Dichloroacetate Not Ready for Therapeutic Use

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Dichloroacetate has been in the headlines recently, reported to be a cheap, effective cancer cure. The article was published in both print and on the website NewScientist.com, and ran with the headline “Cheap, safe drug kills most cancers”, implying incorrectly that it can kill tumor cells in humans.

Researchers at the University of Alberta in Edmonton, Canada, recently reported that they found a cheap and easy drug to produce that is able to cause tumor regression in lung, breast and brain tumor cells grown in culture and lung tumors grown in immunocompromised rats. The drug, Dichloroacetate (DCA), targets mitochondria (meaning an organelle in the cell that produces energy) and induces apoptosis (meaning cell death), decreases proliferation and selectively inhibits cancer cell growth. It did not have any effects on normal, non-cancerous tissue. The findings were published in the January edition of the journal Cancer Cell.

Cancer cells don’t use mitochondria for energy, instead using glycolysis (meaning the initial process of most of carbohydrate metabolism), which is less effective and more wasteful. Researchers have long believed this occurred because mitochondria in cancer cells were damaged. However, this new data suggests that the mitochondria in cancer cells are dormant and DCA reactivates them.

DCA is an analogue of acetic acid, best recognized for giving vinegar its sour taste and acrid smell. It is a byproduct of the water chlorination process and its use has been shown to be hepatotoxic [1] and carcinogenic in rodent models [2]. DCA has been used since the late 1970s to treat children with congenital lactic acidosis [3], a genetic mitochondrial disease caused by the buildup of lactic acid in the body that leads to acidification of the blood (acidosis). It decreases lactate production by shifting the metabolism of pyruvate from glycolysis towards oxidation in the mitochondria. However, its use has been mitigated by reversible peripheral neuropathy (meaning damage to the nerves of the peripheral nervous system, the part of the nervous system lying outside the brain and spinal cord) [4].

A controlled clinical trial of DCA for the treatment of congenital lactic acidosis in children found that the drug was well tolerated at a dose of 12.5 mg/kg every 12 hours and blunted the increase in circulating lactate following a meal [5]. Patients received placebo for 6 months and then were randomly assigned to receive an additional 6 months of placebo or DCA. However, the drug failed to improve neurologic outcome. The efficacy of DCA was also evaluated for the treatment of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) [6]. The clinical trial ended early because of onset or worsening peripheral toxicity; all 15 of 15 patients randomized to DCA (25 mg/kg/day) were removed from the trial compared to 4 of 15 patients randomized to placebo. The authors concluded that DCA-associated neuropathy dominated the assessment of any potential benefit in MELAS.

Neuropathy and neurotoxicity during chronic DCA treatment in rats may be partly due to depletion of thiamine, and thiamine supplementation reduced these effects [7]. However, more recent studies in humans suggest that peripheral neuropathy is a common side effect during chronic DCA treatment, even with coadministration of oral thiamine [8-9]. An additional study reported that high dose DCA treatment (50 mg/kg/day) resulted in sensory-dominant polyneuropathy, unsteady gait and lethargy in two patients, with symptoms occurring after one month for one patient and two months for the second. Gait disturbance and consciousness were recovered with cessation of DCA, however sensory nerve action potentials did not recover in one month [10].

There have been many therapies that were promising in vitro and in animal models that didn’t work in humans. While I’m optimistic about the promise of DCA for cancer treatment, its therapeutic use is by no means assured.

Recommended reading: Orac, Abel Pharmboy, another Abel Pharmboy post and Random John.

A website has been set up by the University of Alberta and the Alberta Cancer Board to reflect progress in their efforts for clinical trials of DCA in patients with cancer.

Other compounds that have recently been shown to be toxic to cancer cells include vitamin C [11], capsaicin [12] and quercetin .

Updated: May 4th, 2007

 

Read the follow-up to this article: Alternative to Dichloroacetate.

