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Natural Phenolic Compounds From Medicinal Herbs andDietary Plants: Potential Use for Cancer PreventionWu-Yang Huang a , Yi-Zhong Cai a & Yanbo Zhang ba School of Biological Sciences, University of Hong Kong, Hong Kong, PR Chinab School of Chinese Medicine, University of Hong Kong, Hong Kong, PR China
Available online: 29 Dec 2009
To cite this article: Wu-Yang Huang, Yi-Zhong Cai & Yanbo Zhang (2009): Natural Phenolic Compounds From Medicinal Herbsand Dietary Plants: Potential Use for Cancer Prevention, Nutrition and Cancer, 62:1, 1-20
To link to this article: http://dx.doi.org/10.1080/01635580903191585
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Nutrition and Cancer, 62(1), 1–20Copyright © 2010, Taylor & Francis Group, LLCISSN: 0163-5581 print / 1532-7914 onlineDOI: 10.1080/01635580903191585
Natural Phenolic Compounds From Medicinal Herbsand Dietary Plants: Potential Use for Cancer Prevention
Wu-Yang Huang and Yi-Zhong CaiSchool of Biological Sciences, the University of Hong Kong, Hong Kong, PR China
Yanbo ZhangSchool of Chinese Medicine, the University of Hong Kong, Hong Kong, PR China
Natural phenolic compounds play an important role in cancerprevention and treatment. Phenolic compounds from medicinalherbs and dietary plants include phenolic acids, flavonoids, tan-nins, stilbenes, curcuminoids, coumarins, lignans, quinones, andothers. Various bioactivities of phenolic compounds are respon-sible for their chemopreventive properties (e.g., antioxidant, an-ticarcinogenic, or antimutagenic and anti-inflammatory effects)and also contribute to their inducing apoptosis by arresting cellcycle, regulating carcinogen metabolism and ontogenesis expres-sion, inhibiting DNA binding and cell adhesion, migration, prolif-eration or differentiation, and blocking signaling pathways. Thisreview covers the most recent literature to summarize structuralcategories and molecular anticancer mechanisms of phenolic com-pounds from medicinal herbs and dietary plants.
INTRODUCTIONCancer is a growing health problem around the world and
is the second leading cause of death after heart disease (1).According to a recent report by the World Health Organiza-tion (WHO) (http://www.who.int/cancer/en/), from a total of 58million deaths worldwide in 2005, cancer accounted for 13%.There are now more than 10 million cases of cancer per yearworldwide, including a group of more than 100 diseases suchas cancer of the liver, lung, stomach, colon, breast, and so forth(2,3). The most rational way to affect carcinogenesis is by in-terfering with modulation steps (initiation, promotion, and pro-gression) as well as the associated signal transduction pathways(4). There are numerous physiological and biochemical carcino-gens, for example, ultraviolet and ionizing radiation; asbestosand tobacco smoke (5); infections by virus (e.g., hepatitis B
Submitted 12 December 2008; accepted in final form 14 April 2009.Address correspondence to Wuyang Huang, School of Bio-
logical Sciences, the University of Hong Kong, Pokfulam Road,Hong Kong, PR China. Phone: 852-22990-846. Fax: 852-25599-114.E-mail: [email protected]
virus causing liver cancer and human papilloma virus caus-ing cervical cancer) (6,7); bacteria (Helicobacter pylori causinggastric cancer) (8) and parasites (schistosomiasis causing blad-der cancer) (9); and contamination of food by mycotoxins (e.g.,aflatoxins causing liver cancer) (10). Some kinds of cancer aredue to oxygen-centered free radicals and other reactive oxygenspecies because overproduction of such free radicals can causeoxidative damage to biomolecules (e.g., lipids, proteins, DNA)(11).
There are no extremely effective drugs to treat most cancers.There is a general call for new drugs that are highly effec-tive, possess low toxicity, and have a minor environment im-pact. Novel natural products offer opportunities for innovationin drug discovery (12). In fact, natural products play a major rolein cancer prevention and treatment. A considerable number ofantitumor agents currently used in the clinic are of natural ori-gin. For instance, over half of all anticancer prescription drugsapproved internationally between the 1940s and 2006 were nat-ural products or their derivatives (13). Among them, plants havebeen the chief source of natural compounds used for medicine.During the 1960s, the National Cancer Institute (United States)began to screen plant extracts with antitumor activity (14). Nat-ural compounds isolated from medicinal plants, as rich sourcesof novel anticancer drugs, have been of increasing interest sincethen. Traditional medicinal herbs have been used for pharma-ceutical and dietary therapy for several millennia in East Asia,for example, in China, Japan, India, Thailand, and are currentlywidely used in cancer therapy (12). During long-term folk prac-tice, a large number of anticancer medicinal herbs and manyrelevant prescriptions have been screened and used for treat-ing and preventing various cancers (15). Recently, many studieshave reported medicinal plants in treatment and prevention ofcancer (13).
Earlier investigation showed that an average of 35% of over-all human cancer-related mortality was attributed to diet (16).Substantial evidence from population as well as laboratory stud-ies have revealed an inverse relationship between sufficient con-sumption of fruit and vegetables and the risk of specific cancers,
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that is, a high dietary intake of fruits and vegetables as well aswhole grains is strongly associated with reduced risk of cancer(2). Many clinical trials on the use of nutritional supplementsand modified diets to prevent cancer are ongoing (17). Dietaryplant—such as fruits, vegetables, spices, cereals, and edibletubers/roots—which also contain significant levels of bioactivenatural compounds, may provide human health benefits beyondbasic nutrition to reduce the risk of many chronic diseases in-cluding cancer (18). The cancer-protective effects elicited bythese dietary compounds are believed to be due to the induc-tion of cellular defense systems including the detoxifying andantioxidant enzymes system as well as the inhibition of anti-inflammatory and anticell growth signaling pathways culminat-ing in cell cycle arrest and/or cell-death (19).
