Dichloroacetate: Panacea or Problematic?
Â Â Â Dichloroacetate (DCA) has hit the headlines with a splash recently being held as a cheap cure for cancer. The recent article in Cancer Cell is very intriguing in that it presents DCA as promoting apoptosis and inhibiting growth selectively in cancer cells while leaving healthy cells alone. The article also presents data showing it is not toxic to the liver.
However, there are a few perspectives of this compound that should be included in the publicâ€™s mind.
Â Â Â Â Trichloroethylene and tetrachloroethylene are precursors of DCA that are used as degreasing agents in industry. Dichloroacetate is a major disinfection by-product of drinking water chlorination. DCA in the drinking water results in daily human consumption of ~1-4 ug/kg/d (microgram/kilogram/day) of body weight. Numerous studies have been conducted to determine the safety of DCA persistence in the drinking water suggesting it is safe at these concentrations.
Â Â Â Animal and human therapeutic doses are in the mg/kg/d range (milligram). DCA is not a known carcinogen but repeated or chronic use at therapeutic levels has been associated with hepatotoxicity (liver damage) and reversible neurotoxicity usually in the form of mild peripheral neuropathy (such as a tingling sensation in the limbs).
DCA is used to treat certain mitochondrial myopathies and lactic acidosis.
Â Â Â Mitochondria are organelles in the cell that produces all the energy the cell uses to live. DCA is shown in the article to change the polarity of mitochondria through an NFAT1-dependent mechanism, resulting in a switch from glycolysis to glucose oxidation producing apoptosis in cancer cells. The article also discusses pyruvate dehydrogenase kinase (PDK) as a target of DCA. However, there are other targets known for DCA with one being maleylacetoacetate isomerase/glutathione S-transferase Zeta (MAAI/GSTz). MAAI is part of phenylalanine and tyrosine catabolism (two amino acids). DCA inhibits MAAI and leads to accumulation of tyrosine metabolites which causes hepatotoxicity and neurotoxicity. Further effects branching from inhibition of tyrosine catabolism is formation of succinylacetone, a potent inhibitor of heme synthesis. Heme is an important molecule doing a multitude of tasks in the body including carrying oxygen.
Â Â Â While the article presents clear data and a convincing model, DCA is a small molecule and interacts with multiple proteins in the cell that play critical functions. While I am optimistic about the promise, the therapeutic windowterm for this molecule seems narrow. The article proposes rapid movement in to phase II and III clinical trials. There are always unforeseen developments and problems with taking data for a drug obtained in an animal and applying it to a human. One caveat is there are still no long term studies done on DCA and its effects on humans at therapeutic levels. Much remains to be proven of DCA.
These are the abstracts for other articles about dichloroacetate, DCA, and DCA. One recent clinical trial with DCA had to be stopped early due to neurotoxicity. This is the abstract for the clinical trial about dichloroacetate.