Townsend's New York Observerby Marcus A. Cohenmarcusacohen@aol.com

Compounds in Fruits andVegetables that Protect AgainstCancer and Heart Disease:Recent Research

I've published four columns in the past year aboutphysicians closely associated with nutraceuticals. Threecolumns were devoted to interviews with Stephen A.DeFelice, MD, the "father" of a mainstream initiativeto establish a separate, quicker approval track fornutraceuticals.' The last column paid tribute to LouisLasagna, MD, an authority on clinical pharmacology andcontrolled clinical trials.-

Dr. DeFelice coined the term "nutraceutical" in 1989,while searching for a word or sound-bite phrase thatembraced foods and food compounds, dietary supplements,herbal remedies, etc., all of them potentially beneficial inprevention and treatment of disease. Through the 1990s,Dr. DeFelice and the non-profit organization he chairs, theFoundation for Innovation in Medicine (FIM), sponsorednutraceutical conferences, hoping to catch the attentionof Congress. In 2000, Representative Frank Pallone (D-NJ)introduced the Nutraceutical Research and Education Act(NREA) in the House.

Dr. Lasagna, a member of FIM's board of directors,made memorable presentations at these conferences onconsensus of opinion among medical experts and the risksinvolved in using new drugs.

The only nutraceutical referred to in those four columnswas carnitine. Dr. DeFelice had conducted seminal studieson this naturally occurring substance in the mid-1960s, andover the following decades, he has continued to investigatethe protective effects of carnitine in the heart and body.

FIM's conferences included presentations on manynutraceuticals. This column reports selectively on studiesin the past two years on a number of foods and compoundsin food that show promise in preventing and treating majordiseases.

Eat RedSour cherries and tomatoes are rich in pigments that

appear to reduce inflammation linked to hardening ofthe arteries. Cherry-enriched diets have lowered bloodcholesterol and triglycérides in animal studies, according toa study conducted by a team of scientists at the Universityof Michigan in 2007.^ One of the authors of this study.Dr. Steven F. Boiling, a cardiac surgeon at the Universityof Michigan Cardiovascular Center, who also heads theCardioprotection Research Laboratory at the University ofMichigan, had the lead quote in a news story about thesefindings;''

We've always known fruits and vegetables were "healthy,"but now we're beginning to better understand preciselywhy...Researchers are uncovering the unique potential forplant compounds, like those in cherries, to affect multipleheart health factors. For cherries, we're learning the benefitsmay come from effects on both cholesterol levels andinflammation.

Sounds like good news for people seeking foods thatpromote health. A recent survey revealed most respondentswould prefer to eat or drink foods with health-promotingproperties, with heart health topping the list, if they knewit could potentially limit the amount of medication theyneeded to take.'

Research on Phytochemicals to Prevent Cancer IsBooming

An editorial last year in Seminars in Cancer Biologynoted that a recent search of PubMed turned up hundredsof publications on phytochemicals and prevention ofcancer.̂ In its opening sentence, the editorial stated that "theimportance of cancer prevention continues to grow due to

106 TOWNSEND LETTER - MAY 2008

poor prognosis of advanced cancers, inadequate therapeuticresponses, and toxicities associated with chemo- and radio-therapies." Other factors in the growth of scientific literatureon phytonutrients, according to the editorial, includedthe limited success of educational programs in reducingtobacco use and exposure to environmental and workplacecarcinogens.

Consequently, the National Institutes of Health (NIH)and other health organizations have been turning more andmore to setting dietary guidelines for cancer preventionand funding studies on how dietary supplements couldaffect the initiation and progression of cancer. Lately, thesestudies have concentrated on protective effects believed tocome from the high levels and variety of phytonutrients indark-colored fruits and vegetables.

Following the prevailing theory of carcinogenesis, theeditorial explained;

Carcinogenesis is a multifaceted process involvinginitiation, promotion, and progression...Opportunities existfor intervention at each of these stages by phytonutrients.Since tumor initiation typically involves irreversible geneticdamage, prevention of initiation by phytonutrients mayinvolve (i) inactivation of the carcinogen, (ii) inhibition ofphase I carcinogen activating enzymes, and/or (iii) inductionof phase II detoxifying enzymes. Thus, phytonutrients mayhave multifunctional mechanisms and moiecular targets incancer prevention.

