Dichloroacetate Not Ready for Therapeutic Use

Reading time: 6 – 9 minutes

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 .

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

References

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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.
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3. Coude et al. Dichloroacetate as treatment for congenital lactic acidosis. N Engl J Med. 1978 Dec 14;299(24):1365-6.
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4. Spruijt et al. Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate. Muscle Nerve. 2001 Jul;24(7):916-24.
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5. Stacpoole et al. Controlled clinical trial of dichloroacetate for treatment of congenital lactic acidosis in children. Pediatrics. 2006 May;117(5):1519-31.
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6. Kaufmann et al. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology. 2006 Feb 14;66(3):324-30.
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7. Stacpoole et al. Chronic toxicity of dichloroacetate: possible relation to thiamine deficiency in rats. Fundam Appl Toxicol. 1990 Feb;14(2):327-37.
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8. Kurlemann et al. Therapy of complex I deficiency: peripheral neuropathy during dichloroacetate therapy. Eur J Pediatr. 1995 Nov;154(11):928-32.
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9. Spruijt et al. Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate. Muscle Nerve. 2001 Jul;24(7):916-24.
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10. Oishi et al. Dichloroacetate treatment for adult patients with mitochondrial disease. Rinsho Shinkeigaku. 2003 Apr;43(4):154-61.
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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.
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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.
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