Dichloroacetic acid

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 pK_a of 1.35,{{RubberBible92nd}} 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.{{cite web|url=http://hazard.com/msds/mf/baker/baker/files/d2144.htm |title=Dichloroacetic Acid |publisher=Hazard.com |date=1998-04-21 |access-date=2015-04-17}}

DCA has been shown to occur in nature in at least one seaweed, Asparagopsis taxiformis [http://paradigmslip.ca/references/uhm_phd_7810263_r.pdf] {{webarchive|url=https://web.archive.org/web/20150416152003/http://paradigmslip.ca/references/uhm_phd_7810263_r.pdf|date=April 16, 2015}} and also in the mushroom Russula nigricans.{{cite journal |doi=10.1016/j.chemosphere.2021.130819 |pmid= 33991903 |title=Is the water disinfection by-product dichloroacetic acid biosynthesized in the edible mushroom Russula nigricans? |journal=Chemosphere |volume=281 |pages=130819 |year=2021 |last1=Lajin |first1=B. |last2=Braeuer |first2=S. |last3=Borovička |first3=J. |last4=Goessler |first4=W. |bibcode= 2021Chmsp.28130819L |doi-access=free }} It is a trace product of the chlorination of drinking water and is produced by the metabolism of various chlorine-containing drugs or chemicals.{{cite journal |doi=10.1093/jnci/djx071|pmid=9703483 |pmc=1533324 |jstor=3434142 |title=Clinical Pharmacology and Toxicology of Dichloroacetate |journal=Environmental Health Perspectives |volume=106 |pages=989–94 |year=1998 |last1=Stacpoole |first1=Peter W. |last2=Henderson |first2=George N. |last3=Yan |first3=Zimeng |last4=James |first4=Margaret O. |issue=Suppl 4 }} DCA is typically prepared by the reduction of trichloroacetic acid (TCA).{{Cite journal |last1=Doughty |first1=Howard Waters. |last2=Derge |first2=Gerhard Julius. |date=1931 |title=Preparation of Dichloroacetic Acid |url=https://pubs.acs.org/doi/abs/10.1021/ja01355a066 |journal=Journal of the American Chemical Society |language=en |volume=53 |issue=4 |pages=1594–1596 |doi=10.1021/ja01355a066 |issn=0002-7863|url-access=subscription }} DCA is prepared from chloral hydrate also by the reaction with calcium carbonate and sodium cyanide in water followed by acidifying with hydrochloric acid.{{Cite journal |date=1939 |title=Dichloroacetic Acid |url=http://orgsyn.org/demo.aspx?prep=CV2P0181 |journal=Organic Syntheses |volume=19 |pages=38 |doi=10.15227/orgsyn.019.0038 |url-access=subscription }}

As a laboratory reagent, both DCA and TCA{{Cite book |last=Koontz |first=Laura |title=Laboratory Methods in Enzymology: Protein Part C |date=2014 |chapter=TCA precipitation |chapter-url=https://pubmed.ncbi.nlm.nih.gov/24674058/ |volume=541 |pages=3–10 |doi=10.1016/B978-0-12-420119-4.00001-X |issn=1557-7988 |pmid=24674058|isbn=978-0-12-420119-4 }} are used as precipitants to prompt macromolecules such as proteins to precipitate out of solution.{{Cite journal |last1=Rajalingam |first1=Dakshinamurthy |last2=Loftis |first2=Charles |last3=Xu |first3=Jiashou J |last4=Kumar |first4=Thallapuranam Krishnaswamy S |date=2009 |title=Trichloroacetic acid-induced protein precipitation involves the reversible association of a stable partially structured intermediate |journal=Protein Science |volume=18 |issue=5 |pages=980–993 |doi=10.1002/pro.108 |issn=0961-8368 |pmc=2771300 |pmid=19388015}}

