Metabolic Modulation of Glioblastoma
E. D. Michelakis, G. Sutendra,P. Dromparis, L. Webster, A. Haromy, E. Niven,2 C. Maguire,
T.-L. Gammer, J. R. Mackey, D. Fulton, B. Abdulkarim, M. S. McMurtry, K. C. Petruk
(Science Translational Medicine, Published 12 May 2010; Volume 2 Issue 31)
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 stemcells, both in vitro and in vivo. DCA therapy also inhibited the hypoxia-inducible factor–1a, 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.
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