polyphenols in human health and disease || polyphenols and skin cancers

C H A P T E R

49

Polyphenols and Skin CancersYashwant Kumar* and Alka Bhatia†

*Department of Immunopathology, Post Graduate Institute of Medical Education & Research, Chandigarh, India†Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education & Research,

Chandigarh, India

1. INTRODUCTION

Polyphenols are natural, organic chemicals charac-terized by the presence of multiple phenol structuralunits. Though they are widely distributed in a vegetar-ian diet, their strong antioxidant effects and other ben-efits have only recently been recognized. The reasonfor the delay on research into polyphenols is theremarkable diversity and complexity of their chemicalstructures.1 Much of the information on the effects ofpolyphenols in health has been obtained from in vitroor animal studies. Results of these studies stronglysupport the beneficial effects of one or other polyphe-nols in several health-related problems.2 The protectiverole of polyphenols has been widely studied in cardio-vascular disease, osteoporosis, diabetes, and neurode-generative diseases.3,4 Dietary polyphenols have alsobeen claimed to provide protection against the risks ofdifferent types of cancer. However, studies supportingthe role of dietary polyphenols in skin cancers arescarce and more work is needed to establish a linkbetween them.3

2. POLYPHENOLS: TYPES AND DIETARYSOURCES

Several hundred different polyphenols have beenidentified in plants. The majority of polyphenols con-sumed are obtained from fruits, beverages, cereals,chocolate, and dry legumes and are all derivatives ofthe common intermediate phenylalanine (Table 49.1).8,9

There are different classes of polyphenols based ontheir general chemical structures, with the commoncharacteristic being at least one aromatic ring structure

with one or more hydroxyl groups (Figure 49.1). Thesecommon dietary polyphenols include phenolic acids,flavonoids, catechins, stilbenes, proanthocyanidins,ellagitannins and anthocyanins.10

2.1 Phenolic Acids

Phenolic acids are major dietary polyphenols andexist in two forms: as derivatives of benzoic acid, andas derivatives of cinnamic acid. The hydroxybenzoicacid content of edible plants is generally very low, theexception being in certain red fruits, black radishes, andonions.11 The hydroxycinnamic acids are more com-mon; however, they are rarely found in the free form,except in processed foods that have undergone freez-ing, sterilization, or fermentation. The bound forms areglycosylated derivatives or esters of quinic acid, shiki-mic acid, and tartaric acid. Hydroxycinnamic acid isfound in all parts of the fruit, although the highest con-centrations are present in the outer parts of ripe fruits.Their concentration generally decreases during thecourse of ripening, but total quantity increases as thefruit increases in size. Fruits having the highest content(blueberries, kiwis, plums, cherries, and apples) contain0.5�2 g hydroxycinnamic acids/kg fresh weight.12

Caffeic acid generally contains the most abundant phe-nolic acid and represents 75�100% of the total hydroxy-cinnamic acid content of most fruits. Often it isesterified with quinic acid, as in chlorogenic acid, whichis the major phenolic compound in coffee (a single cupmay contain 70�350 mg chlorogenic acid).13

Another common phenolic acid is ferulic acid, mostabundant in cereal grains. In wheat grain it comprisesB0.8�2 g/kg dry weight and may represent up to 90%of total polyphenols.14 It is found chiefly in the outer

643Polyphenols in Human Health and Disease.

DOI: http://dx.doi.org/10.1016/B978-0-12-398456-2.00049-9 © 2014 Elsevier Inc. All rights reserved.

http://dx.doi.org/10.1016/B978-0-12-398456-2.00049-9

TABLE 49.1 Important Dietary Sources of Polyphenols

Phenolic acid Flavonoids Lignans Stilbenes

AppleArtichokeAubergineBlackberryBlackcurrantBlueberryCherryChicoryCiderCoffeeCorn flour

Flour: wheat,rice, oatKiwiPearPlumRaspberryRed winePotatoStrawberryTeaTurmeric

AppleApricotBlackcurrantBlack grapeBlack tea infusionBeans, green or whiteBlueberryBroccoliCapsicum pepperCeleryCherryGrapefruit juiceGrape seedsGreen tea infusionCurly kale

Lemon juiceLeekMilk thistleMisoOnionOrange juiceParsleyRed wineSoybeans, boiledSoy flourSoy milkTempehTofuTomatoTurmeric