Phytochemicals are defined as bioactive nonessential nutri-ents from plants (phyto is derived from the Greek word phyto,which means plant). They have a variety of human health effectssuch as possessing putative chemo-reventive properties (anticar-cinogenic and antimutagenic) and interfering with tumor promo-tion and progression (2,19). The National Cancer Institute, basedon numerous reports describing anticancer activity, identifiedabout 40 edible plants possessing cancer-preventive properties(20). Moreover, there are more than 400 species of traditionalChinese medicinal herbs associated with anticancer (12). It isestimated that more than 5,000 individual phytochemicals havebeen identified in fruits, vegetables, grains, and other plants,mainly classified as phenolics, carotenoids, vitamins, alkaloids,nitrogen-containing compounds, and organosulfur compounds.Among the great structural diversity of phytochemicals, pheno-lic compounds have attracted considerable interest and the mostattention for their wide variety of bioactivities (21).
Phenolic compounds provide essential functions in the re-production and growth of plants; act as defense mechanismsagainst pathogens, parasites, and predators; as well as contributeto the color of plants (22). In addition, phenolics abundant invegetables and fruits are reported to play an important role aschemopreventive agents; for example, the phenolic componentsof apples have been linked with inhibition of colon cancer invitro (23). Many phenolic compounds have been reported topossess potent antioxidant activity and to have anticancer oranticarcinogenic/antimutagenic, antiatherosclerotic, antibacte-rial, antiviral, and anti-inflammatory activities to a greater orlesser extent (21–24). Our recent studies have characterized alarge number of natural phenolic compounds from 112 tradi-tional Chinese medicinal herbs associated with anticancer, 133traditional Indian medicinal herbs, and about 50 dietary plants(e.g., spices, cereals, vegetables, and fruits) and evaluated theirantioxidant activity and other bioactivities (12,25–33). Hun-dreds of natural phenolic compounds have been identified fromour tested medicinal herbs and dietary plants, mainly includ-ing phenolic acids, flavonoids, tannins, stilbenes, curcuminoids,coumarins, lignans, quinones, and phenolic mixtures and otherphenylethanoids and phenylpropanoids. Their physiological andpharmacological functions may originate from their antioxidant
and free radical scavenging properties and function of regulat-ing detoxifying enzymes (2). Further, these antioxidant activitiesare related to the structures of phenolic compounds, generallydepending on the number and positions of hydroxyl groups andglycosylation or other substituents (31,34).
CHEMISTRY AND OCCURRENCE OF PHENOLICCOMPOUNDS FROM MEDICINAL HERBS ANDDIETARY PLANTS
Phenolics are compounds possessing one or more aromaticrings bearing one or more hydroxyl groups with over 8,000structural variants and generally are categorized as phenolicacids and analogs, flavonoids, tannins, stilbenes, curcuminoids,coumarins, lignans, quinones, and others based on the numberof phenolic rings and of the structural elements that link theserings (4).
Phenolic Acids and AnalogsPhenolic acids are a major class of phenolic compounds,
widely occurring in the plant kingdom (12). As shown in Fig. 1,predominant phenolic acids include hydroxybenzoic acids (e.g.,gallic acid, p-hydroxybenzoic acid, protocatechuic acid, vanillicacid, and syringic acid) and hydroxycinnamic acids (e.g., fer-ulic acid, caffeic acid, p-coumaric acid, chlorogenic acid, andsinapic acid) (31). Natural phenolic acids, either occurring in thefree or conjugated forms, usually appear as esters or amides. Dueto their structural similarity, several other polyphenols are con-sidered as phenolic acid analogs such as capsaicin, rosmarinicacid, gingerol, gossypol, paradol, tyrosol, hydroxytyrosol, el-lagic acid, cynarin, and salvianolic acid B (4,21) (Fig. 1).
Gallic acid is widely distributed in medicinal herbs, such asBarringtonia racemosa, Cornus officinalis, Cassia auriculata,Polygonum aviculare, Punica granatum, Rheum officinale, Rhuschinensis, Sanguisorba officinalis, and Terminalia chebula aswell as dietary spices, for example, thyme and clove (12,28–31).Other hydroxybenzoic acids are also ubiquitous in medicinalherbs and dietary plants (spices, fruits, vegetables). For example,Dolichos biflorus, Feronia elephantum, and Paeonia lactifloracontain hydroxybenzoic acid; Cinnamomum cassia, Lawsoniainermis, dill, grape, and star anise possess protocatechuic acid;Foeniculum vulgare, Ipomoea turpethum, and Picrorhiza scro-phulariiflora have vanillic acid; Ceratostigma willmottianumand sugarcane straw possess syringic acid (12,28–31,35,36).
Ferulic, caffeic, and p-coumaric acid are present in manymedicinal herbs and dietary spices, fruits, vegetables, and grains(12). Wheat bran is a good source of ferulic acids. Free, soluble-conjugated, and bound ferulic acids in grains are present inthe ratio of 0.1:1:100 (37). Red fruits (blueberry, blackberry,chokeberry, strawberry, red raspberry, sweet cherry, sour cherry,elderberry, black currant, and red currant) are rich in hy-droxycinnamic acids (caffeic, ferulic, p-coumaric acid) andp-hydroxybenzoic, ellagic acid, which contribute to their an-tioxidant activity (38). Chlorogenic acids are the ester of caffeic
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NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS 3
COOHR1
HO
R2
R1
HO
R2
COOH
R1=H, R2=H: p-hydroxybenzoic acidR1=H, R2=OH: protocatechuic acidR1=OH, R2=OH: gallic acidR1=OCH3, R2=H: vanillic acidR1=OCH3, R2=OCH3: syringic acid
R1=H, R2=H: p-coumaric acidR1=H, R2=OH: caffeic acidR1=H, R2=OCH3: ferulic acidR1=OCH3, R2=OCH3: sinapic acid
OH
R
HO
R=H: tyrosolR=OH: hydroxytyrosol
HO
HO
COOH
O
OH
OH
O
rosmarinic acid
H3CO
HO
O OH
gingerol
HN
O
H3CO
HO
capsaicin
O
HOOC
OH
OH
O
OH
OH
HO
HO
O O
cynarin (1,3-dicaffeoylquinic acid)
O
O
O
OH
OH
COOHO
HO
OH
O
O OHHO
HO
salvianolic acid B
OO
OH
OHOH
OH
O
OH
OH
chlorogenic acid
O
O
O
OH
OH
HO
HO
O
ellagic acid
OH
OH
OOH
OHO
HO
HO
gossypol
FIG. 1. Chemical structures of common phenolic acids and analogs from medicinal herbs and dietary plants.
