Pharmacological Ascorbate Induces Sustained Mitochondrial Dysfunction

Details

• Alternative Title:
  Free Radic Biol Med
• Personal Author:
  Carroll, Rory S. ; Du, Juan ; O’Leary, Brianne R. ; Steers, Garett ; Goswami, Prabhat C. ; Buettner, Garry R. ; Cullen, Joseph J.
• 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.
• Subjects:
  Animals Antineoplastic Agents Ascorbic Acid Carcinoma, Pancreatic Ductal Cell Line, Tumor Extracellular Signal-Regulated MAP Kinases Female Humans Hydrogen Peroxide Mice Mitochondria Mitochondrial Dynamics Oxidative Stress Phosphorylation Reactive Oxygen Species Signal Transduction Survival Analysis Xenograft Model Antitumor Assays

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• Keywords:
  Mitochondrial Dynamics Mitochondrial Fission Oxidative Stress Pharmacological Ascorbate
• Source:
  Free Radic Biol Med. 204:108-117
• Pubmed ID:
  37137343
• Pubmed Central ID:
  PMC10375417
• Document Type:
  Journal Article
• Funding:
  R01 CA184051/CA/NCI NIH HHSUnited States/ ; P30 CA086862/CA/NCI NIH HHSUnited States/ ; U48 DP006377/DP/NCCDPHP CDC HHSUnited States/ ; U48 DP006399/DP/NCCDPHP CDC HHSUnited States/ ; U48 DP006389/DP/NCCDPHP CDC HHSUnited States/ ; T32 CA148062/CA/NCI NIH HHSUnited States/ ; P01 CA217797/CA/NCI NIH HHSUnited States/ ; P30 ES005605/ES/NIEHS NIH HHSUnited States/
• Volume:
  204
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha-512:8f72ba6b236ce129a4da6d8764106a93a248fc89cc3bdc94ca2ecedbc5a4ea13470f77de8fc076f7fa92997660ef17e8becdfb7a0b9556e9486d60e52fadb26c
• Download URL:
  https://stacks.cdc.gov/view/cdc/131478/cdc_131478_DS1.pdf
• File Type:
  [PDF - 4.78 MB ]