ApricotBrassica vegetablesBroccoliBrussels sproutCauliflowerCurly kaleCashewFlaxseedFrench beanGarlic

MuesliPeachRed cabbageRyeSauerkrautSesame seedStrawberrySunflower seedWheatWhite cabbage

BlueberriesEastern white pineGrapeKnotweedMulberriesPeanutsRaspberriesRed wineScots pineSoyTea

References Yang et al.,2 Majo et al.,5 Kang et al.,6 and Schwarz.7

OHO

OH

OH

OHHHOH

OH

OH

O

Phenolic acid (chlorogenic acid)

O

O

HO

OH

OH

OH

OH

Flavonol (quercetin)

OHO

OH

OH

OH

Flavanol (catechin)

O

O

HO

OH OH

Isoflavone (genistein)

O

O

HO

OH

OH

HMH

Flavanone (hesperetin)

+OHO

OH

OH

OH

OH

Cyanidin (anthocyanidin)

OHOOH

OH

OOH

OH

OH

OHOH

HO

OH

OH

OH

HO OHO

OH

Flavanol (procyanidin trimer)

OH

OH

CH2OH

CH2OH

Lignan (enterodiol)

HO

HOOH

Stilbene (resveratrol)

FIGURE 49.1 Biochemical structures of common polyphenols.

644 49. POLYPHENOLS AND SKIN CANCERS

6. DIVERSE DISEASE AND PHYSIOLOGICAL STATES MODIFIED BY POLYPHENOLS

parts of the grain. The aleurone layer and the pericarpof wheat grain contain 98% of the total ferulic acid. Upto 10% of ferulic acid is found in soluble free form inwheat bran. The ferulic acid content of different wheatflours is thus directly related to the levels of sieving,and bran is the main source of polyphenols. Rice andoat flours contain approximately the same quantity ofphenolic acids as wheat flour (63 mg/kg), while thecontent in maize flour is about three times higher.15

2.2 Flavonoids

Flavonoids are further classified as flavones, flavo-nols, flavanols (catechins and proanthocyanidins), fla-vanones, isoflavones, anthocyanins, and tannins.Flavonols are the most ubiquitous flavonoids in foodsand mainly present as quercetin and kaempferol. Theyare generally found in low concentrations(B15�30 mg/kg fresh weight). The richest sources areonions (up to 1.2 g/kg fresh weight), curly kale, leeks,broccoli, and blueberries. Red wine and tea also containup to 45 mg flavonols/L. Flavonols predominantlyaccumulate in the outer and aerial tissues (skin andleaves) because their biosynthesis is stimulated bysunlight.

Flavones are much less common than flavonols andconsist chiefly of glycosides of luteolin and apigenin.The only known important edible sources of flavonesare parsley and celery.

Flavanones are found in tomatoes and certain aro-matic plants such as mint but their rich sources are cit-rus fruits. Flavonones are present in the form ofnaringenin in grapefruit, hesperetin in oranges, anderiodictyol in lemons. They are generally glycosylatedby a disaccharide which imparts a bitter taste (such asnaringin in grapefruit), or a rutinose, which is flavor-less. Orange juice contains between 200 and 600 mghesperidin/L and 15�85 mg narirutin/L, and a singleglass of orange juice may contain up to 40 to 140 mgflavanone glycosides.16

Isoflavones are flavonoids having structural resem-blance to estrogen. Isoflavones are not steroids butthey have hydroxyl groups in positions 7 and 4 in aconfiguration analogous to that of the hydroxyls in theestradiol molecule. This gives pseudo hormonal prop-erties to them such as their ability to bind to estrogenreceptors. They are found almost exclusively in legu-minous plants. Isoflavones mainly contain three mole-cules: genistein, daidzein, and glycitein. Soy and itsproducts are their main source in diet. Soybeans con-tain 580�3800 mg isoflavones/kg fresh weight, andsoymilk contains 30�175 mg/L.17,18

Flavanols exist in monomer (catechins) or polymerform (proanthocyanidins). Catechin and epicatechin

are important flavanols in fruits, whereas gallocate-chin, epigallocatechin, and epigallocatechin-3-gallate(EGCG) are present in abundance in green or blacktea, seeds of leguminous plants, and grapes. In con-trast to other flavonoids, flavanols are not glycosylatedin foods. Proanthocyanidins, also known as “con-densed tannins,” are dimers, oligomers, and polymersof catechins. By forming complexes with salivary pro-teins, they give the astringent character to fruit(grapes, peaches, kakis, apples, pears, berries, etc.),beverages (wine, cider, tea, beer, etc.), and bitterness tochocolate.19 This astringency changes with maturationand generally disappears after the fruit reaches itsripeness.

