Clinical pharmacology and toxicology of dichloroacetate.

Abstract

Dichloroacetate (DCA) is a xenobiotic of interest to both environmental toxicologists and clinicians. The chemical is a product of water chlorination and of the metabolism of various drugs and industrial chemicals. Its accumulation in groundwater and at certain Superfund sites is considered a potential health hazard. However, concern about DCA toxicity is predicated mainly on data obtained in inbred rodent strains administered DCA at doses thousands of times higher than those to which humans are usually exposed. In these animals, chronic administration of DCA induces hepatotoxicity and neoplasia. Ironically, the DCA doses used in animal toxicology experiments are very similar to those used clinically for the chronic or acute treatment of several acquired or hereditary metabolic or cardiovascular diseases. As a medicinal, DCA is generally well tolerated and stimulates the activity of the mitochondrial pyruvate dehydrogenase enzyme complex, resulting in increased oxidation of glucose and lactate and an amelioration of lactic acidosis. By this mechanism, the drug may also enhance cellular energy metabolism. DCA is dehalogenated in vivo to monochloroacetate and glyoxylate, from which it can be further catabolized to glycolate, glycine, oxalate, and carbon dioxide. It remains to be determined whether important differences in its metabolism and toxicology exist in humans between environmentally and clinically relevant doses.ImagesFigure 1Figure 2

Dichloroacetate alters Warburg metabolism, inhibits cell growth, and increases the X-ray sensitivity of human A549 and H1299 NSC lung cancer cells

“…Aerobic glycolysis not only increases glucose consumption and lactate production but has also recently been shown to facilitate cell proliferation via biomass incorporation of nucleotides, amino acids, and lipids [25]. Dichloroacetate (DCA) is a synthetic small molecule used to treat hereditary metabolic or cardiovascular diseases [26,27]. It has high bioavailability with 20% of systemic DCA bound to plasma protein [26,27].…”

“…Dichloroacetate (DCA) is a synthetic small molecule used to treat hereditary metabolic or cardiovascular diseases [26,27]. It has high bioavailability with 20% of systemic DCA bound to plasma protein [26,27]. DCA has been shown to be able to partially revert aerobic glycolysis in cancer cells and thereby lower glucose utilization and decrease lactate production [18,19,21,[28][29][30].…”

“…DCA has been shown to be able to partially revert aerobic glycolysis in cancer cells and thereby lower glucose utilization and decrease lactate production [18,19,21,[28][29][30]. Data indicate that DCA reduces lactate production in cancer cells by inhibiting the mitochondrial enzyme pyruvate dehydrogenase kinase that results in an (unphosphorylated) active pyruvate dehydrogenase complex (PDC) that increases pyruvate oxidation in the mitochondria, promotes glucose oxidation, and decreases lactate production in the cell cytoplasm, resulting in an overall increase in oxidative phosphorylation [19,26,30]. However, the true potential for metabolic drugs such as DCA may be as an adjunct to chemotherapy and radiation in multimodality cancer treatment, although to date results have been mixed [14][15][16][17][18][19][20][21]31].…”

Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer

“…Use of PDK inhibitors to elevate PDC activity and thereby promote glucose disposal in peripheral tissues of diabetic animals has been pursued as a therapeutic approach. Initial studies using DCA were encouraging [145], but this compound is a weak PDK inhibitor and a toxic metabolite [146][147][148]. With the objective of designing potent drugs to increase the metabolic use of glucose in individuals with type II diabetes, Glaxo [134], Novartis [123][124][125]149], AstraZeneca [126,135,136], and Pfizer [64] have produced PDK inhibitors.…”

“…Known regulation predicts very low PDP2 activity without insulin. While highly beneficial for myocardial ischemia, DCA has toxic side effects [145][146][147][148]. Testing of the more potent Nov3r class of inhibitors for reducing complications due to lactate build-up during heart ischemia seems warranted.…”