Positive Health Online

Introduction

Cancer is a leading cause of death in the United States, second only to heart disease. One-third of the 556,500 cancer deaths expected to occur in 2003 will be related to lifestyle factors, such as nutrition, obesity, and physical activity.[1] Epidemiologic data from humans and experimental data from animal model studies indicate that a strong relationship between diet and cancer incidence exists. Today's consumers are more aware of that link than ever and are seeking to minimize risk and treat disease states through diet.

Figure 1 Structure of Ellagic Acid

Many of the health benefits associated with the consumption of plant-based foods are attributed to the presence of phytochemicals. Phytochemicals are biologically active components that impart health benefits beyond basic nutrition when consumed in typical or optimal servings. To date, literally hundreds of phytochemicals have been identified and are being evaluated as potential anticarcinogens. Ellagic acid is one such compound. It has been under investigation for the last three decades and is only beginning to receive the well-deserved attention of the scientific community. In their book, Complementary and Alternative Cancer Methods Handbook, as well as on their website (www.cancer.org), the American Cancer Society acknowledges that ellagic acid induces apoptosis in cancerous cells. They also note that ellagic acid "prevents the binding of carcinogens to DNA, and strengthens connective tissue, which may keep cancer cells from spreading".

Sources and Structure

Ellagic acid has been shown to be an effective antimutagen, anticarcinogen, and, in some cases, cancer inhibitor. Ellagic acid is the dilactone of hexahydroxydiphenic acid, derived from the hydrolysis of ellagatannins. It is plentiful in the food supply regularly consumed by humans. It is present in plants, fruits, and nuts in its free form, as a series of ellagitannins, or as a glucoside. The highest content of ellagic acid has been identified in raspberries, strawberries, cranberries, blackberries and nuts[2] (Table 1). Daily consumption of as little as 150g of red raspberries, or about 1 cup, has been shown to slow the growth of abnormal colon cells in humans and prevent human papilloma virus (HPV)-infected cells from developing.

Ellagic acid is an extremely stable polyphenol (Figure 1). Its polycyclic aromatic structure allows for charge-transfer complexes. Rossi et al.[3] used x-ray diffraction techniques to study the crystal and molecular structure of ellagic acid dehydrate. Ellagic acid is a complex planar compound that forms a strong hydrogen-bonding network with surrounding water molecules. The crystalline molecules stack in planes, such that the center of one of the six-member rings in one molecule lies above and below an atom in other molecules. The four hydroxyl and two lactone functional groups act as hydrogen bond acceptors and donors, enabling ellagic acid to participate in a number of reactions.

Mechanisms of Anticarginogen Action

The antitumour activity of ellagic acid has proven an effective inhibitor of chemically induced cancer in the pulmonary and hepatic systems, as well as in the epidermis of mice.[[2,4-5] Several mechanisms by which phytochemicals, such as ellagic acid, can alter carcinogenesis have been identified. Potential mechanisms include the inhibition of Phase I enzymes; modification of carcinogen detoxification through Phase II pathways; antioxidation activities, including scavenging DNA reactive agents; suppressing abnormal proliferation of early preneoplastic lesions; and inhibiting certain properties of the cancer cell.[6]

Ellagic acid decreases the rate of carcinogen metabolism by Phase I enzymes by directly inhibiting the catalytic activity and frequency of gene expression.[4] The inhibitory effect of ellagic acid on the arylamine N-acetyltransferase (NAT) activity exemplifies this action. Arylamines are extremely potent carcinogens, inducing tumours in humans. Cystolic arylamine NAT catalyzes the acetylation of arylamine, thereby activating the procarcinogen. Growth studies of H. pylori demonstrated inhibition by ellagic acid in a dose-dependant relationship.[7] Ellagic acid appears to act as a noncompetitive inhibitor, as evidenced by decreases in kinetic constants of cytosol and intact bacteria examinations.

NAD(P)H:quinone reductase (QR) is a phase II detoxification enzyme. It functions to prevent the formation of superoxide radicals and detoxify a variety of foreign compounds. Barch and Rundhaugen[8] found that ellagic acid induced QR expression through activation of the antioxidant responsive element of the QR gene. Dietary ellagic acid significantly increased pulmonary and hepatic QR activity by 9- and 2-fold, respectively. An 8-fold increase in hepatic QR mRNA was associated with an increase in hepatic QR activity. In this way, ellagic acid effectively increases detoxification of carcinogens and reduces mutagenesis and tumourigenesis. Further studies of the structure-function relationship indicate an interaction between the lactones of ellagic acid and antioxidant responsive elements of the 5´ regulatory region induces NAD(P):
QR activation.[[9]

The inhibitory effect of ellagic acid on aflatoxin-induced mutagenicity is most likely related to its antioxidant property. Aflatoxin B1 (AFB1) is a potent carcinogen and fungal metabolite produced by Aspergillus parasiticus and A. flavus. Cytochrome P450 metabolizes AFB1 to it 2,3-epoxide, which readily forms adducts with DNA. Ellagic acid inhibits the activation of AFB1, thereby reducing its mutagenicity.[10] Loarca-Pina et al.[11] observed similar antimutagenic effects of ellagic acid against AFB1 using a Salmonella microsuspension assay. The results of this study indicated that in addition to antioxidant effect of ellagic acid, two additional mechanisms may also come into play. Ellagic acid may act directly to form an extracellular complex with AFB1, and/or interact with DNA to reduce the number of binding sites available for the activation of AFB[1].

