Alternative to Dichloroacetate

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It’s been three months since an article on dichloroacetate (DCA), the chemotherapeutic agent that selectively inhibits cancer cell growth in lung, breast and brain tumor cells grown in culture and lung tumors grown in immunocompromised rats, was published on Highlight HEALTH. Since then, thousands of people have read the article. Indeed, the blogosphere has been buzzing about DCA, unfortunately focusing on a conspiracy theory accusing big pharma of suppressing a cure for cancer instead of recognizing the study for what it is — a preliminary study in cell culture and rats that cannot be translated to humans without further research and clinical trials.

Safe alternative to DCA?

I was curious to see if there were any new developments regarding DCA use in either cancer prevention or the treatment of cancer. A Google search for “dichloroacetate” returned 340,000 pages, but before I had a chance to start browsing, one of the Sponsored Links at the top of the page caught my eye. In addition to a site where you can buy DCA, another site advertised a “safe alternative” to dichloroacetate.

Intrigued, I clicked on the link. The alternative is a “new flavonoid cancer treatment protocol”, which involves nothing more than dissolving 1000 mg of vitamin C in 0.5 L of water and adding the contents of 1 — 2 quercetin (pronounced “kwer-see-tin”) capsules (500 mg — 1000 mg).

Quercetin

A polyphenol, quercetin is one of a number of water-soluble plant pigments called flavonoids (meaning class of plant secondary metabolites known for their antioxidant activity) and is largely responsible for the color of many flowers, fruits and vegetables. High concentrations of quercetin are found in apples, onions, tea and red wine [1]. Quercetin and other flavonoids (also referred to as bioflavonoids) cannot be produced in the human body.

Quercetin is a powerful antioxidant; from a range of dietary flavonoids, quercetin was found to be the most effective inhibitor of oxidative damage to LDL (bad) cholesterol in vitro [2]. In contrast, another study found that quercetin had mostly prooxidant effects [3]. However, when mixed with other phenolic compounds, significant antioxidant capacity was identified, indicating a synergistic effect.

A number of research studies have demonstrated that quercetin is a natural antihistamine and anti-inflammatory [4-6]. Indeed, quercetin is unique in its ability to inhibit TNF-alpha (a cytokine involved in systemic inflammation) gene expression [7]. Studies have also shown that quercetin exhibits anticancer effects [8].

Clinical trials

A number of phase I clinical trials have been performed with quercetin evaluating pharmacokinetics [9] and adenoma regression [10]. A combination of curcumin and quercetin was evaluated to regress adenomas in patients with familialadenomatous polyposis (FAP), an autosomal-dominant disorder characterized by the development of colorectal adenomas and eventual colorectal cancer. The study found that the combination appeared to decreased polyp number and size from baseline after 6 months of treatment [10].

Epidemiologic data indicates that reduction in colorectal cancer risk associated with the highest 25% of data vs. the lowest 25% was largest for quercetin and catechin [11]. Overall, flavonoids showed strong and linear inverse associations with colorectal cancer risk. Large-scale genomic studies in colon cancer cells suggest that quercetin affects the expression of genes involved in cell cycle control [12-13]. Flavonoids also modulate cell cycle progression in prostate cancer cells [14-15].

Antioxidants and cancer

In September 2005, an article published in CA: A Cancer Journal for Clinicians warned against the use of antioxidants in combination with radiotherapy and chemotherapy [16]. Indeed, quercetin may alter the effects of chemotherapy medications used to treat cancer [17]. However, this position has been refuted by others [18] and a recent meta-analysis suggests that antioxidant supplementation does not interfere with therapeutic modalities for cancer and instead enhances the killing of therapeutic cancer agents, decreases modality side effects and protects normal tissue [19-20]. Another meta-analysis reviewing the evidence from randomized controlled trials on the impact of antioxidant supplementation on chemotherapeutic efficacy, although limited by lack of statistical power, found that many of the studies indicated that antioxidant supplementation resulted in either increased survival times, increased tumor responses or both, as well as fewer toxicities than controls [21].

A recent review assessing the contribution of dietary flavonoids to the total antioxidant capacity of plasma in humans concluded that the large increase in plasma total antioxidant capacity observed after the consumption of flavonoid-rich foods is not caused by the flavonoids themselves, but is likely the consequence of increased uric acid levels [22]. A potent antioxidant, uric acid is a normal constituent of the body and is the end product of purine (meaning the nucleotides adenine and guanine, two of the four building blocks of RNA and DNA) metabolism. Because the increased plasma concentration of uric acid is much greater than the concentration of flavonoids, the change in uric acid levels is thought to be responsible for the relatively large increase in plasma total antioxidant capacity after consumption of flavonoid-rich foods. Most uric acid produced in the body is excreted by the kidneys. However, it has been proposed that renal uric acid clearance is regulated by an unknown signal that is issued in response to the level of oxidative stress [23], allowing the kidneys to reabsorb the potent antioxidant when needed.

