Metabolic Modulation of Glioblastoma with Dichloroacetate

  title={Metabolic Modulation of Glioblastoma with Dichloroacetate},
  author={Evangelos D. Michelakis and Gopinath Sutendra and Peter Dromparis and L. Webster and Alois Haromy and Erin Niven and Cm Maguire and Terri-Lynn Gammer and John R. Mackey and Dorcus Fulton and Bassam Abdulkarim and Michael S Mcmurtry and Kenneth C. Petruk},
  journal={Science Translational Medicine},
  pages={31ra34 - 31ra34}
Dichloroacetate, an inhibitor of pyruvate dehydrogenase kinase, shifts metabolism away from aerobic glycolysis in glioblastoma tumor cells and may have clinical efficacy in patients. 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… 
Pyruvate dehydrogenase kinase inhibition: Reversing the Warburg effect in cancer therapy
This review considers the Warburg effect as a unique phenotype of cancer cells in-line with the history of and current approaches to cancer therapies based on pyruvate dehydrogenase kinase inhibition with particular reference to dichloroacetate and its derivatives.
Pyruvate dehydrogenase kinase as a novel therapeutic target in oncology
Reverting the mitochondrial suppression with metabolic-modulating drugs, like PDK inhibitors or PKM2 activators holds promise in the rapidly expanding field of metabolic oncology.
Therapeutic targeting of cancer cell metabolism
Current concepts of normal metabolism and altered metabolism in cancer cells are reviewed with specific emphasis on molecular targets involved directly in glycolysis or glutamine metabolism, which has been re-discovered as an essential bioenergetic and anabolic substrate for many cancer cell types.
Dichloroacetate inhibits aerobic glycolysis in multiple myeloma cells and increases sensitivity to bortezomib
Myeloma cells display aerobic glycolysis and DCA may complement clinically used MM therapies to inhibit disease progression, and combinatorial treatment of both agents improved the survival of myeloma-bearing mice.
Targeting metabolism with arsenic trioxide and dichloroacetate in breast cancer cells
This study is the first to demonstrate that targeting two key metabolic hallmarks of cancer is an effective anti-cancer strategy with therapeutic potential.
Dichloroacetate shifts the metabolism from glycolysis to glucose oxidation and exhibits synergistic growth inhibition with cisplatin in HeLa cells.
The specific apoptotic mechanism of DCA as distinguished from the cisplatin may be partly responsible for the synergy and further in vivo study on combination chemotherapy of the two agents in cervical cancer xenografts in mice is warranted.
Hypoxia enhances antitumor activity of dichloroacetate.
Hypoxia enhances cytostatic/cytotoxic effects of DCA in glioma C6 cells via high level ofDCA-induced necrosis of tumor cells and hypoxia-induced ROS hyperproduction.
The effect of dichloroacetate in canine prostate adenocarcinomas and transitional cell carcinomas in vitro.
Results display that DCA treatment has a suppressant effect on proliferation of canine cancer cells.
Overexpression of pyruvate dehydrogenase kinase supports dichloroacetate as a candidate for cutaneous melanoma therapy
The results suggest that PDK expression may play a role in melanoma development and that DCA can be useful for CM therapy, alone or in combination with mTOR inhibitors.


Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer
The generic drug dichloroacetate is an orally available small molecule that reverses the suppressed mitochondrial apoptosis in cancer and results in suppression of tumour growth in vitro and in vivo.
The pharmacology of dichloroacetate.
  • P. Stacpoole
  • Medicine, Biology
    Metabolism: clinical and experimental
  • 1989
Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo
It is demonstrated that DCA has anti-proliferative properties in addition to pro-apoptotic properties, and can be effective against highly metastatic disease in vivo, highlighting its potential for clinical use.
'The metabolism of tumours': 70 years later.
As a result of genetic alterations and intratumoral hypoxia, Hif-1alpha is overexpressed in the majority of common human cancers relative to the surrounding normal tissue and in human breast cancer and brain tumours, HIF-1 alpha overexpression is strongly correlated with tumour grade and vascularity.
Metabolic Targeting as an Anticancer Strategy: Dawn of a New Era?
In mice, DCA treatment appears to reactivate mitochondrial respiration in tumor cells, induces their selective killing, and suppresses cancer growth, providing intriguing insights into the plasticity of tumor metabolism that may offer new opportunities for therapeutic intervention.
Mitaplatin, a potent fusion of cisplatin and the orphan drug dichloroacetate
  • S. Dhar, S. Lippard
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences
  • 2009
The cytotoxicity of mitaplatin in a variety of cancer cell lines equals or exceeds that of all known Pt(IV) compounds and is comparable to that of cisplatin.
Metabolic targeting of hypoxia and HIF1 in solid tumors can enhance cytotoxic chemotherapy
A strategy in which the mitochondrial metabolism of tumor cells is increased by pharmacologic inhibition of hypoxia-inducible factor 1 (HIF1) or its target gene pyruvate dehydrogenase kinase 1 (PDK1) and this acute increase in oxygen consumption leads to a corresponding decrease in tumor oxygenation is described.
Hypoxia, HIF1 and glucose metabolism in the solid tumour
  • N. Denko
  • Biology
    Nature Reviews Cancer
  • 2008
New data suggests that this metabolic switch within the solid tumour may provide a benefit to the tumour not by increasing glycolysis but by decreasing mitochondrial activity.