Role of dichloroacetate in the treatment of genetic mitochondrial diseases

Stacpoole, Peter W.; Kurtz, T.; Han, Zongchao; Langaee, Taimour

doi:10.1016/j.addr.2008.02.014

Cited by 127 publications

(129 citation statements)

References 41 publications

(65 reference statements)

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“…Ongoing studies on the cell line specific glycolytic phenotype along with the cell line specific expression of the different PDK isoforms, Kv1.5 channels, and antiapoptotic proteins will further clarify these issues. Tolerable DCA dosages of 25 mg/kg/d given twice daily, which were clinically applied for the treatment of mitochondrial disorders, resulted in peak plasma concentrations of 100-250 µmol/L after the first dose and 200-550 µmol/L after 6 month of therapy [23]. Plasma concentrations of about 1 mmol/L were observed after the first application of 50 mg/kg DCA as well as after chronic exposure to 25 mg/kg DCA [15,24].…”

Section: Discussionmentioning

confidence: 99%

Dichloroacetate metabolically targeted therapy defeats cytotoxicity of standard anticancer drugs

Heshe

Hoogestraat

Brauckmann³

et al. 2010

Cancer Chemother Pharmacol

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Section: Discussionmentioning

confidence: 99%

Dichloroacetate metabolically targeted therapy defeats cytotoxicity of standard anticancer drugs

Heshe

Hoogestraat

Brauckmann³

et al. 2010

Cancer Chemother Pharmacol

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“…By inhibiting PDK, DCA activates PDH, which increases the provision of acetyl CoA to the Krebs cycle and, in turn, stimulates oxidative phosphorylation. By shifting the metabolism of glucose from glycolysis and lactate formation to mitochondrial oxidative phosphorylation, DCA reduces lactate concentrations and reverses the Warburg effect in pulmonary artery smooth muscle cells and cancer cells (Archer et al, 2008;Stacpoole et al, 2008;Michelakis et al, 2010). For these reasons, the mitochondrion is considered to be the primary cellular site of DCA action.…”

Section: Introductionmentioning

confidence: 99%

Mitochondrion as a Novel Site of Dichloroacetate Biotransformation by Glutathione Transferase ζ1

Li¹,

James²,

McKenzie³

et al. 2010

J Pharmacol Exp Ther

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Dichloroacetate (DCA) is a potential environmental hazard and an investigational drug. Repeated doses of DCA result in reduced drug clearance, probably through inhibition of glutathione transferase 1 (GSTZ1), a cytosolic enzyme that converts DCA to glyoxylate. DCA is known to be taken up by mitochondria, where it inhibits pyruvate dehydrogenase kinase, its major pharmacodynamic target. We tested the hypothesis that the mitochondrion was also a site of DCA biotransformation. Immunoreactive GSTZ1 was detected in liver mitochondria from humans and rats, and its identity was confirmed by liquid chromatography/tandem mass spectrometry analysis of the tryptic peptides. Study of rat submitochondrial fractions revealed GSTZ1 to be localized in the mitochondrial matrix. The specific activity of GSTZ1-catalyzed dechlorination of DCA was 2.5-to 3-fold higher in cytosol than in whole mitochondria and was directly proportional to GSTZ1 protein expression in the two compartments. Rat mitochondrial GSTZ1 had a 2.5-fold higher App K m for glutathione than cytosolic GSTZ1, whereas the App K m values for DCA were identical. Rats administered DCA at a dose of 500 mg/kg/day for 8 weeks showed reduced hepatic GSTZ1 activity and expression of ϳ10% of control levels in both cytosol and mitochondria. We conclude that the mitochondrion is a novel site of DCA biotransformation catalyzed by GSTZ1, an enzyme colocalized in cytosol and mitochondrial matrix.

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“…DCA has been reported as a possible pharmacological cure for chronic diseases such as lactic acidosis and other mitochondria associated diseases (Michelakis et al 2010;Miquel et al 2012;Stacpoole et al 2008). In a number of in vitro studies, DCA is reported to enhance reactive oxygen generation (ROS) generation and oxidative stress leading to cell death (Ayyanathan et al 2012;Hassoun and Ray 2003;Wong et al 2008).…”

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confidence: 99%

Long-term dietary exposure to low concentration of dichloroacetic acid promoted longevity and attenuated cellular and functional declines in aged Drosophila melanogaster

Pandey

Vimal

Chandra

et al. 2014

AGE

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Dichloroacetic acid (DCA), a water disinfection by-product, has attained emphasis due to its prospect for clinical use against different diseases including cancer along with negative impact on organisms. However, these reports are based on the toxicological as well clinical data using comparatively higher concentrations of DCA without much of environmental relevance. Here, we evaluate cellular as well as organismal effects of DCA at environmentally and mild clinically relevant concentrations (0.02-20.0 μg/ml) using an established model organism, Drosophila melanogaster. Flies were fed on food mixed with test concentrations of DCA for 12-48 h to examine the induction of reactive oxygen species (ROS) generation, oxidative stress (OS), heat shock genes (hsps) and cell death along with organismal responses. We also examined locomotor performance, ROS generation, glutathione (GSH) depletion, expression of GSH-synthesizing genes (gclc and gclm), and hsps at different days (0, 10, 20, 30, 40, 50) of the age in flies after prolonged DCA exposure. We observed mild OS and induction of antioxidant defense system in 20.0 μg/ml DCA-exposed organism after 24 h. After prolonged exposure to DCA, exposed organism exhibited improved survival, elevated expression of hsp27, gclc, and gclm concomitant with lower ROS generation and GSH depletion and improved locomotor performance. Conversely, hsp27 knockdown flies exhibited reversal of the above end points. The study provides evidence for the attenuation of cellular and functional decline in aged Drosophila after prolonged DCA exposure and the effect of hsp27 modulation which further incites studies towards the therapeutic application of DCA.

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Role of dichloroacetate in the treatment of genetic mitochondrial diseases

Cited by 127 publications

References 41 publications

Dichloroacetate metabolically targeted therapy defeats cytotoxicity of standard anticancer drugs

Dichloroacetate metabolically targeted therapy defeats cytotoxicity of standard anticancer drugs

Mitochondrion as a Novel Site of Dichloroacetate Biotransformation by Glutathione Transferase ζ1

Long-term dietary exposure to low concentration of dichloroacetic acid promoted longevity and attenuated cellular and functional declines in aged Drosophila melanogaster

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