The rest of the editorial specifies some of the mechanismsand molecular targets. The last paragraph ambitiously andoptimistically projects the goals of phytonutrient research:"The future is ripe for identifying fruits and vegetables andindividual phytonutrients with cancer-preventing activity.As we identify the molecular mechanisms and target bywhich individual phytonutrients prevent cancer, we may beable to improve upon nature by formulating phytonutrientcocktails for specific cancers and individual susceptibilityand risk" {emphasis added).

Implicit in improving on nature is the expectation thatthe cocktail formulas wil l be patentable, developed bydrug companies for colossal profits, perhaps available onlyby prescription if the FDA classifies them as "new drugs"that require pre-marketing testing, and outrageously moreexpensive than buying the fruits and vegetables at theproduce market - and maybe not an improvement at all, ifthe phytonutrients are served up as isolates from the wholefruit or vegetable.

Whole Berries in Cancer PreventionA paper appearing in the Journal of Agricultural and

Food Chemistry in February 2008/ reviewed recentlypublished studies of whole berries. Under the term "wholeberries," the author included single and combined berryformulations, berry extracts, freeze-dried powders, purifiedfractions, and beverages. The paper focused on berriescommonly eaten in North America: blackberries, blackraspberries, red raspberries, cranberries, blueberries, andstrawberries.

Berries, the author said, make up the largest percentageamong small, soft-fleshed, colorful fruits in the NorthAmerican diet. "Overwhelming evidence suggests that...berry fruits may have beneficial effects against several typesof human cancers."^That anticancer potential, according tothe author (referring to a growing body of studies), relatesto numerous berry phytochemicals whose bioactivlty isdiverse.

Berry phytochemicals can reduce or repair damagefrom inflammation and oxidative stress. They can regulatesubcellular signaling pathways involved in angiogenesis,cancer proliferation, and apoptosis. (Angiogenesis is theformation and differentiation of blood vessels. Apoptosis isthe genetically determined process of cell self-destruction.)Berry phytochemicals may sensitize tumor cells tochemotherapy by inhibiting pathways that help tumorsresist treatment. Just eating berries may protect against thetoxic effects of chemotherapy and radiation.

As this is a scientific paper, the language is fittinglytechnical, making it a slow and tough read, but the coverageis comprehensive. Berry phytochemicals are specified, andtheir potential mechanisms of action, bioavailability, anddietary intake are discussed briefly. Anticancer studies aresectioned off into research in the laboratory {in vitro), testsin animals, and evaluation in humans.

In the "Summary and Future Perspectives' section, theauthor makes suggestions for further research, three ofwhich merit quoting:

Whether the chemopreventive potential of berry bioactivesis increased by complex interactions of multiple substanceswithin the natural food matrix of berry fruits, and/or incombination with phytochemicals from other foods, shouldbe investigated.

In addition, studies probing potential "herb-drug"interactions of berries and pharmaceutical drugs shouldbe investigated in carefully planned and controlled humanclinical studies.

Finally, interdisciplinary research is highly recommendedso that basic and preclinical studies can lead to translationalresearch (from laboratory to bedside).

"OptiBerry" Smoothies?Hopefully, "translational research" on berries won't

extend a decade or more before general application.Meanwhile, people keen on avoiding cancer might trya combination of extracts from bilberries, blueberries,cranberries, elderberries, raspberry seeds, and strawberries.A research article published in 2007 evaluated this particularselection of berry extracts, finding that it aaed synergisticaliyto produce safer and stronger effects compared with theberries individually and with other combinations of berryextracts.'* "OptiBerry," as the researchers called it, alsoshowed superior bioavailability.

All these berries contain anthocyanins, phytochemicalsthat color fruit blue, purple, or red. In recent studies,berry anthocyanins were mainly responsible for the high

TOWNSEND LETTER - MAY 2008107

Nutraceulicals for Cancer Prevention

Stephen A. DeFelice, MD

antioxidant activity demonstrated, according to theinvestigators. The investigators also found evidence in thestudies that berry anthocyanins have the potential to inhibitcancers of the colon, esophagus, liver, and oral cavitythrough several mechanisms of action.

Tested against Helicobacter pylori, a bacteriumestimated to infect half the population of the world,"OptiBerry" demonstratedbactericidal activity. Acausative factor in manygastrointestinal diseases,including duodenal ulcerand gastric cancer, H.pylori is growing resistantto the antibiotic of choiceagainst it, clarithromycin,so this finding offers anatural treatment for it.

