Written by Irene Fischer, Markus Horneber, Katja Boehm and the CAM-Cancer Consortium.
Updated August 31, 2010

Dichloroacetate

Abstract and key points

  • Dichloroacetate (DCA) is a synthetic halogenated organic acid which has been used in rare diseases like congenital lactic acidosis.
  • DCA activates the pyruvate dehydrogenase complex, a gatekeeper enzyme that regulates the flux of pyruvate into the mitochondria, increasing the ratio of glucose oxidation to glycolysis, possibly resulting in a higher mitochondrial apoptosis rate in cancer cells.
  • DCA is currently being investigated in clinical trials.
  • The risk-benefit balance for DCA fails to be positive.

Dichloroacetate (DCA) is a substance that is being used for medical treatment but is also regarded as a potentially hazardous environmental agent.

The current interest in DCA evolved after the publication in 2007 of a scientific article that reported the ability of this compound to cause selective death of human cancer cells studied in tissue culture or after implantation into animal hosts. Subsequent advertising claims by various non-scientific, for-profit groups were directed at the lay public regarding DCA’s purported anti-cancer effectiveness, based on results from the original pre-clinical studies and subsequent unverifiable testimonials.1

Following the initial report, several independent researchers have confirmed and extended the original findings of DCA’s anti-neoplastic activity in a variety of human cancers, when studied in research laboratories. These studies provide evidence that DCA might interact with fundamental metabolic pathways to inhibit malignant cell proliferation. In order to investigate the clinical effects of DCA in cancer, several clinical trials are ongoing and first results suggest that DCA might be able to disrupt the metabolism of tumor cells and can be administered safely to patients.

Given the current paucity of clinical data, the known risk of adverse effects and possible drug interactions, risk-benefit balance of DCA fails to be positive.

What is it?

Dichloroacetate (DCA) is a xenobiotic, meaning that it does not occur naturally in our bodies or in the environment. However, DCA is widely present in the environment in minute quantities because it is a by-product of the process of water chlorination. It is also a product of the breakdown of certain industrial chemicals and medicinal drugs. DCA is also used as an intermediate for chemical syntheses.2 The U.S. Environmental Protection Agency (EPA) has classified DCA as a hazardous environmental chemical (group B2, probable human carcinogen).3 On the other hand, it is being used as an investigational drug for the treatment of cancer4 and of rare diseases associated with disturbances of cellular energy metabolism, such as congenital lactic acidosis.5,6

Application and dosage

DCA has been administered to patients with genetic mitochondrial diseases for more than 30 years and pharmacokinetic and pharmacodynamic data are available.7 In a recent phase II trial, glioblastoma patients were treated with 12.5 mg/kg orally twice a day for 1 month. After an increase to 25 mg/kg orally twice a day, a dose de-escalation protocol, decreasing the dose by 50% when dose-limiting toxicity occurred. At a dose of 6.25 mg/kg orally twice a day, no toxicities were reported and DCA serum concentrations were similar to those seen in chronic DCA treatment of adults with mitochondrial defects.8

History

Dichloroacetate made its way into the press and media during the past three years. The starting point of the growing interest in DCA were results that were derived from laboratory and animal studies by a cardiologist from the University of Alberta (Edmonton, Canada) who reported effects of DCA on cancerous cells.1 Until July 2007 the principal commercial supplier of DCA for laboratory and clinical research purposes was TCI America in Portland, OR. Subsequently, Jim Tassano also produced the substance in the USA, together with his wife and Dr. Joseph Ryan and distributed it worldwide via the Internet. Part of their distribution marketing was the claim for its positive efficacy of DCA in cancerous diseases (”DCA, the best new approach to cancer treatment in years”).9 The Food and Drug Administration (FDA) banned the website after a ruling in July 2007. Meanwhile, this website has been re-launched with the comment that the sale of DCA is forbidden in the USA and its territories. Nevertheless, there are references for sources of purchasing DCA and a link to hospitals providing DCA-therapies.10

The DCA story and the associated claims raised hope for a cancer cure and received widespread attention. Therefore, DCA is often being labeled as a wonder drug against cancer in the lay media, whereas other critical voices described it as yet another way to make money.11

Claims of efficacy and mechanisms of action

DCA’s supposed mechanisms of action against cancer cells relate to Warburg’s observations in the late 1920s that the metabolism of cancer cells is different from that of most normal cells: malignant cells metabolize glucose primarily by aerobic glycolysis.12,13

Shifting the metabolism from glucose oxidation within the mitochondria towards the aerobic glycolysis in the cytosol might confer several survival advantages for the malignant cell: adaptation to a hypoxic microenvironment,14 resistance to apoptosis,15 and facilitated uptake and incorporation of nutrients needed to proliferate.13

DCA inhibits the pyruvate dehydrogenase kinase which negatively regulates the pyruvate dehydrogenase complex. This mitochondrial enzyme complex catalyzes the oxidative decarboxylation of pyruvate to acetyl–coenzyme A, allowing its entry into the Krebs cycle and away from lactate production.16

Bonnet et al. found that the metabolic shift from glycolysis to glucose oxidation triggered by DCA in cancer cells subsequently led to a number of proapoptotic mitochondrial changes: decreased membrane potential, increased reactive oxygen species, and activated specific potassium channels.1

Michelakis et al hypothesized that the inhibition of aerobic glycolysis and the reversal of the suppressed mitochondrial apoptosis in cancer „results in suppression of tumour growth in vitro and in vivo“.4

Prevalence of use

No data exists regarding the prevalence of use of DCA in cancer patients.

Legal issues

DCA is not legally available as a drug or supplement in the USA or in Europe other than through clinical trials, but is listed as an orphan drug by the FDA.17

There has been an application for a patent for the use of DCA for the treatment of cancer which was subsequently withdrawn.18 The FDA banned Tassano from producing and selling DCA in the USA on July 17, 2007.