Salts of DCA have been studied as potential drugs because they inhibit the enzyme pyruvate dehydrogenase kinase.{{cite journal |doi=10.1093/jnci/djx071 |title=Therapeutic Targeting of the Pyruvate Dehydrogenase Complex/Pyruvate Dehydrogenase Kinase (PDC/PDK) Axis in Cancer |date=2017 |last1=Stacpoole |first1=Peter W. |journal=JNCI: Journal of the National Cancer Institute |volume=109 |issue=11 |pmid=29059435 |doi-access=free }} 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.{{cite web |title=Dichloracetate (DCA) |url=http://www.cancer.org/treatment/treatmentsandsideeffects/complementaryandalternativemedicine/pharmacologicalandbiologicaltreatment/dichloroacetate--dca- |publisher=American Cancer Society |access-date=1 December 2012 |archive-date=3 May 2015 |archive-url=https://web.archive.org/web/20150503003338/http://www.cancer.org/treatment/treatmentsandsideeffects/complementaryandalternativemedicine/pharmacologicalandbiologicaltreatment/dichloroacetate--dca- |url-status=dead }}

A randomized controlled trial in children with congenital lactic acidosis found that while DCA was well tolerated, it was ineffective in improving clinical outcomes.{{cite journal |doi=10.1542/peds.2005-1226 |pmid=16651305 |title=Controlled Clinical Trial of Dichloroacetate for Treatment of Congenital Lactic Acidosis in Children |journal=Pediatrics |volume=117 |issue=5 |pages=1519–31 |year=2006 |last1=Stacpoole |first1=P. W. |last2=Kerr |first2=D. S. |last3=Barnes |first3=C |last4=Bunch |first4=S. T. |last5=Carney |first5=P. R. |last6=Fennell |first6=E. M. |last7=Felitsyn |first7=N. M. |last8=Gilmore |first8=R. L. |last9=Greer |first9=M |last10=Henderson |first10=G. N. |last11=Hutson |first11=A. D. |last12=Neiberger |first12=R. E. |last13=O'Brien |first13=R. G. |last14=Perkins |first14=L. A. |last15=Quisling |first15=R. G. |last16=Shroads |first16=A. L. |last17=Shuster |first17=J. J. |last18=Silverstein |first18=J. H. |last19=Theriaque |first19=D. W. |last20=Valenstein |first20=E |s2cid=38328451 }} 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.{{cite journal |doi=10.1212/01.wnl.0000196641.05913.27 |pmid=16476929 |title=Dichloroacetate causes toxic neuropathy in MELAS: A randomized, controlled clinical trial |journal=Neurology |volume=66 |issue=3 |pages=324–30 |year=2006 |last1=Kaufmann |first1=P. |last2=Engelstad |first2=K. |last3=Wei |first3=Y. |last4=Jhung |first4=S. |last5=Sano |first5=M. C. |last6=Shungu |first6=D. C. |last7=Millar |first7=W. S. |last8=Hong |first8=X. |last9=Gooch |first9=C. L. |last10=Mao |first10=X. |last11=Pascual |first11=J. M. |last12=Hirano |first12=M. |last13=Stacpoole |first13=P. W. |last14=Dimauro |first14=S. |last15=De Vivo |first15=D. C. |s2cid=19623200 }} 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.{{cite journal |doi=10.1056/NEJM199211263272204 |pmid=1435883 |title=A Controlled Clinical Trial of Dichloroacetate for Treatment of Lactic Acidosis in Adults |journal=New England Journal of Medicine |volume=327 |issue=22 |pages=1564–9 |year=1992 |last1=Stacpoole |first1=Peter W. |last2=Wright |first2=Elizabeth C. |last3=Baumgartner |first3=Thomas G. |last4=Bersin |first4=Robert M. |last5=Buchalter |first5=Scott |last6=Curry |first6=Stephen H. |last7=Duncan |first7=Charles A. |last8=Harman |first8=Eloise M. |last9=Henderson |first9=George N. |last10=Jenkinson |first10=Steven |last11=Lachin |first11=John M. |last12=Lorenz |first12=Anthea |last13=Schneider |first13=Stephen H. |last14=Siegel |first14=John H. |last15=Summer |first15=Warren R. |last16=Thompson |first16=Douglas |last17=Wolfe |first17=Christopher L. |last18=Zorovich |first18=Barbara |doi-access=free }}

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.

