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Treating SCA1 Mice with Water-Soluble Compounds to Non-Specifically Boost Mitochondrial Function
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Pharmacological ascorbate induces sustained mitochondrial dysfunction.

Rory S Carroll1, Juan Du2, Brianne R O'Leary2

  • 1Departments of Surgery, University of Iowa College of Medicine, USA.

Free Radical Biology & Medicine
|May 3, 2023
PubMed
Summary
This summary is machine-generated.

Pharmacological ascorbate (P-AscH-) generates hydrogen peroxide (H2O2) that kills cancer cells. Inhibiting the ERK-Drp1 pathway enhances this effect by blocking cancer cell adaptation to H2O2.

Keywords:
Mitochondrial dynamicsMitochondrial fissionOxidative stressPharmacological ascorbate

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Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Pharmacological ascorbate (P-AscH-) selectively kills cancer cells by generating hydrogen peroxide (H2O2).
  • The RAS-RAF-ERK1/2 pathway is activated by H2O2 and regulates mitochondrial fission via dynamin-related protein 1 (Drp1).

Purpose of the Study:

  • To investigate the role of sustained H2O2 exposure and ERK-Drp1 signaling in cancer cell adaptation to P-AscH-.
  • To determine if inhibiting the ERK-Drp1 pathway enhances P-AscH--induced cancer cell cytotoxicity.

Main Methods:

  • Utilized genetic and pharmacological inhibitors of ERK and Drp1.
  • Assessed mitochondrial morphology and fission.
  • Evaluated cancer cell clonogenic survival in vitro.
  • Tested P-AscH- and Drp1 inhibition in murine tumor xenografts.

Main Results:

  • P-AscH- treatment led to increased phosphorylated ERK and Drp1, and enhanced mitochondrial fission.
  • Inhibition of ERK and Drp1 reversed these effects and significantly increased P-AscH- cytotoxicity.
  • Combination therapy improved overall survival in murine tumor models.

Conclusions:

  • Sustained H2O2 from P-AscH- activates the adaptive ERK-Drp1-mitochondrial fission pathway in cancer cells.
  • Inhibiting this adaptive pathway potentiates the anti-cancer effects of pharmacological ascorbate.