Anthocyanins are pigments dissolved in the vacuolarsap of flowers and fruits, to which they impart a pink,red, blue, or purple color.20 They are found in cereals,leafy and root vegetables (aubergines, cabbage, beans,onions, radish), and red wine but are most abundantin fruits. They are mainly present in the skin, exceptfor certain types of red fruits, in which they also occurin the flesh (cherries and strawberries).

Tannins are large molecules and are found in largequantities in red wine, tea and nuts.

2.3 Lignans

Lignans are composed of two phenylpropane units.Linseed is its richest dietary source containing secoiso-lariciresinol (up to 3.7 g/kg dry weight) and low quan-tities of matairesinol. Other cereals, grains, fruits, andcertain vegetables also contain traces but the concen-tration in linseed is B1000 times as high as in otherfood products.21

2.4 Stilbenes

Stilbenes are found in minute quantities in the diet.Resveratrol, one of the stilbenes, has been extensivelystudied due to its anticarcinogenic effects. It is foundin low quantities in red wine (0.3�7 mg aglycones/Land 15 mg glycosides/L). However, because of itspresence in only trace amounts in a routine diet, anyprotective effect of this molecule is unlikely at normalnutritional intake.22

3. FACTORS AFFECTING AVAILABILITYOF POLYPHENOLS IN DIET

Polyphenols in food are generally present as poorlycharacterized, complex mixtures. Apples, for example,contain epicatechin or procyanidin, chlorogenic acid,glycosides of phloretin, several quercetin glycosides,

6453. FACTORS AFFECTING AVAILABILITY OF POLYPHENOLS IN DIET


and anthocyanins such as cyanidin 3-galactoside in theskin of certain red varieties.

Environmental factors also have a major effect onpolyphenol content. These factors may be pedoclimatic(soil type, sun exposure, rainfall) or agronomic (culturein greenhouses or fields, biological culture, hydroponicculture, fruit yield per tree, etc.). Exposure to light andthe degree of ripeness significantly affect the concen-tration and proportion of different polyphenols.Generally, phenolic acid concentrations decrease dur-ing ripening, while anthocyanin concentrationsincrease.12 Storage may affect the content of thosepolyphenols that are easily oxidized. Such changesmay be either beneficial (as is the case with black tea)or harmful (browning of fruit) to consumer acceptabil-ity. Storage of wheat flour results in marked loss ofphenolic acids.14

Methods of culinary preparation can also alter thepolyphenol content of foods. For example, simple peel-ing of fruit and vegetables can eliminate a significantportion of polyphenols since these substances are oftenpresent in higher concentrations in the outer parts thanin the inner parts. Cooking may also have a detrimentaleffect. Onions and tomatoes lose between 75 and 80% oftheir initial quercetin content after boiling for 15 min,65% after cooking in a microwave oven, and 30% afterfrying.23 Steam cooking of vegetables avoids leaching,hence is preferable.

Industrial food processing also affects polyphenolcontent. As with fruit peeling, dehulling of legumeseeds and decortications and bolting of cereals canresult in loss of some polyphenols. Grinding duringthe process of making a jam of plant tissues may leadto significant oxidative degradation. Manufacturedfruit juices thus have low flavonoid content. Also, mac-eration facilitates diffusion of polyphenols in juice, andred wine during its vinification. This macerationaccounts for the fact that the polyphenol content of redwines is 10 times as high as that of white wines and isalso higher than that of grape juice.24

4. DIETARY INTAKE AND METABOLISMOF POLYPHENOLS

A vegetarian diet rich in fruits and vegetables con-tains sufficient amounts of polyphenols. Though, tillnow, no specific recommendations regarding dailyintake of polyphenols have been made, the expectedrange is 500�1000 mg/day.25 This is easily achieved byan intake of fruits and vegetables in the daily diet. Ascompared to other classes of phytochemicals andknown dietary antioxidants, the consumption of poly-phenols is actually much higher. It could be B10 times

higher than the intake of vitamin C and B100 timeshigher than the intake of vitamin E and carotenoids.3