Costs and expenditures

Costs are about € 100 per 100 grams sodium dichloroacetate. Monthly expenses for a dose analog to the current trials of 12.5 mg/kg of body weight DCA daily would add up to about € 26 for a 70kg patient.

Does it work?

Several early-phase clinical trials investigating DCA in cancer patients are currently being registered.19

Clinical trials

A phase II trial with five glioblastoma patients recently was conducted by Michelakis et al.8 Three patients received oral DCA as a sole treatment and in two patients it was administered in addition to radiotherapy and temozolomide. All patients tolerated DCA well at a dose of 6.25 mg/kg twice daily over several months. This dose achieved plasma concentrations at values required for the inhibition of pyruvate dehydrogenase kinase. The authors showed that - as hypothesized - the activity of the pyruvate dehydrogenase complex was higher in tumor samples from patients who had received DCA, compared to that measured in tumor tissue resected from the same patient before starting DCA. Four patients had stable diseases 15 months after study onset and were alive at month 18 of the follow-up. The author’s concluded: „With the small number of treated patients in our study, no firm conclusions regarding DCA as a therapy for GBM [glioblastoma] can be made. Our work supports the need for further studies with DCA in GBM, with an emphasis on combination therapy protocols.”

Case reports

Case reports which all suggest benefits associated with the application of DCA in cancer can be found on some websites.20,21 However, the evidence from these reports is weak, as they have not been independently assessed by applying assessment criteria such as the NCI Best Case Series Criteria.22

Is it safe?

There are several studies that reported a low toxicity profile of DCA when used over a short period of time.6,23-26 Nevertheless, animal studies did not provide a so-called “No Observed Adverse Effect Level”.

Adverse effects

There are several studies that reported a low toxicity profile of DCA when used over a short period of time.6,23-26 Nevertheless, animal studies did not provide a so-called “No Observed Adverse Effect Level”.2

Data from animals suggest renal, glandular and bone marrow toxicity and demonstrate unequivocally that DCA causes benign and malignant liver tumors in inbred rat and mouse strains.2,7,27 In humans the nervous system and the liver have been identified as being sensitive to the toxicity of DCA, especially in adults.3,28

Neuropathies have been observed, especially after long-term application for metabolic illnesses. Kaufmann et al. reported axonal sensory-motor peripheral neuropathy without demyelization in adolescents and adults with a genetic mitochondrial disease who received 25 mg/kg/day DCA for several weeks or months.29 Although severe courses are reported,30 most of the neurologic toxicities are regarded as being reversible, however, their regression can take up to several months.31 Dependent on dose and duration of treatment, DCA induces hepatocellular injury, also being reversible after stopping DCA-treatment.32 There is no evidence that DCA causes liver cancer in humans.

In a recent phase II trial, five participants received DCA 12.5mg/kg orally twice a day for one month followed by 25 mg/kg orally twice a day. The authors then followed a dose de-escalation protocol by which the dose was decreased by 50% when dose-limiting toxicity occurred. The only reported toxicities were reversible grade I-III peripheral neuropathies at the 12.5mg/kg and 25 mg/kg dose levels. At the 6.25 mg/kg level, none of the patients had clinically significant peripheral neuropathy.8

Precautions/warnings

There are no data on the use of DCA during pregnancy and lactation. The majority of in vitro analyses did not show any mutagenic effects of DCA. However, in rats DCA has an embryotoxic and teratogenic effect with dose-dependent damages to the cardiovascular and uro-genital tract.2 Several institutions, including the FDA have listed DCA as a possible “cancer-inducing“ agent in humans.

Interactions

As neurological toxicities often occur in patients being treated with chemotherapy, the risk of neuropathy could escalate.4 This could, for instance, be the case for agents such as bortezomib, oxaliplatin, cisplatin, or thalidomide.
In a recent study, the effects of DCA in combination with cisplatin, doxorubicin and temozolomide on mitochondrial membrane potential, cell viability and induction of apoptosis in malignant and non-malignant cell lines were investigated. The results suggest that DCA might reduce the cytotoxicity of cisplatin and doxorubicin but not that of temozolomide.33

Quality issues

DCA is often sold as industrial or technical grade, which might not be produced with the quality standards as pharmaceutical grade. Regarding the shelf life and storage the providers state that DCA can be stored for up to 1 year.21

Citation

Irene Fischer, Markus Horneber, Katja Boehm, CAM-Cancer Consortium. Dichloroacetate [online document]. http://www.cam-cancer.org/layout/set/print/CAM-Summaries/Dietary-approaches/Dichloroacetate. August 31, 2010.

Document history

Summary is currently being updated and revised.
Summary first published in August 2010, authored by Irene Fischer, Markus Horneber, Katja Boehm.

References

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  2. BG Chemie. Toxikologische Bewertungen und Kurzfassung. Toxikologische Bewertungen Nr. 188b, Dichloressigsäure, Natriumdichloracetat 03/06. 1 BG Chemie , 1-138. 2006.
  3. Ammini, C. V. & Stacpoole, P. W. The Handbook of Environmental Chemistry. Gribble, G. W. (ed.), pp. 215-234 (Springer Verlag, Berlin,2003).
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The present documentation has been compiled by the CAM-CANCER Project with all due care and expert knowledge. However, the CAM-CANCER Project provides no assurance, guarantee or promise with regard to the correctness, accuracy, up-to-date status or completeness of the information it contains. This information is designed for health professionals. Readers are strongly advised to discuss the information with their physician. Accordingly, the CAM-CANCER Project shall not be liable for damage or loss caused because anyone relies on the information.