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4 W.-Y. HUANG ET AL.
acids and are the substrate for enzymatic oxidation leading tobrowning, particularly in apples and potatoes. We also found thatchlorogenic acid is a major phenolic acid from medicinal plantsespecially in the species of Apocynaceae and Asclepiadaceae(39).
Salvianolic acid B is a major water-soluble polyphenolic acidextracted from Radix salviae miltiorrhizae, which is a commonherbal medicine clinically used as antioxidant agent for thou-sands of years in China. There are 9 activated phenolic hydroxylgroups that may be responsible for the release of active hydrogento block lipid peroxidation reaction (3). Rosmarinic acid is anantioxidant phenolic compound, which is found in many dietaryspices such as mint, sweet basil, oregano, rosemary, sage, andthyme (28). Gossypol, a polyphenolic aldehyde, derived fromthe seeds of cotton plant (genus Gossypium, family Malvaceae),has contraceptive activity and can cause hypokalemia in somemen (21). Gingerol, a phenolic substance, is responsible for thespicy taste of ginger (2).
FlavonoidsFlavonoids are a group of more than 4,000 phenolic com-
pounds that occur naturally in plants (40). These compoundscommonly have the basic skeleton of phenylbenzopyrone struc-ture (C6-C3-C6) consisting of 2 aromatic rings (A and B rings)linked by 3 carbons that are usually in an oxygenated centralpyran ring, or C ring (12). According to the saturation level andopening of the central pyran ring, they are categorized mainlyinto flavones (basic structure, B ring binds to the 2 position),flavonols (having a hydroxyl group at the 3 position), flavanones(dihydroflavones) and flavanonols (dihydroflavonols; 2–3 bondis saturated), flavanols (flavan-3-ols and flavan-3,4-diols; C-ringis 1-pyran), anthocyanins (anthocyanidins; C-ring is 1-pyran,and 1–2 and 3–4 bonds are unsaturated), chalcones (C-ringis opened), isoflavonoids (mainly isoflavones; B ring binds tothe 3 position), neoflavonoids (B ring binds to the 4-position),and biflavonoids (dimer of flavones, flavonols, and flavanones)(12,31,40,41) (main structure groups/subgroups; see Fig. 2). Innature, flavonoids can occur either in the free or conjugatedforms, and often in plants they are mainly present as glyco-sides with a sugar moiety or more sugar moieties linked throughan OH group (O-glycosides) or through carbon-carbon bonds(C-glycosides); but some flavonoids are present as aglycones(4,31). More than 80 different sugars have been discoveredbound to flavonoids, and common glycosides include glucoside,glucuronide, galactoside, arabinoside, rhamnoside, apiosylglu-coside, and malonyl (42) (Fig. 2).
Different kinds of flavonoids are present in practically alldietary plants, like fruits and vegetables, and we also found thatflavonoids are the largest class of phenolics in the tested medic-inal herbs and dietary spices in our previous studies (12,28–33,39). Some common different categories of flavonoids frommedicinal herbs and dietary plants are shown in Fig. 3. The mostcommon flavones are luteolin, apigenin, baicalein, chrysin, and
their glycosides (e.g., apigetrin, vitexin, and baicalin), mainlydistributed in the Labiatae, Asteraceae, and so forth, such asroots of Scutellaria baicalensis, inflorescences of Chrysanthe-mum morifolium, and aerial parts of Artemisia annua. Their ma-jor food plant sources are parsley, thyme, cherries, tea, olives,broccoli, and legumes (4,40). Quercetin, kaempferol, myricetin,morin, galangin, and their glycosides (e.g., rutin, quercitrin, andastragalin) are the predominant flavonols. These flavonols havea large range of food sources such as onions, cherries, apples,broccoli, kale, tomato, berries, tea, red wine, caraway, cumin,and buckwheat; and they also occur in many medicinal herbs as-sociated with anticancer, for example, flowers of Sophora japon-ica and Rosa chinensis, aerial parts of A. annua, rhizomes ofAlpinia officinarum, and fruits (hawthorn) of Crataegus pinnat-ifida (12,28). Among these common flavonols, quercetin is oneof the major dietary flavonoids, found in a broad range of fruit,vegetables, and beverages with a daily intake in Western coun-tries of 25–30 mg (3). Flavanones such as naringenin, hesperetin,eriodictyol, and their glycosides (e.g., naringin, hesperidin, andliquiritin) and flavanonols (taxifolin) are mainly found in cit-rus fruits (e.g., oranges, lemons, and aurantium), grape, andthe medicinal herbs of Rutaceae, Rosaceae, Leguminosae, andso forth (12,40). Flavanols, such as catechin, epicatechin, epi-gallocatechin, epicatechin gallate (ECG), and epigallocatechingallate (EGCG), are also widespread in the medicinal herbsand dietary plants (e.g., tea, apples, berries, cocoa, and catechu)(4,40). Anthocyanins, including anthocyanidins (e.g., cyanidin,delphinidin, malvidin, peonidin, pelargonidin, etc.) and theirglycosides, are widely distributed in the medicinal herbs suchas inflorescences of Prunella vulgaris and flowers of Rosa chi-nensis (12). Many dietary plants (e.g., fruits, vegetables, grains,etc.) contain anthocyanins such as grape skins, blueberries, bay-berry, red cabbages, beans, red/purple rice and corn, and purplesweet potatoes (32,40). Chalcones (butein, phloretin, sappan-chalcone, carthamin, etc.) are detected in medicinal herbs suchas Rhus verniciflua, Caesalpinia sappan, and Carthamus tinc-torius (12,31).
