Raspberry Season, 2005
Subject: Update on ellagic acid research from the past year.
It's raspberry season again and the prices are dropping. Expect to see fresh berries sold as a loss leader at $1 a pint between now and July 4 th . At the same time the stores will be trying to clear out last year's stock of frozen berries in time for the 2005 crop, so expect to see low prices in the freezer section as well.
This reminds me of a chore I've been neglecting. These days research on nutritional supplements is published at an astounding rate and it is a challenge to stay up to date. I've written about raspberries numerous times over the past years and it is time to update my files. Since raspberries are in season, I'll take a few minutes to do this now and then tell you what is new.
Raspberries are a primary food source for a chemical called ellagic acid. The other major source is the pomegranate; smaller amounts of ellagic acid are found in walnuts, apricots and watermelon. Ellagic acid from any source has an anticancer effect and eating foods containing high amounts or taking extracts of these foods is useful in preventing or treating cancer. Scientists are very interested in ellagic acid and understanding why it has this anti-cancer effect.
The simplest way I have found to measure the value of a “potential” treatment is to weigh the interest scientists have taken in it. I do this by simply looking at the number of articles which have appeared in peer reviewed scientific journals, especially if the number is increasing with time. The more papers being published, the more interest, and the more possibility the substance of interest may be useful.
For example, I used Pubmed to search the National Library of Medicine's collection today ( 5/26/05 ). A search of the term “ellagic acid” produced 599 articles. Using the combined terms “ellagic acid AND cancer” produced 110. Considering the obscurity of ellagic acid, this is a great deal of interest. Compare this with the popular multilevel marketed extract of Mangosteen fruit; a similar search produced only 8 listings.
Search engines for scientific literature:
The next step is to collect and read through the abstracts to determine which have information that is clinically useful. Then I summarize this information into a short, hopefully understandable article. Which is what you see. It's been a year since we had fresh raspberries and I've last reviewed the literature. There's a lot new. Here are a few highlights.
There's a study about to be published in the June issue of Journal of Cell Biochemistry in which various chemicals were tested first in a lab test and then in rats to see which would be most protective against skin cancer. Of the 20 chemicals tested, ellagic acid was the most effective. [i]
Earlier this month, May 5, a study was published on the effect of ellagic acid on OATs, which isn't oatmeal but an abbreviation for Organic Ion Transporters. This is rather esoteric biochemistry. All I need to you to understand is simple; scientists realize ellagic acid prevents cancer, now they are deep into the biochemistry of trying to understand why. [ii]
In the end of April a study was published in Carcinogenesis describing research done in Montreal which demonstrated that ellagic acid inhibited both vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors. These receptors play important roles in cancer growth and inhibiting both of these receptors has a potent antitumor effect in animals. [iii]
Earlier in April a study published in European Urology looked at the effect of ellagic acid when given to men undergoing chemotherapy for prostate cancer. Ellagic acid reduced toxicity of the chemotherapy on the patients especially neutropenia, that is low white blood cell counts. [iv]
What is interesting about ellagic acid is how complex its effect is on cancer cells. There isn't one single mechanism by which it stops cancer cell growth but multiple mechanisms. A Chinese study published in the March/April issue of Anticancer Research listed some of the effects that they were able to determine:
“Ellagic acid significantly reduced the viable cells, induced G0/G1-phase arrest of the cell cycle and apoptosis. Ellagic acid also increased p53 and p21 and decreased CDK2 gene expression that may lead to the G0/G1 arrest of T24 cells. Ellagic acid also promoted caspase-3 activity after exposure for 1, 3, 6, 12 and 24 h, which led to induction of apoptosis. Furthermore, the ellagic acid-induced apoptosis on T24 cells was blocked by the broad-spectrum caspase inhibitor.” [v]
Not so simple is it?