The effectiveness of polyphenols, however, dependson their metabolism and bioavailability. Most polyphe-nols in foods are present in the form of esters, glyco-sides, or polymers and cannot be absorbed in theirnative form. Small molecules like catechin monomersare easily absorbed but larger molecules like proantho-cyanidins and EGCG are poorly absorbed and needprior hydrolysis by the intestinal enzymes or by thecolonic microflora.26 During the course of absorption,polyphenols are conjugated in the small intestine andthereafter in the liver. This process includes methyla-tion, sulfation, and glucuronidation which facilitatetheir biliary and urinary elimination by increasingtheir hydrophilicity. Polyphenols are then secreted viathe biliary route into the duodenum, where they arefurther subjected to the action of bacterial enzymes,especially β-glucuronidase, in the distal portions of theintestine and then finally reabsorbed. This enterohepa-tic recycling leads to a longer presence of polyphenolswithin the body.8,27 Also, the metabolites that reachthe blood and target organs may differ from theirnative substances in terms of biological activity.

5. OVERVIEW OF SKIN CANCERS

Tumor development is a complex multistage phe-nomenon, characterized by the loss of cell differentia-tion, uncontrolled cell proliferation, invasion into hosttissue, and evasion of the host immune response.28

The process of carcinogenesis involves the stepwiseaccumulation of genetic changes, ultimately leading tomalignancy.11 There are three main steps: initiation,promotion, and progression. During this processtransformed cells become: (1) self-sufficient in growthsignaling and immortal, (2) unresponsive to anti-proliferative signals, (3) escape apoptosis, (4) induceand sustain angiogenesis, and (5) invade and metasta-size in the host tissue.13 This sequence of events pre-sents many opportunities for intervention, with theaim of preventing, slowing down or reversing thetransformation process.12

The skin is the largest organ of the body, and itsmain role is to act as a barrier and protect internalorgans against the deleterious effects of various harm-ful substances, predominantly environmental pollu-tants and solar ultraviolet (UV) radiation.29 Skin ismade up of different types of cells and histologically ithas been divided into the epidermis (outer layer) anddermis (inner layer). The epidermis contains: theuppermost flat and scaly cells called squamous cells;rounded cells called basal cells; and melanocytes, cells



that provide color to the skin. The dermis containsnerves, blood vessels, and sweat glands.

The cancer cells may arise from any of the skin cellsand are named accordingly. The basal cell carcinomas(BCCs) and squamous cell carcinomas (SCCs), collec-tively known as nonmelanomatous skin cancers(NMSCs), and malignant melanomas are by far themost common forms of skin cancers in humans.30

Solar keratoses (actinic keratoses) and Bowen’s disease(carcinoma in situ), though not true invasive tumors,are related to both NMSCs as well as melanoma.

The likelihood of their development depends on anindividual’s genotypic and phenotypic characteristicsand subsequent exposure to environmental risk fac-tors. Skin color contributes most to the risk of malig-nancy and fair skinned people are more prone todevelop these tumors. Other important risk factorsinclude the presence of a large number of moles (bothcommon acquired and dysplastic), freckling, and fam-ily history, i.e., melanoma is more common in thosehaving a personal or family history of dysplastic nevi.The major environmental risk factor for all skin canceris sunlight, particularly UV radiation.28,29 Other riskfactors include diet, smoking, hair dyes, fluorescentlighting, hormone therapy, and stress. A few studiesalso suggest that use of sun beds or tanning parlorscan increase the risk of melanoma.31

Incidences of skin cancer have increased dramati-cally worldwide. This could be because of an increasein environmental pollution and increased exposure toUV radiation. UV radiation induces both direct andindirect biologic effects, including DNA damage, oxi-dative stress, depletion of cutaneous defense system,inflammation, immunosuppression, and prematureaging of the skin all playing an important role in thegeneration and maintenance of neoplasms.32,33 UVexposure also leads to the generation of singlet oxygen,hydrogen peroxide (H2O2), and hydroxyl radicals thatcan cause damage to cellular proteins, lipids andDNA.34 Factors that influence carcinogenic effects ofUV exposure include higher altitude, close proximityto the equator, outdoor occupation, recreational activ-ity, and the use of tanning parlors.29

6. POLYPHENOLS AND SKIN CANCER

Though further research is required still, dietarypolyphenols have gained considerable attention for theprevention of skin cancer. Both in vitro and in vivo sys-tems have shown their protective effects on biochemi-cal processes induced or mediated by UV radiation,suggesting that the routine use of polyphenols, bothtopically and orally, may provide effective protection

against UV radiation and, in turn, skin cancers(Figure 49.2, Table 49.2).5,6,28,35,36