Isoflavones include daidzein, genistein, glycitein, for-mononetin, and their glycosides (e.g., genistin, daidzin), mostlyfrom soybeans, legumes, and red clover, and are also detected inthe medicinal herbs of Leguminosae, such as roots of Astragalusmongholicus (12,31). In addition, biflavonoids are flavonoiddimers connected with a C–C or C–O–C bond (43) and occurin some fruits, vegetables, and medicinal plants such as Citrusfruits, Ginkgo biloba, Rhus succedanea, and Ouratea hexas-perma (12,44,45). Silymarin (Fig. 3), a flavonoid analog, wasfound in fruits of Silybum marianum (46).
TanninsTannins are natural, water-soluble, polyphenolic compounds
with molecular weight ranging from 500 to 4,000, usuallyclassified into 2 classes: hydrolysable tannins (gallo- andellagi-tannins) and condensed tannins (proanthocyanidins) (12)
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NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS 5
O
O
slonovalfsenovalf
O
O
OH
flavanones
O
O
flavanonols
O
O
OH
flavanols
O
OH
chalconesO
isoflavones
O
O
anthocyanidins
+O
OH
O
O
OOH
HO
OH
HO
OH
HO
-apiosylglucoside
O
OH
OH
OH
HO
-galactoside
O
OH
CH3
OH
OH
-rhamnoside
O
HO OH
OH
-arabinoside
O O
HO S
-malonyl
O
OH
OH
OH
HO
-glucoside
O
OHHO
OH
O
HO
-glucuronide
FIG. 2. Structures of major groups/subgroups of flavonoids and their associated glycosides.
(Fig. 4). The former are complex polyphenols, which can bedegraded into sugars and phenolic acids through either pHchanges or enzymatic or nonenzymatic hydrolysis. The basicunits of hydrolysable tannins of the polyster type are gallicacid and its derivatives (4). Tannins are commonly found com-bined with alkaloids, polysaccharides, and proteins, particularlythe latter (21). Hydrolysable tannins contain a central core of
polyhydric alcohol such as glucose and hydroxyl groups, whichare esterified either partially or wholly by gallic acid (gallotan-nins) or by hexahydroxy-diphenic acid or by other substituents(e.g., chebulic acid) (ellagitannins) (31). Ellagitannins differfrom gallotannins in that at least 2 gallic acid units surroundingthe core are linked through carbon-carbon bonds. Condensedtannins are structurally more complex and more widely spread
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6 W.-Y. HUANG ET AL.
O
OOH
HO
R1=H, R2=H, R3=H: chrysinR1=H, R2=H, R3=OH: apigeninR1=H, R2=OH, R3=OH: luteolinR1=OH, R2=H, R3=H: baicalein
OHO
OH O
OH
R1=H, R2=H, R3=H, R4=H: galanginR1=H, R2=H, R3=OH, R4=H: kaempferolR1=H, R2=OH, R3=OH, R4=H: quercetin R1=OH, R2=H, R3=OH, R4=H: morinR1=H, R2=OH, R3=OH, R4=OH: myricetin
R1
R2
R3 R1
R2
R3
R4
+O
OH
OH
HO
R1
OH
R2
R1=H, R2=H: pelargonidinR1=OH, R2=H: cyanidinR1=OCH3, R2=H: peonidinR1=OH, R2=OH: delphinidin R1=OCH3, R2=OCH3: malvidin
O
OH
OH
HO
OH
butein
O
O
R3
HO
R2
R1
R1=H, R2=H, R3=OCH3: formononetinR1=H, R2=H, R3=OH: daidzeinR1=H, R2=OH, R3=OH: genistein R1=OCH3, R2=H, R3=OH: glycitein
O
O
HO
OH
R1
R2
R1=OH, R2=OCH3: hesperetinR1=H, R2=OH: naringeninR1=OH, R2=OH: eriodictyol
O
O
OH
HO
OH
OH
OH
taxifolin
O
OH
OH
OH
OH
HO
catechin
O
OH
R
OH
OH
HO
OH
R=H: epicatechinR=OH: epigallocatechin
O
O
OH
OH
OH
HO
R
OH
OH
OH
O
R=H: epicatechin gallateR=OH: epigallocatechin gallate
O
O
O
OH
OCH3
OHOH
OOH
HO
silymarin
FIG. 3. Representative compounds from different categories of flavonoids from medicinal herbs and dietary plants.
among the plants than hydrolysable tannins. They are mainlythe oligomers and polymers (e.g., monomers, dimmers, andtrimers) of flavan-3-diols (catechin or epicatechin derivatives),also known as proanthocyanidins (47). Some authors have con-sidered that the polymerized products of flavan-3,4-diols also
belong to the category of condensed tannins called leucoan-thocyanidins (31). Complex tannins are constructed of cate-chin units linked glucosidically to gallotannin or ellagitannin; atleast 2 gallic acid units surrounding the core are linked throughcarbon-carbon.
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NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS 7
O
OO
O
O
GOOGOG
OHHO
HO
HO
HO
HO
tellimagrandin II (ellagitannins)
O
OO
O
OH
HO
HO
HO
OH
O
HO
HOH 2C
OHOH
di-O-galloyl-β-D-glucose (gallotannins)
OH
O(H/G)HO
C=O
G = gal loyl
O
GnO
GnO
OGn
OGGnO
Gn = O-3-galloyls
Basic skeleton of gallotannins
Basic skeleton and substituents of ellagitannins
OO
OO
R1
O
R2
R3
O
O
O O
OG
R2
R1
R1=OH/OGR2=H, H/G, G/HHDPR3=H, H/HHDP/BCHT
R1=H, H/CHEB/DHHDPR2=HHDP/H, H
HOOH
OHHOOHHO
O O
OO
OHHO
O O
O
OHHO
O
HHDP BCHT
HOCOOH
OH
O O
O
O
HO
CHEB
HOO
OH
O O
OOHOH
HO
O
OH
HO
OHO
O
O
OH
OH DHHDP
O
OH
OH
OH
HO
OG
nOH
OH
OH
C
O
G =
Basic skeleton of condensed tannins
O
O
OH
OH
OH
OH
OH
OH
OH
HO
HO
HO
oligomeric proanthocyanidins (condensed tannins)
O
OOHO
RO
O
O
O
HO OH
OH
OH
OH
OHOH
OH
HO
HO
HO
complex tannins
FIG. 4. The basic skeletons and structures of different categories of tannins from medicinal herbs and dietary plants.
