Dichloroacetic acid (DCA), sometimes called bichloroacetic acid (BCA), is the

organic compound Some chemical authorities define an organic compound as a chemical compound that contains a carbon–hydrogen or carbon–carbon bond; others consider an organic compound to be any chemical compound that contains carbon. For example, carbon-co ...

with

formula In science, a formula is a concise way of expressing information symbolically, as in a mathematical formula or a ''chemical formula''. The informal use of the term ''formula'' in science refers to the general construct of a relationship betwe ...

. It is an analogue of

acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main compone ...

, in which 2 of the 3 hydrogen

atoms Atoms are the basic particles of the chemical elements. An atom consists of a nucleus of protons and generally neutrons, surrounded by an electromagnetically bound swarm of electrons. The chemical elements are distinguished from each other ...

of the

methyl group In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated a ...

have been replaced by

chlorine Chlorine is a chemical element; it has Symbol (chemistry), symbol Cl and atomic number 17. The second-lightest of the halogens, it appears between fluorine and bromine in the periodic table and its properties are mostly intermediate between ...

atoms. Like the other

chloroacetic acids In organic chemistry, the chloroacetic acids (systematic name chloroethanoic acids) are three related chlorocarbon carboxylic acids: * Chloroacetic acid (chloroethanoic acid), CH2ClCOOH * Dichloroacetic acid (dichloroethanoic acid; bichloroacetic ...

, it has various practical applications. The

salts In chemistry, a salt or ionic compound is a chemical compound consisting of an assembly of positively charged ions ( cations) and negatively charged ions (anions), which results in a compound with no net electric charge (electrically neutral). ...

and

esters In chemistry, an ester is a chemical compound, compound derived from an acid (either organic or inorganic) in which the hydrogen atom (H) of at least one acidic hydroxyl group () of that acid is replaced by an organyl group (R). These compounds c ...

of dichloroacetic acid are called dichloroacetates.

Reactions

The chemistry of dichloroacetic acid is typical for

halogen The halogens () are a group in the periodic table consisting of six chemically related elements: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), and the radioactive elements astatine (At) and tennessine (Ts), though some authors would ...

ated

organic acids An organic acid is an organic compound with acidic properties. The most common organic acids are the carboxylic acids, whose acidity is associated with their carboxyl group –COOH. Sulfonic acids, containing the group –SO2OH, are r ...

. It is an alkylating agent. It forms esters. It is a member of the

family. As such it is more acidic than acetic acid. It fully dissociates into dichloroacetate when dissolved in water, consistent with it p''K''_a of 1.35, pure dichloroacetic acid is classed as a strong organic acid; it is very

corrosive Corrosion is a natural process that converts a refined metal into a more chemically stable oxide. It is the gradual deterioration of materials (usually a metal) by chemical or electrochemical reaction with their environment. Corrosion engine ...

and extremely destructive to tissues of the

mucous membrane A mucous membrane or mucosa is a membrane that lines various cavities in the body of an organism and covers the surface of internal organs. It consists of one or more layers of epithelial cells overlying a layer of loose connective tissue. It ...

s and

upper respiratory tract The respiratory tract is the subdivision of the respiratory system involved with the process of conducting air to the alveoli for the purposes of gas exchange in mammals. The respiratory tract is lined with respiratory epithelium as respiratory ...

via

inhalation Inhalation (or inspiration) happens when air or other gases enter the lungs. Inhalation of air Inhalation of air, as part of the cycle of breathing, is a vital process for all human life. The process is autonomic (though there are exceptions ...

Natural occurrence

DCA has been shown to occur in nature in at least one seaweed, ''

Asparagopsis taxiformis ''Asparagopsis taxiformis'' (red sea plume or limu kohu), formerly ''A. sanfordiana'', is a species of red algae, with cosmopolitan distribution in tropical to warm temperate waters. Researchers have demonstrated that feeding ruminants a diet c ...

'' and also in the mushroom '' Russula nigricans''. It is a trace product of the chlorination of drinking water and is produced by the

metabolism Metabolism (, from ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cellular processes; the co ...

of various

-containing drugs or chemicals. DCA is typically prepared by the reduction of

trichloroacetic acid Trichloroacetic acid (TCA; TCAA; also known as trichloroethanoic acid) is an analogue of acetic acid in which the three hydrogen atoms of the methyl group have all been replaced by chlorine atoms. Salts and esters of trichloroacetic acid are cal ...

(TCA). DCA is prepared from

chloral hydrate Chloral hydrate is a geminal diol with the formula . It was first used as a sedative and hypnotic in Germany in the 1870s. Over time it was replaced by safer and more effective alternatives but it remained in use in the United States until at ...

also by the reaction with

calcium carbonate Calcium carbonate is a chemical compound with the chemical formula . It is a common substance found in Rock (geology), rocks as the minerals calcite and aragonite, most notably in chalk and limestone, eggshells, gastropod shells, shellfish skel ...

and

sodium cyanide Sodium cyanide is a compound with the formula Na C N and the structure . It is a white, water-soluble solid. Cyanide has a high affinity for metals, which leads to the high toxicity of this salt. Its main application, in gold mining, also expl ...

in water followed by acidifying with

hydrochloric acid Hydrochloric acid, also known as muriatic acid or spirits of salt, is an aqueous solution of hydrogen chloride (HCl). It is a colorless solution with a distinctive pungency, pungent smell. It is classified as a acid strength, strong acid. It is ...