Ephraim Lansky and his colleagues in Israel continue methodically publishing study after study on pomegranate extracts. One published in March demonstrated that four separate chemicals extracted from pomegranates other than ellagic acid, each individually inhibited prostate cancer growth and together had a synergistic effect. Synergistic effect means that using them all together produced more effect than you would have expected by adding up the effect each chemical had by itself. This is a good thing. [vi]
Another good word is potentiate. This means make stronger. A study published in March described how ellagic acid potentiates the effect of quercetin on cancer cells. Quercetin stimulates apoptosis in cancer cells; it convinces them to commit suicide. Combined with ellagic acid, quercetin is even more effective at doing this. This study looked carefully at the chemistry of how this works and demonstrated that it did so without interfering with the ‘generation of reactive oxygen species' which is a mechanism used by many chemotherapy drugs to kill cancer cells. Not only does ellagic acid help other natural substances work but it does so by a method that doesn't get in the way of chemotherapy or radiation. This is also a good thing. [vii]
The synergistic effect of ellagic acid was also seen in a study published last February that looked at the combined effect of ellagic acid, resveratrol and quercetin on leukemia cells. Although all of these chemicals are somewhat similar, they are all polyphenols, they work better in combination than they do alone. [viii]
A study from late January examined the metabolic pathway ellagic acid from various foods takes through the body. It appears that absorption and excretion rates vary not just from food to food but also between individuals. The researchers hypothesize that some of this variability has to do with fermentation by bowel bacteria. [ix] This is interesting in light of Lansky's research that shows that fermented pomegranate extracts have far greater anti- cancer effect.
Blackberries have also been investigated, especially to understand why they prevent esophageal and colon cancer. Although ellagic acid is responsible for some of the inhibitory effect seen in blackberry extracts, two other chemicals found in the berries, ferulic acid and beta-sitosterol are receiving most of the credit for the anti-cancer effects seen. [x] I know this is slightly off topic but blackberries are in season as well……
Not all of the publications are driven by the search for patentable medicines. A review of the various plant extracts in Cancer Letters last November looked at the potential benefit of including the now many plant extracts known to have utility in cancer treatment into routine cancer therapy especially in preventing and reversing resistance developed by cancer cells to chemotherapy and radiation treatments. [xi]
Another study published last November looked at the effect of ellagic acid on normal cells, prostate cancer cells, breast cancer cells, and colon cancer cells. The ellagic acid concentrations used were in the range of 1-100 micromol/L. These are levels obtainable simply by eating raspberries. Ellagic acid caused no damage to the healthy cells. It had a significant effect on all the cancer cells. Ellagic acid prevented growth in all the cancer cell lines having the most pronounced effect on the colon cancer cells and the least effect on the breast cancer cells. The cells died due to apoptosis, that fancy word for self destruction. [xii] This selective cyto-toxicity, that is killing cancer cells while leaving healthy cells unaffected, is what would be considered a very desirable trait for any cancer treatment.
An article authored by researchers from MD Anderson published last October, reviewed the research on ellagic acid and a number of other similar chemicals at cancer prevention and treatment and suggested that cancer was easier to prevent than treat. They suggested that these sorts of chemicals should be used individually for cancer prevention and together for cancer treatment. [xiii]
The big interest in berries these days is their anti-cancer effect and my focus in this quick review is looking at research related to cancer. This doesn't mean berries don't have other benefits. A review of the biochemical benefits of strawberries points out a number of other benefits we should be interested in, including, “…. inhibition of LDL-cholesterol oxidation, promotion of plaque stability, improved vascular endothelial function, and decreased tendency for thrombosis. Furthermore, strawberry extracts have been shown to inhibit COX enzymes in vitro, which would modulate the inflammatory process.” [xiv] Any one of these actions is a worthwhile claim to fame and would make a pharmaceutical drug envious.
This is all rather interesting news considering that my review is by no means complete, that I've arbitrarily limited myself only to studies that have appeared since last raspberry season and also limited myself to cancer related studies.
The bottom line on this one is simple:
We are entering the time of year when fresh berries, especially raspberries are plentiful, good tasting and inexpensive. Suffice to say you should eat as many as you can and make sure your freezer is filled. A good helping of raspberries will bring your blood levels of ellagic acid into the experimental range used to kill cancer cells.
If undergoing any form of cancer therapy, ellagic acid, along with a number of other similar chemicals can increase the benefit provided by conventional treatments such as chemotherapy and radiation while reducing their side effects. These polyphenols chemicals can also prevent the cancer cells from becoming resistant to treatment, extending the benefit provided. They act synergistically together, providing benefits that are more than additive in inhibiting cancer cell growth and stimulating cancer cell death without damaging normal healthy cells.
Although eating ellagic rich foods may suffice for cancer prevention, there are now a number of supplements made from ellagic rich foods available. Based on the research by Lansky in Israel we are favoring the fermented pomegranate extracts as a source of ellagic acid.
