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Atovaquone Targets Mitochondrial Metabolism and Enhances Radiosensitivity of Diffuse Intrinsic Pontine Glioma

Faiqa Mudassar1,2, Kristina M Cook1,2,3, Zachary N Warnken4

  • 1Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, NSW 2145, Australia.

Cancers
|May 27, 2026
PubMed

Insights

Atovaquone, an FDA-approved drug, targets mitochondrial metabolism to enhance radiation therapy effectiveness for diffuse intrinsic pontine glioma (DIPG). This approach reduces tumor hypoxia and improves survival in preclinical models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Diffuse intrinsic pontine glioma (DIPG) is a fatal pediatric brain tumor with standard radiotherapy often failing due to tumor recurrence.
  • Tumor hypoxia and associated oxidative metabolism are implicated in DIPG radioresistance.
  • Targeting mitochondrial respiration presents a potential strategy to overcome treatment resistance.

Purpose of the Study:

  • To investigate the FDA-approved mitochondrial inhibitor atovaquone for its potential to target oxidative metabolism and enhance radiation response in DIPG.
  • To evaluate the efficacy of an amorphous solid dispersion (ASD) formulation of atovaquone for improved brain exposure and in vivo activity.

Main Methods:

  • Utilized patient-derived DIPG cell lines for in vitro studies, including extracellular flux analysis, hypoxia and reactive oxygen species assays, clonogenic survival assays, metabolomics, and RNA sequencing.
  • Assessed an amorphous solid dispersion (ASD) atovaquone formulation in an orthotopic DIPG xenograft model for in vivo efficacy.

Main Results:

  • Atovaquone suppressed mitochondrial respiration, reduced hypoxia markers, and decreased HIF-1α expression in DIPG cultures, enhancing radiation response.
  • Higher atovaquone concentrations increased oxidative stress and radiosensitivity, with transcriptomics revealing cell-cycle and mitotic pathway disruptions.
  • In vivo, ASD atovaquone combined with radiation significantly prolonged survival in an orthotopic DIPG model.

Conclusions:

  • Targeting mitochondrial metabolism with atovaquone enhances radiosensitivity in DIPG, highlighting it as a therapeutic vulnerability.
  • Atovaquone's effects involve reduced hypoxia signaling and significant metabolic and transcriptional alterations.
  • Atovaquone, particularly in an ASD formulation, shows promise for improving DIPG treatment outcomes when combined with radiation therapy.
Keywords:
diffuse intrinsic pontine gliomamitochondrial inhibitionoxygen consumption rateradiation

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