6.1 Pathophysiological and Molecular Targets ofPolyphenols in Skin Cancer

6.1.1 Protection from UV Radiation

Studies have shown that polyphenols in green andblack tea prevent penetration of UV radiation into skinand can act as a sunscreen. They also reduce inflam-matory, oxidative stress and DNA damaging effects ofUV radiation in the skin. Thus, local application ofpolyphenols is believed to have photoprotectiveproperties.38

6.1.2 Anti-Inflammatory Effects

Cyclooxygenase-2 (COX-2), an enzyme responsiblefor the production of inflammatory mediators prosta-glandins (PG) and their metabolites, i.e., PGE2, PGF2αand PGD2, is overexpressed in skin cancers. It isinduced by UV radiation and is detectable in SCC andBCC.39,40 This induction of COX-2 is associated withhyperplastic response, myeloperoxidase activity, andleukocyte infiltration into the skin. In animals, topicalapplications of stilbenes, proanthocyanidins and flavo-noids have been found to reduce all of these reactionsin the skin.41,42 UV radiation is also known to activatetumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β)and IL-6. These pro-inflammatory cytokines contributeto tumor promotion.43 Polyphenols have been shownto reduce the levels of these pro-inflammatory cyto-kines in UV-exposed skin.44

6.1.3 Antioxidant Effects

The skin has its own antioxidant defense mecha-nism that protects it from the harmful effects of vari-ous environmental pollutants and carcinogens,including UV radiation that generates oxygenatedmolecules known as “free radicals.” However, in thecase of extensive or chronic exposure to the above, theantioxidant activity may become weaker or inefficient,leading to immunosuppression, premature aging, andthe development of skin cancers. Persistent exposureto carcinogens leads to epidermal lipid peroxidationand excessive infiltration of leukocytes into the skin,thereby leading to overproduction of nitric oxide (NO),hydrogen peroxide (H2O2) and other reactive oxygenspecies (ROS), which creates a state of oxidative stress.Polyphenols protect cell constituents against oxidativedamage through scavenging these free radicals. Theantioxidant activity of polyphenols is due to theirinteraction with metal ions both in vitro and in vivo.Metal ions are the main cause of ROS generation andplay an important role in the generation of oxidative



stress, DNA damage and cell death.29 Cells respond topolyphenols mainly through direct interaction withreceptors or enzymes involved in signal transduction,which may result in a modification of the redox statusof the cell and trigger a series of redox dependent reac-tions.45,46 Polyphenols such as EGCG obtained fromgreen tea have been shown to inhibit leukocyte infiltra-tion and their ROS production, epidermal lipid peroxi-dation as well as the production of inducible NOsynthase and H2O2, both in humans as well asanimals.47�49

Another effect of oxidative stress is protein damage.Toxic carbonyl groups in proteins derived after oxida-tion of certain amino acids like lysine, arginine andproline are produced in excess during chronic expo-sure to UV radiation and lead to skin damage. Topicalapplication of EGCG or grape seed polyphenols hasbeen shown to inhibit protein oxidation in the skin ofmice.50�52 It has been shown to inhibit UV radiation-induced depletion of antioxidant defense enzymessuch as catalase, glutathione peroxidase, superoxidedismutase, and glutathione.53 EGCG has also beenshown to inhibit radiation-induced intracellular release

of H2O2 and oxidation stress-mediated phosphoryla-tion of epidermal growth factor receptor (EGFR) andmitogen activated protein kinase (MAPK) and nuclearfactor kappa B (NF-κB) signaling pathways.51,52

Besides the antioxidative action, pro-oxidant effectsof polyphenols such as DNA degradation in the pres-ence of metal ions like copper have recently beendescribed.54 As antioxidants, polyphenols mayimprove cell survival; as pro-oxidants, they mayinduce apoptosis and prevent tumor growth.3,55

6.1.4 Cell Cycle and Apoptosis

The cell cycle regulates the process of cellular prolif-eration and growth as well as cell division after DNAdamage. Cyclins and cyclin-dependent kinases (CDK)are critical proteins as they facilitate progression of thecell cycle. Inhibition of the cell cycle is coordinated bynegative regulatory proteins called CDK inhibitors(CDKi). CDK inhibition can induce apoptosis. In can-cer cells, there is an imbalance between cyclins, CDKand inhibitory proteins leading to ongoing cell divisionand unchecked cell proliferation. Polyphenols havebeen shown to decrease the expression of cyclin D1

