Research ArticleCancer

Metabolic Modulation of Glioblastoma with Dichloroacetate

Science Translational Medicine  12 May 2010:
Vol. 2, Issue 31, pp. 31ra34
DOI: 10.1126/scitranslmed.3000677

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Metabolic Modulators in Cancer

Cancer cells are optimized for growth, not performance. Their metabolism is geared to provide the raw materials needed for new cells, and that package includes resistance to apoptosis and mitochondria that run on aerobic glycolysis, not oxidative phosphorylation. In a small study, Michelakis et al. have taken advantage of these characteristics seen in glioblastoma, a deadly brain cancer, and examined the effects of a metabolic regulator, dichloroacetate, on tumor cells in culture and in patients, with some promising results.

Dichloroacetate activates pyruvate dehydrogenase, which in turn increases the flow of carbohydrates, in the form of pyruvate, into the mitochondria, where it enhances glucose oxidation by oxidative phosphorylation and decreases glycolysis. When the authors applied this agent to freshly excised glioblastoma tissue from 49 patients, the mitochondrial membrane potential (an index of mitochondrial function) improved, while it did not affect mitochondria from normal brain tissue. They then treated five glioblastoma patients with dichloroacetate, three of whom had recurring disease after traditional chemotherapy and two of whom were newly diagnosed. Three of the patients showed evidence of tumor regression on brain imaging scans, and four were clinically stable 15 months after therapy was initiated. Follow-up studies on cells taken from these patients before and after treatment showed that dichloroacetate normalized several mitochondrial functions, promoted apoptosis, and had other biochemical effects consistent with antitumor activity. Dichloroacetate appears to be safe to give to humans at doses that are required for pyruvate dehydrogenase inhibition. Now, this agent can be added to a growing group of metabolic modulators that may prove useful in cancer therapy.


  • Citation: E. D. Michelakis, G. Sutendra, P. Dromparis, L. Webster, A. Haromy, E. Niven, C. Maguire, T.-L. Gammer, J. R. Mackey, D. Fulton, B. Abdulkarim, M. S. McMurtry, K. C. Petruk, Metabolic modulation of glioblastoma with dichloroacetate. Sci. Transl. Med. 2, 31ra34 (2010).

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