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.{{cite journal |last1=Andy Coghlan |title=Cheap, 'safe' drug kills most cancers |journal=New Scientist |date=Jan 17, 2007 |url=https://www.newscientist.com/article/dn10971-cheap-safe-drug-kills-most-cancers/ |archive-url=https://web.archive.org/web/20190612101355/https://www.newscientist.com/article/dn10971-cheap-safe-drug-kills-most-cancers/ |url-status=dead |archive-date=June 12, 2019 }} The [https://web.archive.org/web/20070202235239/http://www.newscientist.com/channel/health/mg19325874.700-cheap-safe-drug-kills-most-cancers.html original article] did not have quotation marks around the word "safe". Because the drug cannot be patented, financing the broad and expensive testing required to obtain FDA approval is problematic.{{cite journal |title=No patent? No cancer drug development |journal=New Scientist |date=Jan 17, 2007 |url=https://www.newscientist.com/article/mg19325873-000-editorial-no-patent-no-cancer-drug-development/}} 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.{{cite journal |title='Cancer drug' site shut down |journal=New Scientist |date=Jul 25, 2007 |url=https://www.newscientist.com/article/mg19526143-600-cancer-drug-site-shut-down/}}

The American Cancer Society in 2012 stated that "available evidence does not support the use of DCA for cancer treatment at this time." Physicians warned of potential problems if people attempt to try DCA outside a controlled clinical trial.{{cite news | url = https://www.pressreader.com/canada/edmonton-journal/20070318/281779919671127 | title = Patients tout database for drug treatment | author = Andrea Sands | publisher = Edmonton Journal | date = March 18, 2007 |page=A13 |quote= "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. }} 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.{{cite web | url = https://www.justice.gov/opa/pr/canadian-man-sentenced-33-months-prison-selling-counterfeit-cancer-drugs-using-internet | title = Canadian Man Sentenced to 33 Months in Prison for Selling Counterfeit Cancer Drugs Using the Internet | date = 25 August 2010 | publisher = US Department of Justice | access-date = January 5, 2018}}

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.{{cite journal |doi=10.1126/scitranslmed.3000677 |pmid=20463368 |title=Metabolic Modulation of Glioblastoma with Dichloroacetate |journal=Science Translational Medicine |volume=2 |issue=31 |pages=31ra34 |year=2010 |last1=Michelakis |first1=E. D. |last2=Sutendra |first2=G. |last3=Dromparis |first3=P. |last4=Webster |first4=L. |last5=Haromy |first5=A. |last6=Niven |first6=E. |last7=Maguire |first7=C. |last8=Gammer |first8=T. L. |last9=MacKey |first9=J. R. |last10=Fulton |first10=D. |last11=Abdulkarim |first11=B. |last12=McMurtry |first12=M. S. |last13=Petruk |first13=K. C. |s2cid=616711 }}{{cite web|url=http://scienceblog.cancerresearchuk.org/2010/05/12/potential-cancer-drug-dca-tested-in-early-trials |title=Potential Cancer Drug DCA Tested in Early Trials|archive-url=https://web.archive.org/web/20110218164139/http://scienceblog.cancerresearchuk.org/2010/05/12/potential-cancer-drug-dca-tested-in-early-trials |archive-date=February 18, 2011}} 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. In vitro work with DCA on neuroblastomas (which have fewer recognised mitochondrial abnormalities) showed activity against malignant, undifferentiated cells.{{cite journal |doi=10.1002/ijc.26173 |pmid=21557214 |title=Dichloroacetate inhibits neuroblastoma growth by specifically acting against malignant undifferentiated cells |journal=International Journal of Cancer |volume=130 |issue=7 |pages=1484–93 |year=2012 |last1=Vella |first1=Serena |last2=Conti |first2=Matteo |last3=Tasso |first3=Roberta |last4=Cancedda |first4=Ranieri |last5=Pagano |first5=Aldo |doi-access= |s2cid=19111145 }} A 2016 case report discussed and reviewed the application of DCA in central nervous system malignancies.{{cite journal |doi=10.14740/jmc2456w |title=Prolonged Survival After Dichloroacetate Treatment of Non-Small-Cell Lung Carcinoma-Related Leptomeningeal Carcinomatosis|journal=Journal of Medical Cases |volume=7 |issue=4 |pages=136–142 |year=2016 |last1=Lemmo |first1=W |last2=Tan |first2=G|url=http://www.journalmc.org/index.php/JMC/article/download/2456/1817 |doi-access=free }} 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.{{Cite journal|last1=Zhou|first1=Li|last2=Liu|first2=Lianlian|last3=Chai|first3=Wei|last4=Zhao|first4=Ting|last5=Jin|first5=Xin|last6=Guo|first6=Xinxin|last7=Han|first7=Liying|last8=Yuan|first8=Chunli|date=February 2019|title=Dichloroacetic acid upregulates apoptosis of ovarian cancer cells by regulating mitochondrial function|journal=OncoTargets and Therapy|volume= 12|pages=1729–1739|doi=10.2147/ott.s194329|pmid=30881027|pmc=6419601|doi-access=free}}