In answer to my questions about which form of ellagic acid might be most effective, Ephraim Lansky, the principle pomegranate researcher in Israel surprised me. Lansky's opinion is that it isn't the ellagic acid but the combination and interaction of ellagic acid with the other chemicals found in pomegranates which produce the most benefit. It is the synergistic interaction of these substances in the ratios found in nature which produce the most profound effect, more so than simple high doses of one of them. The scientist lectures me on naturopathic philosophy; you've got to love it. For this I am gradually shifting from the simple high ellagic doses we've used for cancer patients to more moderate doses in more complex and carefully designed extracts which combine a number of different chemical fractions.
As far as cancer treatment the words to remember are synergy and potentiate. The chemicals in raspberries and pomegranates have a synergistic effect with each other and with other cancer treatments, both the natural ones and the standard chemotherapy and radiation treatments. Synergy means the combined effect of all the treatments is increased to be more than the sum of the parts. Potentiate means to make stronger. These chemicals make the effect of standard cancer therapy stronger. It does a better job of killing cancer cells without harming healthy cells, in fact reducing side effects of treatment on healthy cells. All this from a raspberry.
[i] J Cell Biochem. 2005 Jun 1;95(3):571-88.
Correlation of in vitro chemopreventive efficacy data from the human epidermal cell assay with animal efficacy data and clinical trial plasma levels.
Elmore E, Siddiqui S, Navidi M, Steele VE, Redpath JL.
Department of Radiation Oncology, University of California Irvine , Irvine , California 92697 .
The human epidermal cell (HEC) assay, which uses carcinogen exposed normal skin keratinocytes to screen for cancer prevention efficacy, was used to screen possible preventive agents. The endpoints measured were inhibition of carcinogen-induced growth and induction of involucrin, an early marker of differentiation. Sixteen of twenty agents (apigenin, apomine, budesonide, N-(2-carboxyphenyl)retinamide, ellagic acid, ibuprofen, indomethacin, melatonin, (-)-2-oxo-4-thiazolidine carboxylic acid, polyphenon E, resveratrol, beta-sitosterol, sulfasalazine, vitamin E acetate, and zileuton) were positive in at least one of the two assay endpoints. Four agents (4-methoxyphenol, naringenin, palmitoylcarnitine chloride, and silymarin) were negative in the assay. Nine of the sixteen agents were positive for both endpoints . Agents that showed the greatest response included: ellagic acid > budesonide, ibuprofen > apigenin, and quinicrine dihydrochloride . Fifty-eight of sixty-five agents that have been evaluated in the HEC assay have also been evaluated in one or more rodent bioassays for cancer prevention and several are in clinical trials for cancer prevention. The assay has an overall predictive accuracy of approximately 91.4% for efficacy in rodent cancer prevention irrespective of the species used, the tissue model, or the carcinogen used. Comparison of the efficacious concentrations in vitro to plasma levels in clinical trials show that concentrations that produced efficacy in the HEC assay were achieved in clinical studies for 31 of 33 agents for which plasma levels and/or C(max) levels were available. For two agents, 9-cis-retinoic acid (RA) and dehydroepiandrosterone (DHEA), the plasma levels greatly exceeded the highest concentration (HC) found to have efficacy in vitro. Thus, the HEC assay has an excellent predictive potential for animal efficacy and is responsive at clinically achievable concentrations. (c) 2005 Wiley-Liss, Inc.
PMID: 15786488 [PubMed - in process]
[ii] Drug Metab Dispos. 2005 May 3; [Epub ahead of print]
The dietary polyphenol ellagic acid is a potent inhibitor of hOAT1.
Whitley AC, Sweet DH, Walle T.
Medical University of South Carolina .
Ellagic acid (EA), a polyphenol present in berries, has been demonstrated to be preventive of esophageal and colon cancer in animals. Here, we have studied the ability of organic anion transporters (OATs) and organic anion transporting polypeptides (OATPs) to transport EA. The accumulation of radiolabeled [(14)C]EA, [(3)H]p-aminohippuric acid (PAH), [(14)C]glutarate, [(3)H]estrone sulfate, [(3)H]ochratoxin A, and [(3)H]taurocholic acid +/- inhibitor(s) was tested in OAT- and OATP-expressing oocytes. Oocytes expressing hOAT1, rOat1 and hOAT4 accumulated 6.5-, 7.1-, and 8.9-fold more EA than water-injected oocytes, respectively. This accumulation was prevented by the prototype OAT inhibitors bromosulfophthalein and probenecid. rOatp1, mOat2, hOAT3, and mOat5 showed no EA transport. The uptake of the prototype OAT substrate PAH in hOAT1-expressing oocytes was dose-dependently and potently inhibited by EA with an IC50 of 207 nM. In conclusion, we have demonstrated that the OAT family members hOAT1, rOat1, and hOAT4 mediate transport of EA, with a very high affinity for hOAT1.