Tested in hamsters foratherosclerosis, "OptiBerry"dramatically amelioratedits incidence. The researchers thought that the protectiveeffect in this cardiovascular condition is due partly to theantioxidant properties of anthocyanins. Other tests of theberries separately indicated that anthocyanins in bilberries,blueberries, and strawberries helped preserve brain andneurological functions that aging often impairs.

Other findings that rate mention include the following:bilberries, used in Europe for centuries to moderatediabetes, were shown to normalize diabetic hyperglycemiain rats. Bilberry and other berry anthocyanins can improvenight vision by enhanced generation of retinal pigments.In addition, these berry phytochemicals appear to increasecirculation in capillaries in the retina, decrease diabeticretinopathy and macular degeneration, and improve orprevent cataracts, glaucoma, and retinitis pigmentosa.In connection with berries and vision, the authors of the2007 research paper noted that British Air Force pilotsloaded up on bilberry jam before bombing missions duringWorld Wars I and II; the jam seems to have sharpened theireyesight, particularly on night runs.

Grape Phytochemicals Inhibit Key Enzyme in CancerPhytochemical constituents of dark-colored grapes work

synergistically to inhibit an enzyme central to proliferationof cancer cells. Two studies published in The Journal ofAgricultural and Food Chemistry in 2005 and 2006 providethe basis for this scientific finding.'" Utilizing advancedmolecular technology, the research team that conductedthese studies evaluated possible inhibitory effects ofgrape cell culture extract and subfractions on humanDNA topoisomerase 11 catalytic activity. Both studies, itshould be noted, were supported by the National Center

for Complementary and Alternative Medicine (NCCAM),established in the National Institutes of Health in 1997.

Topoisomerases are essential enzymes in cellproliferation in all organisms. They are involved inrecombination, replication, transcription, and translation ofDNA, and in chromosome dynamics. Topoisomerase II isvital in cell division and cell proliferation; mitosis cannotbe completed without it. Highly proliferative tumor cellsoften express 25-300 times higher levels of this enzymethan those of differentiated (normal) ceils.

A diverse group ofchemotherapeutic agents for cancerhas been developed to targettopoisomerase li. These inhibit theproliferative action of tumor eel is.Of course, they have undesirabletoxic side effects. The woridwideconsumption of grapes opens anopportunity to investigate theirphytochemical constituents as a"natural" means of preventing cancer.

Grape cell culture extracts arerich in flavonoids, among otherphytochemicals. These studies showedthat two classes of the varied flavonoid

family, proanthocyanidins and anthocyanins, are mainlyresponsible for the synergistic activity. More importantly,they revealed that the fractions of grape celi culture extractpowerfully inhibit the topoisomerase II enzyme through amechanism independent of antioxidant capacity.

Most importantly, the studies found that theantitopoisomerase II catalytic activity of TP-4 and TP-6, thetwo most potent fractions, was significantly greater thanactivity previously reported for recognized chemopreventiveagents such as ellagic acid, genistein, quercetin, andresveratrol.

In a project funded by the US Department of Agriculture,the researchers have since begun tracing where radio-labeled flavonoids from whole grapes congregate in rats. Theultimate aim of ail their studies is to determine reasonabledosages for the therapeutic consumption of fiavonoid-richgrapes.

Compounds that Color Fruits and Vegetables MayProtect Against Colon Cancer

Experiments on rats and on human cancer celis suggestthat anthocyanins appreciabiy siow the growth of coioncancer ceils. These findings were presented at the nationalmeeting of the American Chemical Society in BostonAugust 19th, 2007." Fruits and vegetables with intenseiydeep coior were seiected for the experiments becausethey are the richest in anthocyanins. Common and exoticfruits and vegetables were in the mix, including bilberries,chokeberries, elderberries, grapes, purple carrots, andpurple corn. Some of these plants are commerciaiiy used asfood coiorings.

108 TOWNSEND LETTER - MAY 2008

Whether in laboratory dishes or inside the human body,all edible plants high in anthocyanins, the investigatorssuggested, may inhibit the growth of colon cancer cells.They also suggested that anthocyanins might protectagainst several other forms of gastrointestinal cancer. Theprobable reason, according to the researchers is that thebloodstream absorbs little anthocyanin. A large proportiontravels through the gastrointestinal tract, where these tissuesdo absorb this phytocfiemical.

