Metabolic modulation of glioblastoma with dichloroacetate.
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.
Michelakis
E D
ED
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada. em2@ualberta.ca
Sutendra
G
G
Dromparis
P
P
Webster
L
L
Haromy
A
A
Niven
E
E
Maguire
C
C
Gammer
T-L
TL
Mackey
J R
JR
Fulton
D
D
Abdulkarim
B
B
McMurtry
M S
MS
Petruk
K C
KC
D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D003999:Dichloroacetic Acid / Q000627:therapeutic use*; D005260:Female; D005909:Glioblastoma / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017382:Reactive Oxygen Species / Q000378:metabolism
D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017382:Reactive Oxygen Species; D003999:Dichloroacetic Acid; D017346:Protein Serine-Threonine Kinases