PMID: 15870380 [PubMed - as supplied by publisher]
[iii] Carcinogenesis. 2005 Apr;26(4):821-6. Epub 2005 Jan 20.
Combined inhibition of PDGF and VEGF receptors by ellagic acid, a dietary-derived phenolic compound.
Labrecque L, Lamy S, Chapus A, Mihoubi S, Durocher Y, Cass B, Bojanowski MW, Gingras D, Beliveau R.
Laboratoire de Medecine Moleculaire, Hopital Ste-Justine-Universite du Quebec a Montreal, Centre de Cancerologie Charles-Bruneau, 3175 Chemin Cote-Ste-Catherine, Montreal, Quebec, Canada H3T 1C5.
The vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors play essential and complementary roles in angiogenesis and combined inhibition of these receptors has been shown to result in potent antitumor activity in vivo. In this study, we report that ellagic acid (EA), a natural polyphenol found in fruits and nuts, inhibits VEGF-induced phosphorylation of VEGFR-2 in endothelial cell (EC) as well as PDGF-induced phosphorylation of PDGFR in smooth muscle cells, leading to the inhibition of downstream signaling triggered by these receptors. EA also specifically inhibited VEGF-induced migration of ECs as well as their differentiation into capillary-like tubular structures and abolished PDGF-dependent smooth muscle cell migration. Interestingly, EA presents a greater selectivity for normal cells than for tumor cells since the migration of the U87 and HT1080 cell lines were much less affected by this molecule. The identification of EA as a naturally occurring dual inhibitor of VEGF and PDGF receptors suggests that this molecule possesses important antiangiogenic properties that may be helpful for the prevention and treatment of cancer.
PMID: 15661805 [PubMed - indexed for MEDLINE]
[iv] Eur Urol. 2005 Apr;47(4):449-54; discussion 454-5. Epub 2005 Jan 19.
Support ellagic acid therapy in patients with hormone refractory prostate cancer (HRPC) on standard chemotherapy using vinorelbine and estramustine phosphate.
Falsaperla M, Morgia G, Tartarone A, Ardito R, Romano G.
Operative Unit of Urology, Centro di Riferimento Oncologico della Basilicata , Rionero in Vulture, Potenza , Italy . email@example.com
BACKGROUND: Recent phase III studies in hormone refractory prostate cancer (HRPC) showed an improvement in terms of overall survival (OS), objective response (OR) and biochemical response (BR); however, chemotherapy is usually accompanied by negative side effects that determines poor quality of life (QoL) and only marginally improves individual clinical response (ICR) in terms of pain relief and performance status. Ellagic acid is a polyphenol that is found in many species of flowering plants. It is an antioxidant that determines apoptosis, down regulation of IGF-II, activates p21 (waf1/Cip1), mediates the cumulative effect on G1/S transition phase and prevents destruction of p-53 gene by cancer cells. ENDPOINTS: The aim of this study was to assess the effects of ellagic acid support therapy on toxicity, OR, ICR and BR in HRPC patients treated with estramustine phosphate and vinorelbine. MATERIALS AND METHODS: Patients with HRPC were randomly distributed in two study groups: a control group (group A) who underwent chemotherapy with vinorelbine and estramustine phosphate, and an experimental group (group B) where chemotherapy regimen was associated with ellagic acid. RESULTS: The mean number of chemotherapy cycles/patient was 4 (range 3-8 cycles) and 6.5 (range 5-11) in group A and B patients, respectively. A reduction in systemic toxicity, statistically significant for neutropenia, associated with better results in term of OR rate, ICR, and BR were observed in group B compared with group A . On the contrary no significant difference in OS and PFS was detected between groups.
CONCLUSIONS : our study suggests that the use of ellagic acid as support therapy reduces chemotherapy induced toxicity, in particular neutropenia, in HRCP patients; however, further studies are required to confirm our results.
PMID: 15774240 [PubMed - in process]
[v] Anticancer Res. 2005 Mar-Apr;25(2A):971-9.
Ellagic acid induced p53/p21 expression, G1 arrest and apoptosis in human bladder cancer T24 cells.
Li TM, Chen GW, Su CC, Lin JG, Yeh CC, Cheng KC, Chung JG.
School of Chinese Medicine, China Medical University , Taichung City 400, Taiwan , ROC.