Flavonoids have been shown to induce detoxifying Phase II enzymes [24-25], indicating that they are recognized by the body as foreign compounds. Thus, it has been proposed that the ability of flavonoids to induce detoxifying enzymes may be a major mechanism by which flavonoids protect against mutagens and carcinogens, and act as cancer chemopreventive agents [22].

References

Sampson et al. Flavonol and flavone intakes in US health professionals. J Am Diet Assoc. 2002 Oct;102(10):1414-20.
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O’Reilly et al. Flavonoids protect against oxidative damage to LDL in vitro: use in selection of a flavonoid rich diet and relevance to LDL oxidation resistance ex vivo? Free Radic Res. 2000 Oct;33(4):419-26.
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Cirico and Omaye. Additive or synergetic effects of phenolic compounds on human low density lipoprotein oxidation. Food Chem Toxicol. 2006 Apr;44(4):510-6. Epub 2005 Oct 10.
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Middleton and Drzewiecki. Flavonoid inhibition of human basophil histamine release stimulated by various agents. Biochem Pharmacol. 1984 Nov 1;33(21):3333-8.
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Taguchi et al. Pharmacological studies of Houttuyniae herba: the anti-inflammatory effect of quercitrin. Yakugaku Zasshi. 1993 Apr;113(4):327-33.
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Loggia Della et al. Anti-inflammatory Activity of Benzopyrones that are Inhibitors of Cyclo- and Lipo-oxygenase. Pharmacol Res Commun. 1988 Dec;20 Suppl 5:91-4.
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Wadsworth et al. Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced signaling pathways involved in the release of tumor necrosis factor-alpha. Biochem Pharmacol. 2001 Oct 1;62(7):963-74.
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Morrow et al. Dietary supplementation with the anti-tumour promoter quercetin: its effects on matrix metalloproteinase gene regulation. Mutat Res. 2001 Sep 1;480-481:269-76.
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Ferry et al. Phase I clinical trial of the flavonoid quercetin: pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin Cancer Res. 1996 Apr;2(4):659-68.
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Cruz-Correa et al. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2006 Aug;4(8):1035-8. Epub 2006 Jun 6.
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Theodoratou et al. Dietary flavonoids and the risk of colorectal cancer. Cancer Epidemiol Biomarkers Prev. 2007 Apr;16(4):684-93.
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van Erk et al. Integrated assessment by multiple gene expression analysis of quercetin bioactivity on anticancer-related mechanisms in colon cancer cells in vitro. Eur J Nutr. 2005 Mar;44(3):143-56. Epub 2004 Apr 30.
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Murtaza et al. A preliminary investigation demonstrating the effect of quercetin on the expression of genes related to cell-cycle arrest, apoptosis and xenobiotic metabolism in human CO115 colon-adenocarcinoma cells using DNA microarray. Biotechnol Appl Biochem. 2006 Jul;45(Pt 1):29-36.
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Kobayashi et al. Effect of flavonoids on cell cycle progression in prostate cancer cells. Cancer Lett. 2002 Feb 8;176(1):17-23.
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Knowles et al. Flavonoids suppress androgen-independent human prostate tumor proliferation. Nutr Cancer. 2000;38(1):116-22.
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D’Andrea GM. Use of antioxidants during chemotherapy and radiotherapy should be avoided. CA Cancer J Clin. 2005 Sep-Oct;55(5):319-21.
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Desai et al. Human liver microsomal metabolism of paclitaxel and drug interactions. Eur J Drug Metab Pharmacokinet. 1998 Jul-Sep;23(3):417-24.
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Moss RW. Should patients undergoing chemotherapy and radiotherapy be prescribed antioxidants? Integr Cancer Ther. 2006 Mar;5(1):63-82.
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Simone et al. Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, part 1. Altern Ther Health Med. 2007 Jan-Feb;13(1):22-8.
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Simone et al. Antioxidants and other nutrients do not interfere with chemotherapy or radiation therapy and can increase kill and increase survival, Part 2. Altern Ther Health Med. 2007 Mar-Apr;13(2):40-7.
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Block et al. Impact of antioxidant supplementation on chemotherapeutic efficacy: A systematic review of the evidence from randomized controlled trials. Cancer Treat Rev. 2007 Mar 14; [Epub ahead of print].
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Lotito and Frei. Consumption of flavonoid-rich foods and increased plasma antioxidant capacity in humans: cause, consequence, or epiphenomenon? Free Radic Biol Med. 2006 Dec 15;41(12):1727-46. Epub 2006 Jun 3.
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Kirschbaum B. Renal regulation of plasma total antioxidant capacity. Med Hypotheses. 2001 Jun;56(6):625-9.
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Kong et al. Induction of xenobiotic enzymes by the MAP kinase pathway and the antioxidant or electrophile response element (ARE/EpRE). Drug Metab Rev. 2001 Aug-Nov;33(3-4):255-71.
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Walle and Walle. Induction of human UDP-glucuronosyltransferase UGT1A1 by flavonoids-structural requirements. Drug Metab Dispos. 2002 May;30(5):564-9.
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