Drug Detail

Information about Dichloroacetate

Generic Name
Brand Name (US)
Drug Type
Small molecule
Approval Status
Phase 2
Overall Strategy
GIST cell based
Unblock cell death genes
Drug Category
PDK inhibitor (activates PDH)

Comments by Jerry Call: (A review by Rick Ware follows these initial comments)

Clinical trial results are limited to a very small phase II trial of glioblastoma (brain cancer).
In the 5 patients tested, the drug took 3 months to reach blood levels high enough to alter the tumor's metabolism. At those levels, there were no significant adverse effects. However, at some of the higher doses tested, DCA caused nerve malfunction, i.e. numbing of toes and fingers. Reportedly, in some patients there was also evidence for clinical benefit, with the tumors either regressing in size or not growing further during the 18 month study.
As reported in the phase II trial results (see link below) DCA therapy also inhibited the hypoxia-inducible factor–1α, 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.
The drug does have some side effects, especially neuropathy. Interested readers are encouraged to read the "DCA in Wikipedia" link for a good overview.

If the drug were to have any activity in GIST, the most likely candidate for benefit might be those with Carney/Stratakis Syndrome or pediatric-type GIST. Pediatric-type GIST, including Carney/Stratakis Syndrome and Carney's Triad are associated with defects in the succinate dehydrogenase protein (SHD). This defect results in increased hypoxia-inducible factor–1α (HIF1α) expression with resultant upregulation of growth factors (EGFR, VEGF, IGF1R, etc) See the following paragraph from a 2007 AACR presentation:

Several familial cancer syndromes have been linked to HIF-1 through mutations of tumor suppressors that are enzymes or proteins involved in metabolism. Mutations of the TCA cycle enzyme succinate dehydrogenase are associated with paragangliomas, while mutations of fumarate hydratase are linked to uterine leiomyomatosis and renal cancer. These mutations produce high levels of succinate, which inhibit prolyl hydroxylases (PHDs) resulting in increased stability of the hypoxia inducible factor HIF-1 protein. The PHDs hydroxylate HIF-1 prolyl residues and target HIF-1 for recognition by the von Hippel-Lindau protein (vHL), subsequent ubiquitination and proteasomal degradation. Inactivating mutations of vHL, which are associated with renal cancers, also stabilize HIF, which is important for stimulation of glycolysis and angiogenesis. These observations indicate that mutations of tumor suppressors may compromise mitochondrial function as well as activate glycolysis through the stabilization of HIF-1.

The following review was done by Science Team Member Rick Ware.

A unique metabolic signature routinely observed in cancer cells is an energy-dependence-shift from normal oxidative phosphorylation to aerobic glycolysis. Cellular metabolic transformation to this new energy phenotype, known as ‘The Warburg Effect” involves shifting energy production from the more efficient mitochondrial oxidative phosphorylation pathway to less efficient glycolysis in the cell cytoplasm.
Permanent damage to the mitochondria is thought to be responsible for initiating the cellular transition from anaerobic to aerobic glycolysis that is observed in cancer cells. Recently however, renewed interest in the metabolic hypothesis of cancer has provided further insight into the integrity of cancer cell mitochondria suggesting that these organelles may not be irreversibly damaged but merely functionally suppressed.
In the present study titled ‘A Mitochondria-K+ Channel Axis Is Suppressed in
Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth’, the authors (Bonnet et al) investigate the hypothesis that “the metabolic phenotype in cancer is due to a potentially plastic mitochondrial remodeling that results in suppressed oxidative phosphorylation, enhanced glycolysis and suppressed apoptosis”.
The investigators postulate that reversal of key electrical/metabolic changes (ie membrane hyperpolarization and deficiency in Kv channels) observed in the mitochondria of cancer cells might induce a shift back to oxidative phosphorylation, increase apoptosis and lead to inhibition of cancer cell growth. To test this hypothesis, the authors use dichloroacetate (DCA), a water soluble orally-administered agent and inhibitor of pyruvate dehydrogenase kinase (PDK).
A) Re-establishment of a robust mitochondrial metabolic profile.
i) DCA inhibition of pyruvate dehydrogenase kinase is a key step that leads to re-establishment of the mitochondrial oxidative phosphorylation pathway as the main source for cell energy. DCA inhibition of PDK frees up the mitochondrial gate-keeping enzyme pyruvate dehydrogenase (PDH) which is then able to convert pyruvate to acetyl-CoA and initiate normal oxidative phosphoryaltion via the Krebs cycle.
ii) Reactivation of the Krebs cycle generates reactive oxygen species (ROS) and H+ ions. Release of ROS into the cell cytoplasm regulates both opening of plasma membrane ion channels and stabilizes calcium sensitive nuclear transcription factors. Efflux of H+ ions helps re-establish a negative mitochondrial membrane potential and thereby aids in the synthesis of ATP. Maintenance of a negative membrane potential also opens mitochondrial transition pores (MTP) permitting efflux of cytochrome c and apoptosis- inducing factor (AIF) into the cytoplasm. Cytochrome c and ROS act to open the plasma membrane redox-sensitive K+ channel Kv1.5 which results in cell hyperpolarization and inhibition of voltage-dependent calcium ion movement into the cell. Decreased intracellular [Ca+2] suppresses tonic activation of the nuclear factor of activated T lymphocytes (NFAT) resulting in its efflux from the nucleus and further expression of Kv1.5 membrane channels. This added efflux of K+ from the cell decreases tonic inhibition of [K+] on caspase 3 and caspase 9 and leads to enhancement of apoptosis.
B) Authors Conclusion
i) The metabolic profile (aerobic glycolysis) observed in cancer cells may be due to a potentially plastic mitochondrial remodeling that results in suppressed oxidative phosphorylation, enhanced glycolysis, and suppressed apoptosis.
ii) Dichloroacetate (DCA) re-establishes a robust mitochondrial profile.
iii) DCA inhibits PDK, shifts metabolism from glycolysis to glucose oxidation, decreases mitochondrial membrane potential, increases mitochondrial H2O2 and activates Kv channels, induces apoptosis, decreases cell proliferation, and inhibits tumor growth without apparent toxicity.
iv) The mitochondria-NFAT-Kv axis and PDK are important therapeutic targets
in cancer and orally available DCA is a promising selective cancer agent.