FIGURE 49.2 Physiological and molecular targets of polyphenols in skin cancer.



and increase the expression of CDKi, i.e., p21 and p27.Hence, they induce cell cycle arrest especially at G2/Mphase and apoptosis in several cancer cell lines includ-ing the skin.56�58

Apoptosis involves a series of biochemical events,leading to a variety of cellular changes; importantly,changes in the cell membrane. Polyphenols, especiallyEGCG, have been shown to inhibit the expression ofanti-apoptotic proteins Bcl-2 and Bcl-XL while increas-ing the expression of Bax and Bak pro-apoptotic pro-teins.59 Polyphenols also trigger intrinsic apoptoticpathways by regulating the mitochondrial functions,activating caspase-3 and caspase-9 and cleavingPARP.60 Besides these the tumor necrosis factor relatedapoptosis inducing ligand (TRAIL) and caspase-8 havealso been reported to be targeted by polyphenols inhuman melanoma cell lines.61

6.1.5 Cell Signaling Pathways

Various growth factors and cytokines convey theirsignals from cell membrane to nucleus via proteinkinase networks called “signal transduction path-ways.” One such pathway is the mitogen activatedprotein kinase (MAPK) pathway, also known as theextracellular signal regulated protein (ERK) pathway.The extracellular growth factors bind to their receptorson cell membranes and induce certain conformational

changes that lead to autophosphorylation, receptordimerization and recruitment of proteins like Ras atthe inner surface of the cell membrane. Ras stimulatesanother protein, Raf, which in turn phosphorylatesMEK, thereby activating ERK. ERK then coordinatesand responds to extracellular signals by regulatinggene expression, metabolism, cell proliferation, differ-entiation, and apoptosis. Activation of this pathwayhas been seen in several cancers.62

Mutations in the Ras gene and constitutively activeRas lead to cellular transformation by activating signaltransduction pathways.63 Similarly, other MAPK pro-teins like ERKs, stress activated c-Jun N-terminalkinase (JNKs/SAPKs) and p38 kinase may increasecell survival in various malignancies including skincancers.64 Polyphenols have been shown to regulatevarious molecules in the MAPK pathway, thereby inhi-biting cell survival.52

Phosphatidylinositol 3-kinases (PI3 kinase/Akt) is apro-survival signaling pathway. The growth factorreceptors activate PI3 kinase which phosphorylates theinositol ring of phosphoinositol to give PIP3. PIP3binds to Akt causing its phosphorylation. The acti-vated Akt then inhibits apoptosis by phosphorylationof apoptotic proteins like Bad and caspase-9.65,66

Polyphenols have been shown to inhibit the PI3/Aktpathway in many cancers like those of the breast, pros-tate and cervix. EGCG has been found to suppresspathological characteristics of a benign skin tumor,keloid, through inhibition of PI3 kinase, ERK andSTAT3.67

6.1.6 Transcription Factors

NF-κB is a transcription factor sensitive to oxidativestress. It stays in the cytoplasm as it is bound to IκBduring its resting state. Due to oxidative stress NF-κBinducing kinase/IκB kinase regulates IκB phosphoryla-tion. This causes the release of active NF-κB that trans-locates to the nucleus and induces expression of over200 genes. Many of these genes suppress apoptosisand lead to cell proliferation. This aberrant activationof NF-κB has been frequently observed in many can-cers.68 In a study by Afaq et al.,69 EGCG was shown toinhibit UV radiation-induced NF-κB activation in nor-mal human epidermal keratinocytes. Similarly, an inhi-bition of NF-κB was also noted in epidermoid cancercells in a dose/time-dependent manner.70

Activation protein-1 (AP-1) is a transcription factorassociated with invasive and metastatic characteristicsof cancer cells. The AP-1 genes are induced rapidly inresponse to external stimuli. These genes are compo-nents of the signal transduction pathway which areresponsible for cell proliferation. Polyphenols inhibitthe activity of AP-1 by inhibiting MAPK; particularlyby inhibiting c-Jun and c-fos that encode for AP-1.71

TABLE 49.2 Molecular Targets of Important Dietary Polyphenolsfor Cancer Prevention

