Dichloroacetic acid explained

Dichloroacetic acid (DCA), sometimes called bichloroacetic acid (BCA), is the organic compound with formula . It is an analogue of acetic acid, in which 2 of the 3 hydrogen atoms of the methyl group have been replaced by chlorine atoms. Like the other chloroacetic acids, it has various practical applications. The salts and esters of dichloroacetic acid are called dichloroacetates.

Reactions

The chemistry of dichloroacetic acid is typical for halogenated organic acids. It is an alkylating agent. It forms esters.

It is a member of the chloroacetic acids family. As such it is more acidic than acetic acid. It fully dissociates into dichloroacetate when dissolved in water, consistent with it pKa of 1.35, pure dichloroacetic acid is classed as a strong organic acid; it is very corrosive and extremely destructive to tissues of the mucous membranes and upper respiratory tract via inhalation.[1]

Natural occurrence

DCA has been shown to occur in nature in at least one seaweed, Asparagopsis taxiformis [2] and also in the mushroom Russula nigricans.[3] It is a trace product of the chlorination of drinking water and is produced by the metabolism of various chlorine-containing drugs or chemicals.[4] DCA is typically prepared by the reduction of trichloroacetic acid (TCA).[5] DCA is prepared from chloral hydrate also by the reaction with calcium carbonate and sodium cyanide in water followed by acidifying with hydrochloric acid.[6]

As a laboratory reagent, both DCA and TCA[7] are used as precipitants to prompt macromolecules such as proteins to precipitate out of solution.[8]

Therapeutic uses

Salts of DCA have been studied as potential drugs because they inhibit the enzyme pyruvate dehydrogenase kinase.[9] Although preliminary studies found that DCA can slow the growth of certain tumors in animal studies and in vitro studies, as of 2012 insufficient evidence supported the use of DCA for cancer treatment.[10]

Lactic acidosis

A randomized controlled trial in children with congenital lactic acidosis found that while DCA was well tolerated, it was ineffective in improving clinical outcomes.[11] A separate trial of DCA in children with MELAS (a syndrome of inadequate mitochondrial function, leading to lactic acidosis) was halted early, as all 15 of the children receiving DCA experienced significant nerve toxicity without any evidence of benefit from the medication.[12] A randomized controlled trial of DCA in adults with lactic acidosis found that while DCA lowered blood lactate levels, it had no clinical benefit and did not improve hemodynamics or survival.[13]

Thus, while early case reports and pre-clinical data suggested that DCA might be effective for lactic acidosis, subsequent controlled trials have found no clinical benefit of DCA in this setting. In addition, clinical trial subjects were incapable of continuing on DCA as a study medication owing to progressive toxicities.

Cancer

In 2007 reports emerged in the press and via the Internet that Evangelos Michelakis and coworkers at the University of Alberta had reported that sodium dichloroacetate reduced tumors in rats and killed cancer cells in vitro.[14] Because the drug cannot be patented, financing the broad and expensive testing required to obtain FDA approval is problematic.[15] The US Food and Drug Administration enforces the law that prohibits the sale of substances with the suggestion that they are cancer treatments unless they have been approved by the FDA.[16]

The American Cancer Society in 2012 stated that "available evidence does not support the use of DCA for cancer treatment at this time."[10] Physicians warned of potential problems if people attempt to try DCA outside a controlled clinical trial.[17] One problem with attempting this is obtaining the chemical. One fraudster was sentenced to 33 months in prison for selling a white powder containing starch, but no DCA, to people with cancer.[18]

The only monitored in vivo dosage of five human patients with glioblastoma with DCA was not designed to test its efficacy against their cancer. This study was rather to see whether it could be given at a specific dosage safely without causing side effects (e.g. neuropathy). All five patients were receiving other treatments during the study.[19] [20] Observations in vitro and of tumours extracted from those five patients suggest that DCA might act against cancer cells by depolarising abnormal mitochondria found in glioblastoma cancer cells – allowing the mitochondria to induce apoptosis (cell death) of the malignant cells.[19] In vitro work with DCA on neuroblastomas (which have fewer recognised mitochondrial abnormalities) showed activity against malignant, undifferentiated cells.[21] A 2016 case report discussed and reviewed the application of DCA in central nervous system malignancies.[22] A 2018 study found that DCA could trigger a metabolic switch from glycolysis (the Warburg effect) to mitochondrial OXPHOS and increase reactive oxygen stress affecting tumor cells. These effects were not observed in non-tumor cells.[23]

Neuropathy

Neuropathy has been a problem in some clinical trials with DCA causing them to be effectively halted,[12] but a 2008 BJC review found that it has not occurred in other DCA trials.[24] The mechanism of DCA induced neuropathy is not well understood.[25] On the one hand in vitro work with nerves has suggested a mechanism for the neuropathic effect of DCA; with DCA showing a dose and exposure dependent demyelination of nerves (stripping of the nerve 'sheath'), which demyelination was partially reversible over time, following washout of DCA.[26] On the other hand, the 2008 review in BJC [24] states "This neurotoxicity resembled the pattern of length-dependent, axonal, sensorimotor polyneuropathy without demyelination." with regard to the 2006 study by Kaufman et al.[12]