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OH
R1O
R2O
R1=H, R2=H, R3=H: trans-resveratrol R1=H, R2=Gluc, R3=H: trans-piceid R1=CH3, R2=CH3, R3=H: trans-pterostilbeneR1=H, R2=H, R3=OH: trans-piceatannol
R3
R1
HO
R2
OH
O OH
R1=OCH3, R2=OCH3: curcumin R1=H, R2=OCH3: demethoxycurcuminR1=H, R2=H: bisdemethoxycurcumin
FIG. 5. The structures of typical stilbenes and curcuminoids from medicinal herbs and dietary plants.
Tannins are a large class of polyphenolics in dietary plantsand medicinal herbs. Oligomeric proanthocyanidins, which arewidely distributed in grape seed and skin and pine bark, are con-sidered to be the most potent antioxidants and frequently usedin health care and cancer treatment (48). Many fruits (e.g., applejuice, strawberries, longan, raspberries, pomegranate, walnuts,peach, blackberry, olive, and plum), vegetables (e.g., chickpeas,black-eyed peas, lentils, and haricot beans), and spices (e.g.,clove and cinnamon) contain high levels of proanthocyanidinsor ellagitannins (21,28). More than 32 species in 112 testedtraditional Chinese medicinal plants associated with anticancercontain tannin constituents (e.g., gallotannins, ellagitannins, andproanthocyanidins) (12). Of these, 19 species contained par-ticularly high proportions of tannins such as Chinese Galls,catechu, P. granatum, and S. officinalis. Ten of 126 Indianmedicinal herbs also possess high levels of hydrolysable tan-nins (29). Some gallotannins were detected in Euphorbia hirta,Glycyrrhiza glabra, and Rhus succedanea. Several ellagitan-nins (e.g., corilagin, casuarictin) were isolated from fruits of T.chebula and peels of P. granatum. Camellia sinensis and Arecacatechu contained proanthocyanidins and leucoanthocyanidins,respectively. Some plant species (e.g., Acacia catechu, S. offic-inalis, Rosa chinensis, and P. granatum) may produce complexmixtures containing both hydrolysable and condensed tannins(12,29,31).
StilbenesStilbenes are phenolic compounds displaying 2 aromatic
rings linked by an ethane bridge, structurally characterizedby the presence of a 1,2-diarylethene nucleus with hydroxylssubstituted on the aromatic rings (4) (Fig. 5). They are dis-tributed in higher plants and exist in the form of oligomers andin monomeric form (e.g., resveratrol, oxyresveratrol) and asdimeric, trimeric, and polymeric stilbenes or as glycosides. Thewell-known compound, trans-resveratrol, a phytoalexin pro-duced by plants, is the member of this chemical family moreabundant in the human diet (especially rich in the skin of redgrapes), possessing a trihydroxystilben skeleton (21). We iden-tified the monomeric stilbenes in 4 species of medicinal herbs,that is, trans-resveratrol in root of Polygonum cuspidatum,
Polygonum multiflorum, and P. lactiflora; piceatannol in rootof P. multiflorum; and oxyresveratrol in fruit of Morus alba(12,31). It was reported that dimeric stilbenes and stilbene glyco-sides were identified from these species (33,49). In addition, 40stilbene oligomers were isolated from 6 medicinal plant species(Shorea hemsleyana, Vatica rassak, Vatica indica, Hopea utilis,Gnetum parvifolium, and Kobresia nepalensis) (50). Other stil-benes that have recently been identified in dietary source, suchas piceatannol and its glucoside (usually named astringin) andpterostilbene, are also considered as potential chemopreventiveagents (4). These and other in vitro and in vivo studies providea rationale in support of the use of stilbenes as phytoestrogensto protect against hormone-dependent tumors (51).
CurcuminoidsCurcuminoids are ferulic acid derivatives, which contain 2
ferulic acid molecules linked by a methylene with a β-diketonestructure in a highly conjugated system. Curcuminoids andginerol analogues are natural phenolic compounds from plantsof the family Zingiberaceae (12). Curcuminoids include 3 mainchemical compounds: curcumin, demethoxycurcumin, and bis-demethoxycurcumin (31) (Fig. 5). All 3 curcuminoids impartthe characteristic yellow color to turmeric, particularly to itsrhizome, and are also major yellow pigments of mustard (3).Curcuminoids containing Curcuma longa (turmeric) and ginerolanalogues containing Zingiber officinale (ginger) are not onlyused as Chinese traditional medicines but also as natural coloragents or ordinary spices (12). In addition, curcuminoids withantioxidant properties were isolated from various Curcuma orZingiber species, such as Indian medicinal herb Curcuma xan-thorrhiza, the spice Curcuma domestica, Curcuma zedoariagrown in Brazil, and Zingiber cassumunar from tropic regions(29,52,53).
CoumarinsCoumarins are lactones obtained by cyclization of cis-
ortho-hydroxycinnamic acid, belonging to the phenolics withthe basic skeleton of C6+ C3(12) (Fig. 6). This precursoris formed through isomerization and hydroxylation of thestructural analogs trans-hydroxycinnamic acid and derivatives.
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NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS 9
O
R
OOH
O OO
O OO
O O
O O
O
O
R
R
R
O
O
O
HOO
OH
HO
HO
O
O
H3CO
HO
O
OH
OH
OH
CH2OH
O
O
OH
OH
O
OH
H3CO
OH
OH
H3CO
OCH3
OH
H3CO
HO
OCH3
R
HO
O
OCH3
OCH3
O
O
R3
R2R1
O
O
OCH3
OCH3
O
O
H3CO
O
O
OCH3
OCH3
O
O
R
O
O
O
O
O
O
O
O
OH
HOO
O
O
O
O
O
O
R=OH: esculetin R=OCH3: scopoletinR=CH3: escopoletinR=Gluc: aesculin
psoralen
isopsoralen
R=H: xanthyletinR=OCH3: xanthoxyletinR=H: seselin
R=OH: khellactone
bicoumarin bergenin
wedelolactone
magnolol
secoisolariciresinol R=OH: matairesinolR=OCH3: arctigenin
R1=H, R2=H, R3=OCH3:deoxypodophyllotoxinR1=H, R2=OH, R3=OCH3: podophyllotoxinR1=OH, R2=H, R3=OCH3: β-peltatinR1=H, R2=H, R3=H: bursehemin
anhydropodorhizol R=H: morelensinR=OCH3: yatein
hinokininsesamin
FIG. 6. The structures of representative coumarins and lignans from medicinal herbs and dietary plants.