It is well known that dietary phenolic compounds can elicit vital cellular responses such as cytotoxicity, cell cycle arrest and apoptosis by activating a cascade of molecular events. Ellagic acid is one of these phenolic compounds, but the exact mechanism of its action is still unclear. The objective of this study was to investigate ellagic acid-induced cell cycle arrest and apoptosis in T24 human bladder cancer cells in vitro. Assays were performed to determine cell viability, cell cycle arrest, apoptosis, caspases-3 activity and gene expression, measured by flow cytometric assay, polymerase chain reaction (PCR) and determination of caspase-3 activity. Ellagic acid significantly reduced the viable cells, induced G0/G1-phase arrest of the cell cycle and apoptosis. Ellagic acid also increased p53 and p21 and decreased CDK2 gene expression, that may lead to the G0/G1 arrest of T24 cells. Ellagic acid also promoted caspase-3 activity after exposure for 1, 3, 6, 12 and 24 h, which led to induction of apoptosis. Furthermore, the ellagic acid-induced apoptosis on T24 cells was blocked by the broad-spectrum caspase inhibitor (z-VAD-fmk).
PMID: 15868936 [PubMed - in process]
[vi] Invest New Drugs. 2005 Mar;23(2):121-2.
Pomegranate (Punica granatum) pure chemicals show possible synergistic inhibition of human PC-3 prostate cancer cell invasion across Matrigel.
Lansky EP, Harrison G, Froom P, Jiang WG.
Rimonest Ltd., P.O.B. 9945, Haifa , Israel .
Four pure chemicals, ellagic acid (E), caffeic acid (C), luteolin (L) and punicic acid (P), all important components of the aqueous compartments or oily compartment of pomegranate fruit (Punica granatum), and each belonging to different representative chemical classes and showing known anticancer activities, were tested as potential inhibitors of in vitro invasion of human PC-3 prostate cancer cells in an assay employing Matrigel artificial membranes. All compounds significantly inhibited invasion when employed individually. When C, P, and L were equally combined at the same gross dosage (4 microg/ml) as when the compounds were tested individually, a supradditive inhibition of invasion was observed, measured by the Kruskal-Wallis non-parametric test.
PMID: 15744587 [PubMed - in process]
[vii] J Nutr. 2005 Mar;135(3):609-14.
Ellagic acid potentiates the effect of quercetin on p21waf1/cip1, p53, and MAP-kinases without affecting intracellular generation of reactive oxygen species in vitro.
Mertens-Talcott SU, Bomser JA, Romero C, Talcott ST , Percival SS.
Department of Food Science and Human Nutrition, Institute of Food and Agricultural Sciences, University of Florida , Gainesville , FL 32611-0370 , USA .
Anticarcinogenic effects attributed to polyphenols in fruits may be based on synergistic, additive, or antagonistic interactions of many compounds. In a previous study, it was demonstrated that quercetin and ellagic acid interacted synergistically in the induction of apoptosis in the human leukemia cell line, MOLT-4. To investigate possible cellular mechanisms, this study evaluated whether synergistic effects might be detectable within proapoptotic or antiproliferative signal transduction pathways. We found that quercetin and combinations of quercetin and ellagic acid nonsynergistically increased p53 protein levels. In contrast, ellagic acid potentiated the effects of quercetin for p21(cip1/waf1) protein levels and p53 phosphorylation at serine 15, possibly explaining the synergistic effect observed in apoptosis induction. Phosphorylation of the mitogen-activated protein (MAP) kinases, c-jun N-terminal (JNK)1,2 and p38, was also increased by the combination of ellagic acid and quercetin, whereas quercetin alone induced only p38. We further evaluated whether the generation of reactive oxygen species (ROS) and/or quercetin stability were influenced by interactions of ellagic acid with quercetin. Quercetin increased the generation of ROS, which was neither potentiated nor inhibited by ellagic acid. The stability of intracellular and extracellular quercetin was not influenced by the presence of ellagic acid. In summary, quercetin and ellagic acid combined increase the activation of p53 and p21(cip1/waf1) and the MAP kinases, JNK1,2 and p38, in a more than additive manner, suggesting a mechanism by which quercetin and ellagic acid synergistically induce apoptosis in cancer cells.
PMID: 15735102 [PubMed - indexed for MEDLINE]
[viii] Cancer Lett. 2005 Feb 10;218(2):141-51.
Ellagic acid and quercetin interact synergistically with resveratrol in the induction of apoptosis and cause transient cell cycle arrest in human leukemia cells.
