Related Experiment Video
Updated: Jun 13, 2026
Advancements in the Metabolic Profiling of Three-Dimensional Brain Tumor Spheroids for Drug Screening
Published on: September 5, 2025
Metabolic modulation of glioblastoma with dichloroacetate
E D Michelakis1, G Sutendra, P Dromparis
1Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. em2@ualberta.ca
Abstract:
Solid tumors, including the aggressive primary brain cancer glioblastoma multiforme, develop resistance to cell death, in part as a result of a switch from mitochondrial oxidative phosphorylation to cytoplasmic glycolysis. This metabolic remodeling is accompanied by mitochondrial hyperpolarization. We tested whether the small-molecule and orphan drug dichloroacetate (DCA) can reverse this cancer-specific metabolic and mitochondrial remodeling in glioblastoma. Freshly isolated glioblastomas from 49 patients showed mitochondrial hyperpolarization, which was rapidly reversed by DCA. In a separate experiment with five patients who had glioblastoma, we prospectively secured baseline and serial tumor tissue, developed patient-specific cell lines of glioblastoma and putative glioblastoma stem cells (CD133(+), nestin(+) cells), and treated each patient with oral DCA for up to 15 months. DCA depolarized mitochondria, increased mitochondrial reactive oxygen species, and induced apoptosis in GBM cells, as well as in putative GBM stem cells, both in vitro and in vivo. DCA therapy also inhibited the hypoxia-inducible factor-1alpha, promoted p53 activation, and suppressed angiogenesis both in vivo and in vitro. The dose-limiting toxicity was a dose-dependent, reversible peripheral neuropathy, and there was no hematologic, hepatic, renal, or cardiac toxicity. Indications of clinical efficacy were present at a dose that did not cause peripheral neuropathy and at serum concentrations of DCA sufficient to inhibit the target enzyme of DCA, pyruvate dehydrogenase kinase II, which was highly expressed in all glioblastomas. Metabolic modulation may be a viable therapeutic approach in the treatment of glioblastoma.
Insights
Dichloroacetate (DCA) reverses metabolic changes in glioblastoma, a brain cancer. DCA therapy showed promise by inducing cancer cell death and inhibiting tumor growth with manageable side effects.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Glioblastoma multiforme (GBM) exhibits metabolic reprogramming, shifting from oxidative phosphorylation to glycolysis, which contributes to treatment resistance.
- This metabolic switch is associated with mitochondrial hyperpolarization in solid tumors, including GBM.
- Dichloroacetate (DCA), a small-molecule drug, is investigated for its potential to reverse cancer-associated metabolic alterations.
Purpose of the Study:
- To evaluate DCA's ability to reverse metabolic and mitochondrial remodeling in glioblastoma.
- To assess the efficacy and toxicity of DCA in patient-derived glioblastoma models and patients.
Main Methods:
- Analysis of mitochondrial membrane potential in freshly isolated glioblastomas.
- Development of patient-specific glioblastoma and glioblastoma stem cell lines.
- In vitro and in vivo treatment of glioblastoma models and patients with oral DCA.
- Assessment of mitochondrial function, apoptosis, hypoxia-inducible factor-1alpha (HIF-1α), p53 activation, and angiogenesis.
Main Results:
- DCA rapidly reversed mitochondrial hyperpolarization in glioblastomas.
- DCA treatment led to mitochondrial depolarization, increased reactive oxygen species, and induced apoptosis in GBM cells and stem cells.
- DCA inhibited HIF-1α, promoted p53 activation, and suppressed angiogenesis.
- The primary toxicity was reversible peripheral neuropathy, with no significant hematologic, hepatic, renal, or cardiac toxicity observed.
Conclusions:
- Metabolic modulation using DCA demonstrates potential as a therapeutic strategy for glioblastoma.
- DCA effectively targets cancer-specific metabolic pathways and exhibits anti-tumor effects in vitro and in vivo.
- Clinical efficacy was observed at non-neuropathic doses, suggesting a therapeutic window for DCA in glioblastoma treatment.