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10 W.-Y. HUANG ET AL.
Coumarins are present in plants in the free form and asglycosides. In general, coumarins are characterized by greatchemical diversity, mainly differing in the degree of oxygena-tion of their benzopyrane moiety. In nature, most coumarins areC7-hydroxylated (4,31). Major coumarin constituents includedsimple hydroxylcoumarins (e.g., aesculin, esculetin, scopoletin,and escopoletin), furocoumarins and isofurocoumarin (e.g.,psoralen and isopsoralen from Psoralea corylifolia), pyra-nocoumarins (e.g., xanthyletin, xanthoxyletin, seselin, khellac-tone, praeuptorin A), bicoumarins, dihydro-isocoumarins (e.g.,bergenin), and others (e.g., wedelolactone from Eclipta pros-trata) (29–31). Plants, fruits, vegetables, olive oil, and beverages(coffee, wine, and tea) are all dietary sources of coumarins; forexample, seselin from fruit of Seseli indicum, khellactone fromfruit of Ammi visnaga, and praeuptorin A from Peucedanumpraeruptorum (4,54). In our previous studies, we foundcoumarins occurred in the medicinal herbs Umbelliferae, Aster-aceae, Convolvulaceae, Leguminosae, Magnoliaceae, Oleaceae,Rutaceae, and Ranunculaceae, such as simple coumarins fromA. annua, furocoumarins (5-methoxyfuranocoumarin) fromAngelica sinensis, pyranocoumarins from Citrus aurantium,and isocoumarins from Agrimonia pilosa (12). Some Indianmedicinal plants (e.g., Toddalia aculeata, Murraya exotica,Foeniculum vulgare, and Carum copticum) and dietary spices(e.g., cumin and caraway) are also detected to possesscoumarins (28,29). In addition, coumestans, derivatives ofcoumarin, including coumestrol, a phytoestrogen, are found ina variety of medicinal and dietary plants such as soybeans andPueraria mirifica (http://en.wikipedia.org/wiki/).
LignansLignans are also derived from cis-o-hydroxycinnamic acid
and are dimers (with 2 C6-C3 units) resulting from tail–taillinkage of 2 coniferl or sinapyl alcohol units (31) (Fig. 6).Lignans are mainly present in plants in the free form and as gly-cosides in a few (4). Main lignan constituents are lignanolides(e.g., arctigenin, arctiin, secoisolariciresinol, and matairesinolfrom Arctium lappa), cyclolignanolides (e.g., chinensin fromPolygala tenuifolia), bisepoxylignans (e.g., forsythigenoland forsythin from Forsythia suspensa), neolignans (e.g.,magnolol from Cedrus deodara and Magnolia officinalis), andothers (e.g., schizandrins, schizatherins, and wulignan fromSchisandra chinensis; pinoresinol from Pulsatilla chinensis;and furofuran lignans from Cuscuta chinensis) (12,29). Thefamous tumor therapy drug podophyllotoxin (cyclolignanolide)was first identified in Podophyllum peltatum, which NativeAmericans used to treat warts, and also found in a traditionalmedicinal plant Podophyllum emodi var. chinense (13). Twonew lignans (podophyllotoxin glycosides) were isolated fromthe Chinese medicinal plant, Sinopodophyllum emodi (55). Dif-ferent lignans (e.g., cubebin, hinokinin, yatein, and isoyatein)were identified from leaves, berries, and stalks of Piper cubebaL. (Piperaceae), an Indonesian medicinal plant (56). Milder
et al. (57) established a lignan database from Dutch plant foodsby quantifying lariciresinol, pinoresinol, secoisolariciresinol,and matairesinol in 83 solid foods and 26 beverages commonlyconsumed in The Netherlands (57). They reported that flaxseed(mainly secoisolariciresinol), sesame seeds, and Brassicavegetables (mainly pinoresinol and lariciresinol) containedunexpectedly high levels of lignans. Sesamol, sesamin, and theirglucosides are also good examples of this type of compound,which come from sesame oil and sunflower oil (4).
QuinonesNatural quinones in the medicinal plants fall into 4 cate-
gories, that is, anthraquinones, phenanthraquinones, naphtho-quinones, and benzoquinones (12) (Fig. 7). Anthraquinones arethe largest class of natural quinones and occur more widelyin the medicinal and dietary plants than other natural quinones(31). The hydroxyanthraquinones normally have 1 to 3 hydroxylgroups on the anthraquinone structure. Our previous investi-gation found that quinones were distributed in 12 species ofmedicinal herbs from 9 families such as Polygalaceae, Rubi-aceae, Boraginaceae, Labiatae, Leguminosae, Myrsinaceae, andso forth (12,29). For example, high content benzoquinones andderivatives (embelin, embelinol, embeliaribyl ester, embeliol)are found in Indian medicinal herbs Embelia ribes; naphtho-quinones (shikonin, alkannan, and acetylshikonin) come fromLithospermum erythrorhizon and juglone comes from Juglansregia; phenanthraquinones (tanshinone I, IIA, and IIB) were de-tected in Salvia miltiorrhiza; denbinobin was detected in Den-drobium nobile; and many anthraquinones and their glycosides(e.g., rhein, emodin, chrysophanol, aloe-emodin, physcion, pur-purin, pseudopurpurin, alizarin, munjistin, emodin-glucoside,emodin-malonyl-glucoside, etc.) were identified in the rhizomesand roots from P. cuspidatum (also in leaves), P. multiflorum,and R. officinale in the Polygalaceae and Rubia cordifolia in theRubiaceae (12,29,33). In addition, some naphthoquinones wereisolated from maize (Zea mays L.) roots (58).