Mertens-Talcott SU, Percival SS.
Department of Food Science and Human Nutrition, Institute of Food and Agricultural Sciences, University of Florida , P.O. Box 110370 , Gainesville , FL 32611-0370 , USA .
Anticarcinogenic effects of polyphenolic compounds in fruits and vegetables are well established. Although polyphenols naturally occur as combinations, little information is available regarding possible synergistic or antagonistic biochemical interactions between compounds. Identifying potential interactions between polyphenols may provide information regarding the efficiency of polyphenol-containing foods in cancer prevention. The objective of this study was to investigate the interactions of ellagic acid and quercetin with resveratrol, polyphenols which occur in muscadine grapes, with the hypothesis that the selected polyphenols would interact synergistically in the induction of apoptosis and reduction of cell growth in human leukemia cells (MOLT-4). To test this hypothesis, alterations in cell cycle kinetics, proliferation, and apoptosis (caspase-3 activity) were examined after incubation with ellagic acid, quercetin, and resveratrol as single compounds and in combination. Results showed a more than additive interaction for the combination of ellagic acid with resveratrol and furthermore, significant alterations in cell cycle kinetics induced by single compounds and combinations were observed. An isobolographic analysis was performed to assess the apparent synergistic interaction for the combinations of ellagic acid with resveratrol and quercetin with resveratrol in the induction of caspase 3 activity, confirming a synergistic interaction with a combination index of 0.64 for the combination of ellagic acid and resveratrol and 0.68 for quercetin and resveratrol. Results indicate that the anticarcinogenic potential of foods containing polyphenols may not be based on the effects of individual compounds, but may involve a synergistic enhancement of the anticancer effects.
PMID: 15670891 [PubMed - in process]
[ix] J Agric Food Chem. 2005 Jan 26;53(2):227-35.
Metabolism of antioxidant and chemopreventive ellagitannins from strawberries, raspberries, walnuts, and oak-aged wine in humans: identification of biomarkers and individual variability.
Cerda B, Tomas-Barberan FA, Espin JC.
Research Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS-CSIC, P.O. Box 164 , 30100 Campus de Espinardo, Murcia , Spain .
Ellagitannins (ETs) are dietary polyphenols, containing ellagic acid (EA) subunits, with antioxidant and cancer chemopreventive activities that might contribute to health benefits in humans. However, little is known about their metabolic fate. We investigate here the metabolism of different dietary ETs and EA derivatives in humans. Forty healthy volunteers were distributed in four groups. Each group consumed, in a single dose, a different ET-containing foodstuff, i.e., strawberries (250 g), red raspberries (225 g), walnuts (35 g), and oak-aged red wine (300 mL). After the intake, five urine fractions (F) were collected at 8 (F1), 16 (F2), 32 (F3), 40 (F4), and 56 (F5) h. Neither ETs nor EA were detected in urine after LC-MS/MS analysis. However, the microbial metabolite 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one (urolithin B) conjugated with glucuronic acid was detected along the fractions F3-F5 in all of the subjects, independently of the consumed foodstuff. The mean percentage of metabolite excretion ranged from 2.8 (strawberries) to 16.6% (walnuts) regarding the ingested ETs. Considerable interindividual differences were noted, identifying "high and low metabolite excreters" in each group, which supported the involvement of the colonic microflora in ET metabolism. These results indicate that urolithin B (a previously described antiangiogenic and hyaluronidase inhibitor compound) is a biomarker of human exposure to dietary ETs and may be useful in intervention studies with ET-containing products. The antioxidant and anticarcinogenic effects of dietary ETs and EA should be considered in the gastrointestinal tract whereas the study of potential systemic activities should be focused on the bioavailable urolithin B derivatives.
PMID: 15656654 [PubMed - indexed for MEDLINE]
[x] Nutr Cancer. 2005;51(2):207-17.
Inhibition of the growth of premalignant and malignant human oral cell lines by extracts and components of black raspberries.
Han C, Ding H, Casto B, Stoner GD, D'Ambrosio SM.
Department of Radiology, The Ohio State University , Columbus 43210 , USA .