References

  1. Yang et al. Dichloroacetic acid treatment increases hepatic CYP2E1 in male and female rats. Toxicol Appl Pharmacol. 1996 Dec;141(2):382-8.
    View abstract
  2. Tao et al. DNA hypomethylation induced by drinking water disinfection by-products in mouse and rat kidney. Toxicol Sci. 2005 Oct;87(2):344-52.
    View abstract
  3. Coude et al. Dichloroacetate as treatment for congenital lactic acidosis. N Engl J Med. 1978 Dec 14;299(24):1365-6.
    View abstract
  4. Spruijt et al. Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate. Muscle Nerve. 2001 Jul;24(7):916-24.
    View abstract
  5. Stacpoole et al. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics. 2006 May;117(5):1519-31.
    View abstract
  6. Kaufmann et al. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology. 2006 Feb 14;66(3):324-30.
    View abstract
  7. Stacpoole et al. Chronic toxicity of dichloroacetate: possible relation to thiamine deficiency in rats. Fundam Appl Toxicol. 1990 Feb;14(2):327-37.
    View abstract
  8. Kurlemann et al. Therapy of complex I deficiency: peripheral neuropathy during dichloroacetate therapy. Eur J Pediatr. 1995 Nov;154(11):928-32.
    View abstract
  9. Spruijt et al. Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate. Muscle Nerve. 2001 Jul;24(7):916-24.
    View abstract
  10. Oishi et al. Dichloroacetate treatment for adult patients with mitochondrial disease. Rinsho Shinkeigaku. 2003 Apr;43(4):154-61.
    View abstract
  11. Chen et al. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: action as a pro-drug to deliver hydrogen peroxide to tissues. Proc Natl Acad Sci U S A. 2005 Sep 20;102(38):13604-9.
    View abstract
  12. Mori et al. Capsaicin, a component of red peppers, inhibits the growth of androgen-independent, p53 mutant prostate cancer cells. Cancer Res. 2006 Mar 15;66(6):3222-9.
    View abstract
About the Author

Walter Jessen is a senior writer for Highlight HEALTH Media.

Comments

  1. Although some early, overly optimistic reports about DCA did more harm than good, the underlying fascination is not at all whether it “works” or “doesn’t work”.

    The fascination is in if, and how, we’ll find out.

    It is about $$$, like most other things in life.

    The recent wave in interest has led to a proffessional rebutal of the claims, yet I have not heard anyone, not the harshest critic, dispute the Potential of DCA in cancer therapy.

    For this reason, I feel the recent surge of internet awareness is entirely reasonable and healthy. Through discussion, awareness is raised. Not just for DCA, but for cancer research and cancer itself.

    Jeff
    http://www.dichloroacetate.org

  2. I think this is an excellent idea Jeff!

    Might I suggest that your forum also provide links to other sites that offer real information and discussion regarding DCA. This is a very controversial topic and there’s a lot of hype and paranoia out there that people have to navigate.

  3. Hello Walter,

    Thank you for the suggestion, and the offer. These articles are full of fact, as you point out. I can’t help but appreciate their honesty, and have incorporated appropriate links into my site.

  4. Looking for more info about DCA , I came to your website

    My comment on approved or not approved drug by FDA is very, very simple.
    The moneymakers in the classical pharmaceutical firms refused constantly to look to products they could not take a patent on. They are ” pharmafiosi ” because due to their “fundamentalistic” believe in the holly dollar they kept very helpful health products from the market. This even by obstructing high-tech research from scientist and/or lobbying by the legal “regulaters” as the FDA.
    On their account are millions of death people.
    When will people understand this are terrorists as well ?

  5. Whatever the arguments against DCA may be, whether or not it causes peripheral neuropathy is not a serious argument against DCA. In fact, using that as the main argument is completely specious, irresponsible, and transparent to anyone with any medical knowledge.

    Numerous chemotherapy drugs have the potential — indeed, the likelihood — to cause peripheral neuropathy. These include Avastin, Alimta, Taxol, carboplatin — to name just a few. These drugs still get used to combat cancer because they work. Whether or not they cause peripheral neuropathy when used as chemo agents is far beside the point.

    Arguing against using DCA because it causes peripheral neuropathy is like arguing against using a chemo drug because it causes hair loss. You wouldn’t tell someone not to use a chemo drug just because it might cause hair loss.

    By the same token, DCA must be proven NOT to work in vivo and in vitro and argued against ON THOSE GROUNDS. Not the completely laughable grounds that it causes peripheral neuropathy — along with a slew of other chemotherapy drugs that work very well.

  6. Hi V – Please note that nowhere did I argue against the use of DCA because it causes peripheral neuropathy. Indeed, my main concern is that people will think that it HAS TO work in humans because it worked in vitro, and, as I’m sure you are well aware, this frequently isn’t the case. Thanks for your comments.

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