OthersBecause phenolic alkaloids, phenolic terpenoids (including
aromatic volatile oils), special phenolic glycosides, and m-benzo-triphenol derivatives contain one or more aromatic ringsbearing one or more hydroxy groups (Fig. 8), they also struc-turally belong to phenolic compounds and are widely distributedin medicinal herbs and dietary plants. There are different pheno-lic alkaloids detected in our previously investigated traditionalChinese medicinal plants such as Aconitum carmichaeli (e.g.,demethylsalsoline), Coptis chinensis (e.g., magnoflorine), Phel-lodendron amurense (e.g., phellodendrine and magnoflorine),and Zanthoxylum nitidum (e.g., nitidine and dihydronitidine)(12). Magnoflorine was also found in the traditional medicalherbal tea, Toddalia asiatica Lam. in Okinawa (59). Some Chi-nese and Indian medicinal herbs and many spices contain highlevels of various aromatic volatile oils or phenolic terpenoids
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NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS 11
O
O OHOH
R2 R1
R1=CH3, R2=H: chrysophanolR1=CH3, R2=OH: emodinR1=CH2OH, R2=H: aloe-emodinR1=COOH, R2=H: rheinR1=CH3, R2=OCH3: physcion
O
OOH
OH
R1=H, R2=OH: alkannanR1=OH, R2=H: shikoninR1=COCH3, R2=H: acetylshikonin
O
O
OH
juglone
R1 R2
O
O
HO
OH
C11H23
embelin
O
O
O
O
R
O
O
R=H: tanshinone IIAR=OH: tanshinone IIBtanshinone I
FIG. 7. The structures of representative quinones from medicinal herbs and dietary plants.
such as carnosic acid in Andrographis paniculata, Nerium ole-ander, Xanthium sibiricum, sweet basil, and sage; carnosol andepirosmanol in rosemary; carvacrol in oregano, sweet basil, androsemary; anethole in star anise; menthol in mint; thymol inthyme; eugenol in clove; estragole and xanthoxylin in Chineseprickly ash; cinnamaldehyde in cinnamon; and triptophenolideand its methyl ether in Tripterygium wilfordii (12,28,29,60).
Additionally, simple phenols (only C6 skeleton) are iden-tified in the aromatic volatiles of some medicinal herbs suchas vanillin and p-cresol from A. sinensis (12). Other pheno-lics also include syringaresinol (Clematis chinensis), paeonol(Paeonia suffruticosa), m-benzo-triphenols (agrimol A, B fromA. pilosa) and their derivatives (filicic acids from Matteucciastruthiopteris), and so forth. (12,28–31). Triptophenlolide hasbeen isolated from the roots of T. wilfordii Hook. Oleuropeinand its glycoside have been obtained from olive oil (24).
CANCER PREVENTION AND POSSIBLE MECHANISMSOF PHENOLIC COMPOUNDS FROM MEDICINALHERBS AND DIETARY PLANTS
Phenolic compounds from medicinal herbs and dietary plantspossess a range of bioactivities and play an important role inprevention of cancer (Table 1). They have complementary andoverlapping mechanisms of action including antioxidant ac-tivity and scavenging free radicals; modulation of carcinogenmetabolism; regulation of gene expression on oncogenes andtumor suppressor genes in cell proliferation and differentiation;induction of cell-cycle arrest and apoptosis; inhibition of sig-nal transduction pathways including nuclear factor kappa-light-
chain-enhancer of activated B cells (NF-κB), activator protein-1(AP-1), mitogen-activated protein kinases (MAPK), and others;modulation of enzyme activities in detoxification, oxidation,and reduction; anti-inflammatory properties by stimulation ofthe immune system; regulation of hormone metabolism; sup-pression of angiogenesis; antiatherosclerosis by inhibition pro-liferation and migration of vascular cells; neuroprotective effectson antiaging; antibacterial and antiviral effects; and action onother possible targets (4,19,21,61–114,117,118).
Phenolic Acids and AnalogsPhenolic acids and analogs possess broad bioactivities, some
of which can play a role in cancer prevention. Most pheno-lic acids have antioxidant capacity, and the radical scavengingability of phenolic acids depends on the number and position ofhydroxyl groups and methoxy substituents in the molecules (31).In addition, phenolic acids and analogs can inhibit tumor cellsand induce apoptosis by inducing cell cycle arrest; regulatingsignal transduction pathways; inducing or inhibiting some en-zymes, and enhancing detoxification. And some phenolic acidsand analogs also exhibit antibacterial, antifungal, antiviral, an-timutagenic, and anti-inflammatory activities (21,64,67,74,82)(Table 1).
Gallic acid as a natural antioxidant had significant inhibitoryeffects on cell proliferation, induced apoptosis in a series ofcancer cell lines, and showed selective cytotoxicity against tu-mor cells with higher sensitivity than normal cells (95). Cin-namic, caffeic, and ferulic acids and their esters inhibited thegrowth of bacteria and fungi, and hydroxytyrosol (an analog
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N+
H3CO
HO
HO
H3CO
magnoflorine
N
O
O
H3CO
H3CO
dihydronitidine
O
OCH3
Otriptophenolide
OH
HO
COOH
carnosic acid
R1
R2
R1=OH, R2=H: carvacrolR1=H, R2=OH: thymol
R1
R2
R1=OH, R2=OCH3: eugenolR1=OCH3, R2=H: estragole
OCH3
OH
OH
R2
R1
O
paeonolR1=OCH3, R2=CHO: vanillinR1=H, R2=CH3: p-cresol
O
O
H3CO
HO
H3CO
OCH3
OH
OCH3syringaresinol
O
O
O
COOCH3
OC6H11O5
HO
HO
oleuropein
OH
HO
O
O
carnosol
OCH3
anethole
OH
HOO
epirosmanol
OH
O
FIG. 8. The structures of some other typical phenolic compounds from medicinal herbs and dietary plants.