Neuropathy has been a problem in some clinical trials with DCA causing them to be effectively halted, but a 2008 BJC review found that it has not occurred in other DCA trials.{{cite journal |doi=10.1038/sj.bjc.6604554 |pmid=18766181 |pmc=2567082 |title=Dichloroacetate (DCA) as a potential metabolic-targeting therapy for cancer |journal=British Journal of Cancer |volume=99 |issue=7 |pages=989–94 |year=2008 |last1=Michelakis |first1=E D |last2=Webster |first2=L |last3=MacKey |first3=J R }} The mechanism of DCA induced neuropathy is not well understood.{{Cite web|url=https://cancerquest.org/patients/integrative-oncology/dichloroacetate-dca|archiveurl=https://web.archive.org/web/20150406023506/http://www.cancerquest.org/complementary-alternative-medicine-dca.html|url-status=dead|title=Complementary Approaches: Dichloroacetate (DCA)|archivedate=April 6, 2015|website=CancerQuest}} 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.{{cite journal |doi=10.1111/j.1471-4159.2006.04248.x |pmid=17241159 |title=Dichloroacetate causes reversible demyelination in vitro: Potential mechanism for its neuropathic effect |journal=Journal of Neurochemistry |volume=100 |issue=2 |pages=429–36 |year=2007 |last1=Felitsyn |first1=Natalia |last2=Stacpoole |first2=Peter W. |last3=Notterpek |first3=Lucia |doi-access=free }} On the other hand, the 2008 review in BJC states "This neurotoxicity resembled the pattern of length-dependent, axonal, sensorimotor polyneuropathy without demyelination." with regard to the 2006 study by Kaufman et al.

DCA has been investigated as a treatment for post-ischemic recovery.{{cite journal |pmid=2221115 |title=Dichloroacetate stimulation of glucose oxidation improves recovery of ischemic rat hearts. | volume=259 |issue=4 Pt 2 | date=Oct 1990 |journal=Am J Physiol |pages=H1079-85 |author=McVeigh JJ, Lopaschuk GD|doi=10.1152/ajpheart.1990.259.4.H1079 }} There is also evidence that DCA improves metabolism by NADH production stimulation, but may lead to a depletion of NADH in normoxia.{{cite journal |pmid=26142699 |title=Functional response of the isolated, perfused normoxic heart to pyruvate dehydrogenase activation by dichloroacetate and pyruvate. |last1=Jaimes |first1=R 3rd |doi=10.1007/s00424-015-1717-1 |date=Jul 2015 |journal=Pflügers Arch |pmc=4701640 |volume=468 |issue=1 |pages=131–42}}

• 2,2-Dichloropropionic acid (Dalapon)

{{Reflist|colwidth=30em}}

• {{ICSC|0868|08}}
• [https://dcaguide.org/dca-information/dca-dosage-and-usage-long-guide/ Sodium dichloroacetate (DCA) dosage and usage]

{{Unproven and disproven cancer treatments}}

{{DEFAULTSORT:Dichloroacetic Acid}}

Category:Dichloromethyl compounds

Category:IARC Group 2B carcinogens

Category:Acetic acids

Category:Alternative cancer treatments

Category:Experimental cancer drugs