying RAS mutations and is known to be activated by H|O|. Activated ERK1/2 also phosphorylates the GTPase dynamin-related protein (Drp1), which then stimulates mitochondrial fission. Although early generation of H|O| leads to cytotoxicity of cancer cells, we hypothesized that sustained increases in H|O| activate ERK-Drp1 signaling, leading to an adaptive response; inhibition of this pathway would enhance the toxicity of P-AscH|. Increases in phosphorylated ERK and Drp1 induced by P-AscH| were reversed with genetic and pharmacological inhibitors of ERK and Drp1, as well as in cells lacking functional mitochondria. P-AscH| increased Drp1 colocalization to mitochondria, decreased mitochondrial volume, increased disconnected components, and decreased mitochondrial length, suggesting an increase in mitochondrial fission 48 h after treatment with P-AscH|. P-AscH| decreased clonogenic survival; this was enhanced by genetic and pharmacological inhibition of both ERK and Drp1. In murine tumor xenografts, the combination of P-AscH| and pharmacological inhibition of Drp1 increased overall survival. These results suggest that P-AscH| induces sustained changes in mitochondria, through activation of the ERK/Drp1 signaling pathway, an adaptive response. Inhibition of this pathway enhanced the toxicity P-AscH| to cancer cells.
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Pubmed ID:37137343
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Pubmed Central ID:PMC10375417
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Volume:204
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