. As a laboratory

reagent In chemistry, a reagent ( ) or analytical reagent is a substance or compound added to a system to cause a chemical reaction, or test if one occurs. The terms ''reactant'' and ''reagent'' are often used interchangeably, but reactant specifies a ...

, both DCA and TCA are used as precipitants to prompt

macromolecule A macromolecule is a "molecule of high relative molecular mass, the structure of which essentially comprises the multiple repetition of units derived, actually or conceptually, from molecules of low relative molecular mass." Polymers are physi ...

s such as

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

s to precipitate out of solution.

Therapeutic uses

Salts of DCA have been studied as potential

drug A drug is any chemical substance other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. Consumption of drugs can be via insufflation (medicine), inhalation, drug i ...

s because they inhibit the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

pyruvate dehydrogenase kinase. Although preliminary studies found that DCA can slow the growth of certain tumors in

animal studies Animal studies is a recently recognised field in which animals are studied in a variety of cross-disciplinary ways. Scholars who engage in animal studies may be formally trained in a number of diverse fields, including art history, anthropology ...

and ''

in vitro ''In vitro'' (meaning ''in glass'', or ''in the glass'') Research, studies are performed with Cell (biology), cells or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in ...

'' studies, as of 2012 insufficient evidence supported the use of DCA for cancer treatment.

Lactic acidosis

randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical ...

in children with congenital lactic acidosis found that while DCA was well tolerated, it was ineffective in improving clinical outcomes. A separate trial of DCA in children with

MELAS Melas may refer to: People * Melas (mythology), a number of different characters in Greek mythology * Melas, an Ancient Greek first name. Its most notable holders were Melas the Elder and Younger, two tyrants of Ephesus whose dynasty intermarried ...

(a syndrome of inadequate

mitochondria A mitochondrion () is an organelle found in the cells of most eukaryotes, such as animals, plants and fungi. Mitochondria have a double membrane structure and use aerobic respiration to generate adenosine triphosphate (ATP), which is us ...

l 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. 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

hemodynamic Hemodynamics or haemodynamics are the dynamics of blood flow. The circulatory system is controlled by homeostatic mechanisms of autoregulation, just as hydraulic circuits are controlled by control systems. The hemodynamic response continuously ...

s or survival. 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 The University of Alberta (also known as U of A or UAlberta, ) is a public research university located in Edmonton, Alberta, Canada. It was founded in 1908 by Alexander Cameron Rutherford, the first premier of Alberta, and Henry Marshall Tory, t ...

had reported that sodium dichloroacetate reduced tumors in rats and killed cancer cells ''

''. Because the drug cannot be patented, financing the broad and expensive testing required to obtain FDA approval is problematic. The

US Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

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. The

American Cancer Society The American Cancer Society (ACS) is a nationwide non-profit organization dedicated to eliminating cancer. The ACS publishes the journals ''Cancer'', '' CA: A Cancer Journal for Clinicians'' and '' Cancer Cytopathology''. History The society w ...

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 Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

. 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. The only monitored ''

in vivo Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, an ...

'' dosage of five human patients with

glioblastoma Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has a very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nons ...

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 Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...

). All five patients were receiving other treatments during the study. Observations ''in vitro'' and of tumours extracted from those five patients suggest that DCA might act against cancer cells by depolarising abnormal

found in glioblastoma cancer cells – allowing the mitochondria to induce apoptosis (cell death) of the

malignant cells Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not ...

. ''In vitro'' work with DCA on

neuroblastoma Neuroblastoma (NB) is a type of cancer that forms in certain types of nerve tissue. It most frequently starts from one of the adrenal glands but can also develop in the head, neck, chest, abdomen, or Vertebral column, spine. Symptoms may include ...

s (which have fewer recognised mitochondrial abnormalities) showed activity against malignant, undifferentiated cells. A 2016 case report discussed and reviewed the application of DCA in central nervous system malignancies. A 2018 study found that DCA could trigger a metabolic switch from

glycolysis Glycolysis is the metabolic pathway that converts glucose () into pyruvic acid, pyruvate and, in most organisms, occurs in the liquid part of cells (the cytosol). The Thermodynamic free energy, free energy released in this process is used to form ...

(the Warburg effect) to mitochondrial OXPHOS and increase reactive oxygen stress affecting tumor cells. These effects were not observed in non-tumor cells.

Neuropathy

Neuropathy Peripheral neuropathy, often shortened to neuropathy, refers to damage or disease affecting the nerves. Damage to nerves may impair sensation, movement, gland function, and/or organ function depending on which nerve fibers are affected. Neuropa ...

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. The mechanism of DCA induced neuropathy is not well understood. 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. 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''.

Heart failure

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

References

External links

*
Sodium dichloroacetate (DCA) dosage and usage
{{DEFAULTSORT:Dichloroacetic Acid Dichloromethyl compounds IARC Group 2B carcinogens Acetic acids Alternative cancer treatments Experimental cancer drugs