In additional experiments, the researchers discoveredthat anthocyanin pigments from black carrots and radishesslowed the growth of cancer cells anywhere from 507o to807o. Pigments from chokeberries and purple corn not onlycompletely stopped cancer cell growth, they also killedroughly 207o of the cancer cells while having little adverseeffect on normal cells.

Studies on rats induced with colon cancer cellsdemonstrated similar beneficial results. Fed a daily diet ofanthocyanin extracts from either bilberries or blackberries,these animals bad signs of cancer reduced by 70% and607o, respectively, compared to control rats. There wasscarcely any effect on normal cells. (Extracts from bilberriesand blackberries bave proven safe in commercial use asflavorings or to make jams and juices.)

The foods tested contain many compounds, said theresearchers. Scientists are only beginning to identify themand piece out which ones offer the best health benefits.There are 600 different anthocyanins,and investigation has merely scratchedthe surface of grasping how the bodyabsorbs and uses the.se differentstructures.

Nutraceuticals for Cancer Prevention

castration.") But androgen-insensitive prostate cancer cellsare capable of undergoing apoptosis, so the discoveryof novel means to get prostate cancer cells to commit"suicide," regardless of their response to hormones, is abusy avenue of research.

Enter pectin, a polysaccharide constituting roughly 307oof primary cell walls in higher plants - and thus a dietarycomponent of all fruits and vegetables. A study publishedin Glycobioiogy in 2007 demonstrated that pectininduces apoptosis in hormone-responsive and hormone-independent prostate cancer cells.'- Their study, claim theauthors, is the "first extensive analysis correlating structuralfeatures of pectin with apoptosis-inducing activity in cancercells."

Summarizing previous findings on pectin and cancer byother researchers, the authors referred to reports dating from1992 that pectin has indicated anti-carcinogenic activity incolon, lung, myeloma, skin (melanoma), and even prostatecancers. (Oral administration of pH-modified citrus pectinreduced metastatic prostate cancer in rats.) They thoughtit "noteworthy that those anti-metastatic effects of pectinoccurred in the absence of cell toxicity." Let's highlightthose effects in late-stage cancer: unlike chemotherapy.

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Pectin Causes Prostate Cancer Cellsto Commit "Suicide"

Normal cells mature to performthe functions nature intended them toperform in the organ or the place inthe body to which they belong. Thisprocess is known as differentiation.Cancer cells don't grow up but keepproliferating, behaving as though theyare immortal.

Some conventional chemotherapyand anti-hormone treatments forcertain cancers are designed to induceapoptosis. Prostate cancer - in men,the commonest malignancy and thesecond-leading cause of death -creates a treatment challenge, becausethere are prostate cancer cells forwhich androgen deprivation therapycan induce apoptosis and androgen-insensitive cells that remain unaffected.{Androgens are male sex hormones,and androgen deprivation treatmentis referred to casually as "chemical

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TOWNSEND LETTER - MAY 2008109

Nutraceuticals for Cancer Prevention

pectin is non-toxic. The authors, in an aside of sorts, addedthat pectin has been shown to lower cholesterol andglucose levels in humans.

According to the authors, pectin is a very complexmolecule, potentially able to bind to several cell sites andproduce several different cellular responses at the sametime. The investigators analyzed three different typesof commercially available pectin, observing significantdifferences in anti-cancer activity. Heat treatment increasedthe activity. Exposing prostate cancer cells to pectin underlaboratory conditions reduced the number of cells by asmuch as 40%.

In conclusion, the authors called for more studiesto support use of specific pectin supplements, advisingAmericans simply to eat lots of fruits and vegetables,which by itself would supply lots of pectin and provideother naturally occurring beneficial phytochemicals. "Anapple a day keeps the doctor away' - there lots of pectinin an apple. Old wives' tale, folk wisdom, or empiricalacceptance, there's now some science behind the adage.

Same Old, Same Old...By citing studies published between 2005 and 2008,

this column may have created the impression that researchon phytochemicals and cancer prevention is a relativelylate development. But the peer-reviewed literature ondiet and disease in general extends back more than halfa century. Herbert F. Pierson, PhD, published one paperthat is especially pertinent to phytochemicals in 1993J^In the early 1990s, Dr. Pierson headed the phytochemicaldivision of the Chemoprevention section in the NationalCancer Institute (NCI). His division specialized in "DesignerFoods" - a term spawned within the NCI oriented towardresearch on the connections between phytochemicalconstituents in foods and dietary supplements and cancerprevention.