Black raspberries are a rich natural source of chemopreventive phytochemicals. Recent studies have shown that freeze-dried black raspberries inhibit the development of oral, esophageal, and colon cancer in rodents, and extracts of black raspberries inhibit benzo(a)pyrene-induced cell transformation of hamster embryo fibroblasts. However, the molecular mechanisms and the active components responsible for black raspberry chemoprevention are unclear. In this study, we found that 2 major chemopreventive components of black raspberries, ferulic acid and beta-sitosterol, and a fraction eluted with ethanol (RO-ET) during silica column chromatography of the organic extract of freeze-dried black raspberries inhibit the growth of premalignant and malignant but not normal human oral epithelial cell lines. Another fraction eluted with CH2Cl2/ethanol (DM:ET) and ellagic acid inhibited the growth of normal as well as premalignant and malignant human oral cell lines. We investigated the molecular mechanisms by which ferulic acid and beta-sitosterol and the RO-ET fraction selectively inhibited the growth of premalignant and malignant oral cells using flow cytometry and Western blotting of cell cycle regulatory proteins. There was no discernable change in the cell cycle distribution following treatment of cells with the RO-ET fraction. Premalignant and malignant cells redistributed to the G2/M phase of the cell cycle following incubation with ferulic acid. beta-sitosterol treated premalignant and malignant cells accumulated in the G0/G1 and G2/M phases, respectively. The RO-ET fraction reduced the levels of cyclin A and cell division cycle gene 2 (cdc2) in premalignant cells and cyclin B1, cyclin D1, and cdc2 in the malignant cell lines. This fraction also elevated the levels of p21waf1/cip1 in the malignant cell line. Ferulic acid treatment led to increased levels of cyclin B1 and cdc2 in both cell lines, and p21waf1/cip1 was induced in the malignant cell line. beta-sitosterol reduced the levels of cyclin B1 and cdc2 while increasing p21waf1/cip1 in both the premalignant and malignant cell lines. These results show for the first time that the growth inhibitory effects of black raspberries on premalignant and malignant human oral cells may reside in specific components that target aberrant signaling pathways regulating cell cycle progression.
PMID: 15860443 [PubMed - in process]
[xi] Cancer Lett. 2004 Nov 25;215(2):129-40.
Role of chemopreventive agents in cancer therapy.
Dorai T, Aggarwal BB.
Comprehensive Cancer Center, Our Lady of Mercy Medical Center, New York Medical College, Bronx, NY 10466, USA.
Tumorigenesis or carcinogenesis is a multi-step process that is induced primarily by carcinogens leading to the development of cancer. Extensive research in the last few years has revealed that regular consumption of certain fruits and vegetables can reduce the risk of acquiring specific cancers. Phytochemicals derived from such fruits and vegetables, referred to as chemopreventive agents include genistein, resveratrol, diallyl sulfide, S-allyl cysteine, allicin, lycopene, capsaicin, curcumin, 6-gingerol, ellagic acid, ursolic acid, silymarin, anethol, catechins and eugenol. Because these agents have been shown to suppress cancer cell proliferation, inhibit growth factor signaling pathways, induce apoptosis, inhibit NF-kappaB, AP-1 and JAK-STAT activation pathways, inhibit angiogenesis, suppress the expression of anti-apoptotic proteins, inhibit cyclooxygenase-2, they may have untapped therapeutic value. These chemopreventive agents also have very recently been found to reverse chemoresistance and radioresistance in patients undergoing cancer treatment. Thus, these chemopreventive agents have potential to be used as adjuncts to current cancer therapies.
[xii] J Nutr Biochem. 2004 Nov;15(11):672-8.
In vitro anti-proliferative activities of ellagic acid.
Losso JN, Bansode RR, Trappey A 2nd, Bawadi HA, Truax R.
Department of Food Science, Louisiana State University , Agricultural Center, Baton Rouge , LA 70803 , USA . firstname.lastname@example.org
The potential cytotoxic and anti-proliferative activities of ellagic acid (a naturally occurring bioactive compound in berries, grapes, and nuts) was evaluated using human umbilical vein endothelial cells (HUVEC), normal human lung fibroblast cells HEL 299, Caco-2 colon, MCF-7 breast, Hs 578T breast, and DU 145 human prostatic cancer cells. Ellagic acid at concentration in the range 10-100 micromol/L did not affect the viability of normal fibroblast cells during a 24-hour incubation. An increase in adenosine triphosphate (ATP) bioluminescence of approximately 18-21% was observed in normal cells incubated with ellagic acid. In contrast, ellagic acid at 1-100 micromol/L dose-dependently inhibited HUVEC tube formation and proliferation on a reconstituted extracellular matrix and showed strong anti-proliferative activity against the colon, breast, and prostatic cancer cell lines investigated . The most sensitive cells were the Caco-2, and the most resistant were the breast cancer cells . Ellagic acid induced cancer cell death by apoptosis as shown by the microscopic examination of cell gross morphology. Ellagic acid induced reduced cancer cell viability as shown by decreased ATP levels of the cancer cells. After 24 hours incubation of 100 micromol/L of ellagic acid with Caco-2, MCF-7, Hs 578T, and DU 145 cancer cells, ellagic acid suppressed fetal bovine serum (FBS) stimulation of cell migration. The apoptosis induction was accompanied by a decreased in the levels of pro-matrix metalloproteinase-2 (pro-MMP-2 or gelatinase A), pro-matrix metalloproteinase-9 (pro-MMP-9 or gelatinase B), and vascular endothelial growth factor (VEGF(165)) in conditioned media. The results suggest that ellagic acid expressed a selective cytotoxicity and anti-proliferative activity, and induced apoptosis in Caco-2, MCF-7, Hs 578T, and DU 145 cancer cells without any toxic effect on the viability of normal human lung fibroblast cells . It was also observed that the mechanism of apoptosis induction in ellagic acid-treated cancer cells was associated with decreased ATP production, which is crucial for the viability of cancer cells.