Perchellet, et al.[5] demonstrated the inhibitory effects of ellagic acid on biochemical markers of skin tumour promotion. Epidermal tumourigenesis progresses in 3 defined stages; initiation, propagation and promotion. Tumour initiation results in alterations in programme of grown and differentiation, as well as resistance to cytotoxic agents. Stage 2 propagation is marked by accelerated 12-O-tetradecanoyl-phorbol-13-acetate(TPA)-induced ornithine decarboxylase activity, increased hydrogen peroxide production and altered DNA synthesis. Topically applied ellagic acid significantly inhibited carcinogenesis, as determined by reduced activity of Stage 2 biochemical markers. Although the mechanism of inhibition is unclear, it was concluded that ellagic acid inhibits the biochemistry and biology of tumour promotion beyond its antioxidant effects.

Clinical Studies

Clinical studies are underway to substantiate the positive findings of the anticarcinogenic effects of ellagic acid in humans. The Hollings Cancer Center at the University of South Carolina is conducting a double blind study on cervical cancer patients (n=500). Women with atypical squamous cells of undetermined significance will ingest ellagic acid at dosages providing detectable tissue levels in the cervix over a two year period. Preceding studies associated with the Hollings Center have found that ellagic acid at a concentration of 10-5 M induced G arrest within 48 hours, inhibited overall cell growth, and induced apoptosis in cervical carcinoma cells after 72 hours of treatment.[12]

References

1. Cancer Facts & Figures. American Cancer Society. 2003.
2. Daniel EM. Quantification and liberation of ellagic acid in dietary sources, and its effects, in combination with 13-sic retinoic acid, on the development of N-nitrosobezylmethylamine-induced esophageal tumors in F344 rats. Diss Abstr Int. 51(10):4787. 1991.
3. Rossi M, Erlebacher F, Zacharias DE, Carrell HL and Iannucci B. The crystal and molecular structure of ellagic acid dihydrate: a dietary anti-cancer agent. Carcinogenesis. 12(12): 2227-2232. 1991.
4. Ahn D, Putt D, Kresty L, Stoner GD, Fromm D and Hollenberg PF. The effects of dietary ellagic acid on rat hepatic and esophageal mucosal cytochromes P450 and phase II enzymes. Carcinogenesis. 17(4): 821-828. 1996.
5. Perchellet J, Gali HU, Perchellet EM, Klish DS and Armbrust AD. Antitumor-promoting activities of tannic acid, ellagic acid, and several gallic acid derivatives in mouse skin. Plant Polyphenols. in Hemingway RW and Lakes PE (Ed.). Plenium Press. NY. 1992.
6. Wargovich MJ. Experimental evidence for cancer preventive elements in foods. Cancer Lett. 114(1-2):11-17. 1997.
7. Chung JG. Inhibitory actions of ellagic acid on growth and arylamine N-acetyltransferase activity in strains of Helicobacter pylori from peptic ulcer patients. Microbios.<b> 93:115-127. 1998.
8. Barch DH and Rundhaugen LM. Ellagic acid induces NAD(P)H:quinone reductase gene. Carcinogenesis. 15(9): 2065-2068. 1994.
9. Barch DH, Rundhaugen LM, Stoner GD, Sokalingum N and Rosche WA et al. Structure-function relationships of the dietary anticarcinogen ellagic acid. Carcinogenesis. 17(2): 265-269. 1996.
10. Soni KB, Lahiri M, Chackradeo P, Bhide SV and Kuttan R. Protective effect of food additives on aflatoxin-induced mutagenicity and hepatocarcinogenicity. Cancer Lett. 115:129-133. 1997.
11. Loarca-Pina G, Kuzmicky PA, Gonzales de Mejia E and Kato NY. Inhibitory effects of ellagic acid on the direct-acting mutagenicity of aflotoxin B1 in the Salmonella microsuspension assay. Mutat. Res.398:183-187. 1998.
12. Narayanan BA, Geoffroy O, Willingham MC, Re GG, Nixon DW. p53/21 (WAF1/CIP1) expression and its possible role in G1 arrest and apoptosis in ellagic acid treated cancer cells. Cancer Lett. 1;136(2): 215-21. 1999.