Polyphenols Molecular Targets

Phenolic acid

Caffeic acidCurcuminFerulic acid

Inhibits ROS, H2O2, iNOSInhibition of NF-κB, AP-1, ERK and MAPKproteins

FlavonoidsCatechinsEGCGProanthocyanidinsSilymarin

H2O2, PG, cyclooxygenases, iNOSEnhance antioxidant defense enzymesTranscription factors NF-κB, AP-1, MAPKproteinsCell cycle arrest and pro-apoptoticInhibition of DNA damageDNA repair mechanismAnti-angiogenic and prevention of metastasis

Lignans

EnterolignansAntioxidant

Stilbenes

ResveratrolH2O2, PG, cyclooxygenasesTumor suppressors p53Cell cycle regulators e.g., cyclins, CDKsTranscription factors NF-κB, AP-1, c-Jun, and c-fVEGFMatrix metalloproteaseTRAIL, Akt, Bcl-2 and Bcl-XL

References: Rechner et al.,27 Kang et al.,6 Andreasen et al.,35 Athar et al.,36 andKampa et al.37



6.1.7 The Tumor Suppressor p53 Gene

Tumor suppressor genes follow a two-hit hypothe-sis. This means that if one allele for the gene is dam-aged, the second gene can still produce the correctprotein. Mutations in the p53 tumor suppressor geneare found in almost all cancers, where they contributeto various molecular events responsible for tumor for-mation. EGCG has been found to augment tumorgrowth inhibitory effects of erlotinib in squamous cellcarcinoma of the head and neck.72

6.1.8 Growth Factors

Several growth factors like vascular endothelialgrowth factor (VEGF), hepatocyte growth factor(HGF), tissue growth factor (TGF), platelet derivedgrowth factor (PDGF), insulin like growth factor (IGF),fibroblast growth factor (FGF), and many others havebeen found to be overexpressed in various malignan-cies. One of the important factors for angiogenesis isVEGF. It is increased in cancers and promotes neovas-cularization, thereby facilitating cancer growth andmetastasis. Tea polyphenols decrease levels of VEGF,possibly by inhibiting an expression of HIF-1α, whichstrongly activates VEGF expression. IGF initiates thesignaling cascade that regulates cell proliferation, dif-ferentiation and apoptosis. Increased expression ofIGF-binding proteins is associated with the risk of can-cer. Several studies focusing on the effects of green teapolyphenols have been carried out. It has been foundthat polyphenols inhibit IGF-binding proteins in bothhumans and animals.73�75

6.1.9 DNA Repair Mechanisms

Harmful effects that result after prolonged exposureto carcinogens are either due to the failure of or defec-tive DNA repair mechanisms.76 UV radiation causesthe formation of cyclobutane pyrimidine dimers (CPD)in the DNA, which triggers an induction of immuno-suppression and initiation of photocarcinogenesis.77

Polyphenols in a dose-dependent manner, by inducinginterleukin-12 (IL-12), reduce UV radiation-inducedDNA damage in cultured human cells.7,78 Anothermechanism of DNA repair is proposed to be mediatedthrough nucleotide excision repair (NER), which isagain dependent on IL-12.79,80

6.1.10 Telomere and Telomerase

Telomeres are repetitive nucleotide sequences at eachend of chromosomes. Their function is to protect theends of the chromosomes from deterioration or fusion toother chromosomes during cell division.81 With everycell division, telomeres shorten. This blocks further celldivision and induces senescence. In healthy cells, telo-meres lose up to 300 bp of DNA per cell division. An

enzyme called telomerase is responsible for maintainingthe length of telomeres. Many cancer cells overexpressthe telomerase, therefore bypassing this restriction.82 Thetelomerase has catalytic subunit hTERT essential for itsfunctioning and is shown to be expressed in 90% of allcancers. Polyphenols have been shown to decreasehTERT transcription in many cancer cell lines.83,84

6.1.11 Tumor Metastasis

Proteolytic enzymes like urokinase plasminogenactivator (uPA) play an important role in tumor inva-sion and metastasis by degrading the extracellularmatrix (ECM). uPA catalyzes the cleavage of plasmino-gen to plasmin. Plasmin then facilitates the release ofseveral proteolytic enzymes.85 Polyphenols can modu-late the release of uPA and inhibit invasive behavior ofcancer cells by suppressing the constitutively activetranscription factors AP-1 and NF-κB.86 Also, matrixmetalloproteins and endopeptidases are involved inECM degradation and remodeling. MMPs also haveanti-apoptotic properties and aid in tumor progressionand metastasis by promoting angiogenesis, tumor cellproliferation and differentiation. EGCG inhibits MMPsexpression and enzymatic activity in cancers.87,88