PMID: 15590271 [PubMed - indexed for MEDLINE]
[xiii] Expert Opin Investig Drugs. 2004 Oct;13(10):1327-38.
From chemoprevention to chemotherapy: common targets and common goals.
Aggarwal BB, Takada Y, Oommen OV.
The University of Texas M.D. Anderson Cancer Center, Cytokine Research Section, Department of Experimental Therapeutics, PO Box 143, 1515 Holcombe Boulevard, Houston, Texas 77030, USA. email@example.com
Three decades of research have revealed that cancer is easier to prevent than to treat and that consumption of certain fruits and vegetables can reduce the risk of cancer. Whereas chemotherapy is designed to destroy cancer after it appears, chemoprevention involves the abrogation or delay in the onset of cancer. Regardless of whether a chemopreventive or chemotherapeutic approach is taken, cancer is a multifactorial disease that requires modulation of multiple pathways and multiple targets. Various molecular targets of chemoprevention are also relevant to the therapy of cancer. These targets include the activation of apoptosis; suppression of growth factor expression or signalling; downregulation of antiapoptotic proteins; suppression of phosphatidylinositol-3'-kinase/Akt, NF-kappaB, Janus kinase-signal transducer and activator of transcription and activator protein-1 signalling pathways; and downregulation of angiogenesis through inhibition of vascular endothelial growth factor expression, cyclooxygenase-2, matrix metalloproteinase-9, urokinase-type plasminogen activator, adhesion molecules and cyclin D1. Pharmacologically safe phytochemicals that have been identified from plants or their variant forms can modulate these molecular targets. These phytochemicals include genistein, resveratrol, dially sulfide, S-ally cysteine, allicin, lycopene, capsaicin, curcumin, 6-gingerol, ellagic acid, ursolic acid, betulinic acid, flavopiridol, silymarin, anethol, catechins and eugenol. Recent work has shown that these phytochemicals also can reverse chemoresistance and radioresistance. Because of their pharmacological safety, these agents can be used alone to prevent cancer and in combination with chemotherapy to treat cancer.
PMID: 15461561 [PubMed - in process]
[xiv] Crit Rev Food Sci Nutr. 2004;44(1):1-17.
Potential impact of strawberries on human health: a review of the science.
Nutritional Sciences, University of Illinois , USA .
Epidemiological studies have noted a consistent association between the consumption of diets rich in fruits and vegetables and a lower risk for chronic diseases including cancer and cardiovascular disease. There is accumulating evidence that much of the health-promoting potential of these plant foods may come from phytochemicals, bioactive compounds not designated as traditional nutrients. In strawberries, the most abundant of these are ellagic acid, and certain flavonoids: anthocyanin, catechin, quercetin and kaempferol. These compounds in strawberries have potent antioxidant power. Antioxidants help lower risk of cardiovascular events by inhibition of LDL-cholesterol oxidation, promotion of plaque stability, improved vascular endothelial function, and decreased tendency for thrombosis. Furthermore, strawberry extracts have been shown to inhibit COX enzymes in vitro, which would modulate the inflammatory process. Individual compounds in strawberries have demonstrated anticancer activity in several different experimental systems, blocking initiation of carcinogenesis, and suppressing progression and proliferation of tumors. Preliminary animal studies have indicated that diets rich in strawberries may also have the potential to provide benefits to the aging brain.
PMID: 15077879 [PubMed - in process]