The following paragraph from that paper describes oneof four approaches to designer food development:

One approach...involves the evaluation of humangastrointestinal absorption of food phytochemicals(physiological approach). Citrus is used as a model forthis approach in that citrus is a rich source of antioxidants,antimutagens, anticarcinogens, and chemoprotectivecompounds. The first step is to chemically fingerprint themajor classes of total citrus phytochemicals in pure orangeiuice (free plus bound phytochemicals). After determiningthe concentration of the top twenty antioxidative andantimutagenic citrus phytochemicals in pure orange juice,the standardized juice (where eight ounces representsequivalence to four oranges) is fed to healthy humans whoare subsequently evaluated for the presence of the twentyphytochemicals in their blood sera. Analysis reveals thateight out of twenty citrus phytochemicals are absorbed andmeasurable in sera. Next, a redesigned orange juice is made

by fractioning and concentrating the eight absorbable citrusphytochemicals in pure orange juice so that eight ouncesrepresents the equivalence of perhaps twenty oranges.There is no legal restriction on anyone consuming twentyoranges daily, but if you construct a juice beverage wheretwenty orange equivalents of absorbable phytochemicals arepresent in an eight-ounce serving, it could be considered bythe FDA to be a drug. It will certainly be considered a drugif the natural phytochemica! enrichment with flavonoids isdesigned to chelate and help eliminate lead from the bodiesof school children or inhibit aldol reductase, the cataract-causing enzyme in the eyes of diabetics.

Uh, oh! What would the FDA do if the scientists whoreported on "OptiBerry" interested a food company inmarketing the blend and the company slapped a labelon the bottle saying there is scientific evidence that"Optiberry " prevents cancer, kills H. pylori, works againstcardiovascular disease, etc.?

A rational plan to cover uninsured Americans whileslashing the cost of health care might include ways toincrease consumption of tbe sort of phytochemicalsdiscussed in this column - ways not limited to the uninsured.With a presidential election upcoming this fall, and thefront-running Democratic contenders offering competingplans for universal health coverage, the next column willpropose several means and routes around obstacles to therealization of such proposals.

Notes1. Cohen M. Townsend's New York Observer. Jownsend Letter. |uly and Oclober

2007. January 2008.2. Cohen M. Townsend's New York Observer. Townsend ieiier. April 2008.3. Seymour EM, et al, Cherry enriched diets reduce metabolic syndrome and

oxidative stress in lean Datil-SS rats. Presented at the Experimental Biology 2007Conference, Washington, DC, April 30. 2007. in mini-symposium 225, DietaryBioactive Compounds: Chronic Disease Risk Reduction. Meeting abstractpublished in M5ES tourna/. 2O07;21:225-8.

4. Eating red may prevent dropping dead. Available at: www.UPI.com. AccessedFebruary 1, 2008.Also Celebrate American heart monthby eating red. Availableat: www.reuters.com. Accessed January 28. 2008.

5. Survey of 1.507 adults age 45 and older by the Caravan Services, OpinionResearch Corporation, November 2007, on behalf of the Cherry MarketingInstitute.

6. D'Ambrosio SM. Piiytonutrients: A more natural approach toward cancerprevention. Editorial. Seminars in Cancer Biology- 17 (2007) 345-346.

7. Seeram NP. Berry fruits for cancer prevention: current status and futureprospects, I. Agrie. Food Chem. 56: 630-635, 2008.

S. Ibid.9. Zafra-Stone S, et al, Beny anthocyanins as novel antioxidants in human health

and disease prevention. Mol. Nutr. Food Res. 2007, 51: 675-683.10. )o l , etal. Effects of grape cell culture extracts on human topoisomerase II

catalytic activity and characterization of active fractions, /. Agrie. Food Chem.2005; 53, 2489-2498.Jo J, et al. Catalytic inhibition of human DNA topoisomerase It by interactions ofgrape cell culture polyphenols, ,/. Agrie. Food Cftem. 2006; 54. 2083-2087.

11. EurekAlert.org; 8/19/07.12. lackson CL et al. Pectin induces apoptosis in human prostate cancer cells:

correlation of apoptotic function with pectin structure, C/yco6io/ogy. 2007; 17(8): 805-619.

13. Pierson HF )r. Food phytochemical pharmacology: the basis for designer fooddevelopment. Regulatory Afíairs. 1993;5: 219-222.

110 TOWNSEND LETTER - MAY 2008