Heart failure

DCA has been investigated as a treatment for post-ischemic recovery.[27] There is also evidence that DCA improves metabolism by NADH production stimulation, but may lead to a depletion of NADH in normoxia.[28]

See also

External links

Notes and References

  1. Web site: Dichloroacetic Acid . Hazard.com . 1998-04-21 . 2015-04-17.
  2. http://paradigmslip.ca/references/uhm_phd_7810263_r.pdf
  3. 10.1016/j.chemosphere.2021.130819 . 33991903 . Is the water disinfection by-product dichloroacetic acid biosynthesized in the edible mushroom Russula nigricans? . Chemosphere . 281 . 130819 . 2021 . Lajin . B. . Braeuer . S. . Borovička . J. . Goessler . W. . 2021Chmsp.28130819L . free .
  4. 10.1093/jnci/djx071. 9703483 . 1533324 . 3434142 . Clinical Pharmacology and Toxicology of Dichloroacetate . Environmental Health Perspectives . 106 . 989–94 . 1998 . Stacpoole . Peter W. . Henderson . George N. . Yan . Zimeng . James . Margaret O. . Suppl 4 .
  5. Doughty . Howard Waters. . Derge . Gerhard Julius. . 1931 . Preparation of Dichloroacetic Acid . Journal of the American Chemical Society . en . 53 . 4 . 1594–1596 . 10.1021/ja01355a066 . 0002-7863.
  6. 1939 . Dichloroacetic Acid . Organic Syntheses . 19 . 38 . 10.15227/orgsyn.019.0038 .
  7. Book: Koontz, Laura . Laboratory Methods in Enzymology: Protein Part C . 2014 . TCA precipitation . https://pubmed.ncbi.nlm.nih.gov/24674058/ . 541 . 3–10 . 10.1016/B978-0-12-420119-4.00001-X . 1557-7988 . 24674058. 978-0-12-420119-4 .
  8. Rajalingam . Dakshinamurthy . Loftis . Charles . Xu . Jiashou J . Kumar . Thallapuranam Krishnaswamy S . 2009 . Trichloroacetic acid-induced protein precipitation involves the reversible association of a stable partially structured intermediate . Protein Science . 18 . 5 . 980–993 . 10.1002/pro.108 . 0961-8368 . 2771300 . 19388015.
  9. 10.1093/jnci/djx071 . Therapeutic Targeting of the Pyruvate Dehydrogenase Complex/Pyruvate Dehydrogenase Kinase (PDC/PDK) Axis in Cancer . 2017 . Stacpoole . Peter W. . JNCI: Journal of the National Cancer Institute . 109 . 11 . 29059435 . free .
  10. Web site: Dichloracetate (DCA) . American Cancer Society . 1 December 2012 . 3 May 2015 . https://web.archive.org/web/20150503003338/http://www.cancer.org/treatment/treatmentsandsideeffects/complementaryandalternativemedicine/pharmacologicalandbiologicaltreatment/dichloroacetate--dca- . dead .
  11. 10.1542/peds.2005-1226 . 16651305 . Controlled Clinical Trial of Dichloroacetate for Treatment of Congenital Lactic Acidosis in Children . Pediatrics . 117 . 5 . 1519–31 . 2006 . Stacpoole . P. W. . Kerr . D. S. . Barnes . C . Bunch . S. T. . Carney . P. R. . Fennell . E. M. . Felitsyn . N. M. . Gilmore . R. L. . Greer . M . Henderson . G. N. . Hutson . A. D. . Neiberger . R. E. . O'Brien . R. G. . Perkins . L. A. . Quisling . R. G. . Shroads . A. L. . Shuster . J. J. . Silverstein . J. H. . Theriaque . D. W. . Valenstein . E . 38328451 .
  12. 10.1212/01.wnl.0000196641.05913.27 . 16476929 . Dichloroacetate causes toxic neuropathy in MELAS: A randomized, controlled clinical trial . Neurology . 66 . 3 . 324–30 . 2006 . Kaufmann . P. . Engelstad . K. . Wei . Y. . Jhung . S. . Sano . M. C. . Shungu . D. C. . Millar . W. S. . Hong . X. . Gooch . C. L. . Mao . X. . Pascual . J. M. . Hirano . M. . Stacpoole . P. W. . Dimauro . S. . De Vivo . D. C. . 19623200 .
  13. 10.1056/NEJM199211263272204 . 1435883 . A Controlled Clinical Trial of Dichloroacetate for Treatment of Lactic Acidosis in Adults . New England Journal of Medicine . 327 . 22 . 1564–9 . 1992 . Stacpoole . Peter W. . Wright . Elizabeth C. . Baumgartner . Thomas G. . Bersin . Robert M. . Buchalter . Scott . Curry . Stephen H. . Duncan . Charles A. . Harman . Eloise M. . Henderson . George N. . Jenkinson . Steven . Lachin . John M. . Lorenz . Anthea . Schneider . Stephen H. . Siegel . John H. . Summer . Warren R. . Thompson . Douglas . Wolfe . Christopher L. . Zorovich . Barbara . free .