6.1.12 Immunosuppression

The tumor microenvironment influences the antitu-mor immune response. Escape from immune surveil-lance facilitates the rapid progression of cancers.60

Various immune escape mechanisms in cancer havebeen proposed.61,89 Certain cancer cells may secreteimmunosuppressive factors to modify the hostimmune responses.62,63 It has been observed that intumor-bearing mice, the tumor cells secrete immuno-suppressive cytokines, transforming growth factor-beta(TGF-β) and IL-10 that induce a general T helper cellstype 2 (Th2) response dampening the T cytotoxic cellpopulation. Interestingly, in a study,90 black teareduced TGF-β and IL-10 in tumor cells in vivo, therebypreventing Th2 dominance in the tumor bearers andinitiating a Th1/cytotoxic T cell response. Mandalet al.91 showed that oral administration of black tea sig-nificantly reduced depletion of CD41 and CD81 cellsin peripheral blood, inhibited tumor-induced thymicapoptosis and ensured its proper functioning by pre-venting IL-7 receptor alpha (IL-7Rα) downregulationand restoration of the JAK-STAT signaling cascade.Hence, by potentiating the host’s immune system,polyphenols-rich tea helps in regressing tumors.92

An increased apoptosis of the immunocytes has alsobeen noted in certain malignancies in animal studies.Bhattacharya et al.93 in a study on Ehrlich’s ascites car-cinoma (EAC)-bearing mice found an increasedexpression of the pro-apoptotic proteins p53 and Baxin splenic lymphocytes with normal levels of



proproliferative protein Bcl-2. The antitumor doses ofblack tea were found to downregulate p53, and reduceBax while augmenting Bcl-2 in these cells. Thisincreased the Bcl-2/Bax ratio and protected the immu-nocytes from tumor-induced apoptosis.93 Hence, poly-phenols have both immunomodulatory andimmunorestorative functions and may add to tumorregression.

7. FUTURE PERSPECTIVES

Despite significant advances in our understandingof multistage carcinogenesis, little is known about themechanisms of action of most chemopreventive agents.The dietary polyphenols that exert chemopreventiveeffects are likely to target multiple pathways and atvarious steps of carcinogenesis. With extensive ongo-ing research, it is possible that many more targets ofpolyphenols will be revealed in future. Because of thepromising results obtained so far, chemoprevention byedible polyphenols is gaining popularity as an inex-pensive, readily applicable, acceptable and accessibleapproach to cancer control and management. Severalother nutrients and non-nutritive phytochemicals arealso being evaluated in intervention trials for theirpotential as cancer chemopreventive agents. As aresult tailored supplementation with designer foodsconsisting of chemopreventive phytochemicals, eachhaving their own distinct anticancer mechanisms, maybe available in the near future.

Since polyphenols are often present as glycosides orare converted to other conjugated forms after absorp-tion, this might affect their bioavailability. Their phar-macokinetic properties and bioavailability need to beassessed carefully while investigating the dietary pre-vention of cancer and before undertaking interventiontrials with dietary supplements.

The term “nutragenomics,” which means to studythe effects of foods and food constituents on geneexpression, has recently evolved. With the advance intechniques of assessing single nucleotide polymorph-isms (SNPs), as well as other genetic analysis tools, wecan now identify the specific genes that contribute toindividual differences in the susceptibility to carcino-genesis. If high risk groups are identified, they may beadvised to take specific dietary supplements that canmodulate or restore the physiological and molecularpathways that are likely to be disrupted in these indi-viduals. Though nutragenomics is in its beginningstages, it may be hoped that the progress in this areawill increase our understanding of the role of nutritionon metabolic pathways and homeostasis, and prove tobe a useful science in preventing various bodyailments.

In summary, the consumption of polyphenols in ourdaily diet has a significant role in maintaining goodhealth and, in the future, polyphenols may play a cru-cial role in the prevention and management of variousdisorders including cancers. Hence, promoting aware-ness about consumption of polyphenols could prove acost-effective, cancer preventive strategy for the gen-eral population.

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