  14. Andy Coghlan . Cheap, 'safe' drug kills most cancers . New Scientist . Jan 17, 2007 . https://web.archive.org/web/20190612101355/https://www.newscientist.com/article/dn10971-cheap-safe-drug-kills-most-cancers/ . dead . June 12, 2019 . The original article did not have quotation marks around the word "safe".
  15. No patent? No cancer drug development . New Scientist . Jan 17, 2007 .
  16. 'Cancer drug' site shut down . New Scientist . Jul 25, 2007 .
  17. News: Patients tout database for drug treatment . Andrea Sands . Edmonton Journal . March 18, 2007 . A13 . "If it starts going badly, who is following you before it gets out of control? By the time you realize your liver is failing, you're in big trouble", said Laura Shanner, Associate Professor of Health Ethics at the University of Alberta. .
  18. Web site: Canadian Man Sentenced to 33 Months in Prison for Selling Counterfeit Cancer Drugs Using the Internet . 25 August 2010 . US Department of Justice . January 5, 2018.
  19. 10.1126/scitranslmed.3000677 . 20463368 . Metabolic Modulation of Glioblastoma with Dichloroacetate . Science Translational Medicine . 2 . 31 . 31ra34 . 2010 . Michelakis . E. D. . Sutendra . G. . Dromparis . P. . Webster . L. . Haromy . A. . Niven . E. . Maguire . C. . Gammer . T. L. . MacKey . J. R. . Fulton . D. . Abdulkarim . B. . McMurtry . M. S. . Petruk . K. C. . 616711 .
  20. Web site: Potential Cancer Drug DCA Tested in Early Trials. https://web.archive.org/web/20110218164139/http://scienceblog.cancerresearchuk.org/2010/05/12/potential-cancer-drug-dca-tested-in-early-trials . February 18, 2011.
  21. 10.1002/ijc.26173 . 21557214 . Dichloroacetate inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells . International Journal of Cancer . 130 . 7 . 1484–93 . 2012 . Vella . Serena . Conti . Matteo . Tasso . Roberta . Cancedda . Ranieri . Pagano . Aldo . 19111145 .
  22. 10.14740/jmc2456w . Prolonged Survival After Dichloroacetate Treatment of Non-Small-Cell Lung Carcinoma-Related Leptomeningeal Carcinomatosis. Journal of Medical Cases . 7 . 4 . 136–142 . 2016 . Lemmo . W . Tan . G. free .
  23. Zhou. Li. Liu. Lianlian. Chai. Wei. Zhao. Ting. Jin. Xin. Guo. Xinxin. Han. Liying. Yuan. Chunli. February 2019. Dichloroacetic acid upregulates apoptosis of ovarian cancer cells by regulating mitochondrial function. OncoTargets and Therapy. 12. 1729–1739. 10.2147/ott.s194329. 30881027. 6419601. free.
  24. 10.1038/sj.bjc.6604554 . 18766181 . 2567082 . Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer . British Journal of Cancer . 99 . 7 . 989–94 . 2008 . Michelakis . E D . Webster . L . MacKey . J R .
  25. Web site: Complementary Approaches: Dichloroacetate (DCA). https://web.archive.org/web/20150406023506/http://www.cancerquest.org/complementary-alternative-medicine-dca.html. dead. April 6, 2015. CancerQuest.
  26. 10.1111/j.1471-4159.2006.04248.x . 17241159 . Dichloroacetate causes reversible demyelination in vitro: Potential mechanism for its neuropathic effect . Journal of Neurochemistry . 100 . 2 . 429–36 . 2007 . Felitsyn . Natalia . Stacpoole . Peter W. . Notterpek . Lucia . free .
  27. 2221115 . Dichloroacetate stimulation of glucose oxidation improves recovery of ischemic rat hearts. . 259 . 4 Pt 2 . Oct 1990 . Am J Physiol . H1079-85 . McVeigh JJ, Lopaschuk GD. 10.1152/ajpheart.1990.259.4.H1079 .
  28. 26142699 . Functional response of the isolated, perfused normoxic heart to pyruvate dehydrogenase activation by dichloroacetate and pyruvate. . Jaimes . R 3rd . 10.1007/s00424-015-1717-1 . Jul 2015 . Pflügers Arch . 4701640 . 468 . 1 . 131–42.

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