of phenolic acid) showed antimycoplasmal activity against My-coplasma pneumoniae, Mycoplasma hominis, and Mycoplasmafermentans (64). In addition, hydroxytyrosol could inhibit cellproliferation and the activities of lipoxygenases (LOXs), in-crease catalase (CAT) and superoxide dismutase (SOD) activ-ities, reduce leukotriene B4 production, decrease vascular celladhesion molecule-1 (VCAM-1) mRNA and protein, slow thelipid peroxidation process, attenuate Fe2+– and NO-inducedcytotoxicity, and induce apoptosis by arresting the cells in theG0/G1 phase (96–98). Many phenolic acids and analogs pos-sess anti-inflammatory effects and enhance immune functionsuch as cinnamic acids, rosmarinic acid, gingerol, paradol, andhydroxytyrosol (4). Both chlorogenic acid and caffeic acids areantioxidants and inhibit the formation of mutagenic and car-cinogenic N -nitroso compounds in vitro (21). Chlorogenic acid
could also inhibit the formation of DNA single strand breaksand prevent the formation of dinitrogen trioxide by scaveng-ing nitrogen dioxide generated in the human oral cavity (89).Furthermore, caffeic acids, capsaicin, and gingerol (an analogof phenolic acids) modulate the ceramide-induced signal trans-duction pathway, suppress the activation of NF-κB and AP1,and inhibit protein tyrosine kinase (PTK) activity (2,21,62).Gingerol could also inhibit tumor promotion, epidermal growthfactor, tumor necrosis factor-alpha (TNF-α) production, andphorbol-12-myristate-13-acetate (PMA)-induced ornithine de-carboxylase activity (2). Moreover, some phenolic acids (caf-feic acid, ferulic acid, gallic acid, protocatechuic acid, etc.) ingrape extracts and wine contribute to their activity against var-ious types of cancer such as breast, lung, and gastric cancer(36).
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NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS 13
TABLE 1Cancer prevention and possible mechanisms of phenolic compounds from medicinal herbs and dietary plantsa
Phenolic CompoundsMechanisms of Action (Representative Phenolics) References
Antioxidant and antiaging activityScavenge free radicals and ROS, such as superoxide
anion, singlet oxygen, hydroxyl radical, peroxylradical, nitric oxide, nitrogen dioxide andperoxynitrite; increase SOD activities; decreaselipoperoxidation.
Phenolic acids and analogs (caffeic acid,gallic acid, chlorogenic acid, and ellagicacid), flavonoids (catechin and quercetin),tannins (proanthocyanidins, corilagin),stilbenes (resveratrol), curcuminoids,coumarins, lignans, quinones, and others.
4,19,21,29,31,34,63,95,108, 111
Antiangiogenesis and antimutagenic propertiesInhibit cell proliferation; inhibit oncogene expression;
induce tumor suppressor gene expression; inhibitvascular endothelial growth factor.
Phenolic acids and analogs (chlorogenic acidand hydroxytyrosol), flavonoids andanalogs (apigenin, daidzein, hesperetin,luteolin, kaempferol, myricetin, quercetin,EGCG, genistein, and silymarin), tannins(proanthocyanidins), stilbenes(resveratrol), curcuminoids (curcumin),coumarins, lignans, quinones, and others.
4,21,101,103, 110,118
DNA binding prevention Flavonoids (methoxylated flavonoids andflavones), stilbenes (resveratrol),curcuminoids (curcumin), and quinones.
91,92
Enhancement of immune functions and surveillanceSuppress production of TNF, a pro-inflammatory
cytokine and growth factor for most tumor cells;suppress LOXs, iNOS, chemokines, and otherinflammatory molecules.
Phenolic acids and analogs (cinnamic acids,rosmarinic acid, gingerol, paradol, andhydroxytyrosol), flavonoids and analogs(apigenin, genistein, luteolin, quercetin,ECG, EGCG, and silymarin), tannins(proanthocyanidins, tannic acid), stilbenes(resveratrol), curcuminoids (curcumin),coumarins (coumarin), lignans (sesamol),quinones, and others.
4,19,21,61, 66–70
Enzyme inhibitionPhase I enzyme (block activation of carcinogens);
COX-2; iNOS; XO; signal transduction enzymes,such as PKC and PTK; topoisomerase I and II;telomerase; urease; lipase; angiotensin I-convertingenzyme; DNA methytransferases (consequentreactivation of key tumor suppressor gene p16).
Phenolic acids and analogs (chlorogenicacid, caffeic acid, ellagic acid, andhydroxytyrosol), flavonoids and analogs(apigenin, luteolin, quercetin, and EGCG),tannins (proanthocyanidins, corilagin),stilbenes (resveratrol), curcuminoids(curcumin), coumarins, lignans(podophyllotoxin), and quinones.
4,19,21, 74–78,100
Enzyme induction and enhancing detoxification
Phase II enzymes, such as UDP-glucuronosyltransferase and quinine reductases; glutathioneperoxidase; catalase; SOD; cytochrome P450epoxide hydrolase; NADPH:quinone reductase.
Phenolic acids and analogs (protocatechuicacid and ellagic acid), flavonoids(hesperidin and anthocyanins), tannins,stilbenes (resveratrol), curcuminoids(curcumin), lignans, and quinones.
4,71–73
Inhibition of cell adhesion and invasionInhibit expression of cell-adhesion molecules, namely
ICAM-1 and VCAM-1; inhibit tumor cell invasionthrough Matrigel, cell migration, and cellproliferation.
Phenolic acids and analogs (hydroxytyrosol),flavonoids (baicalein, apigenin, and citrusflavonoids), stilbenes (resveratrol),curcuminoids (curcumin), and lignans.
4,87,88, 96–97
(Continued on next page)
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TABLE 1Cancer prevention and possible mechanisms of phenolic compounds from medicinal herbs and dietary plantsa (Continued)
Phenolic CompoundsMechanisms of Action (Representative Phenolics) References
Induction of cell differentiation Flavonoids (apigenin), tannins (chebulinicacid), and coumarins.
79,80
Induction of cell-cycle arrest and induction of apoptosisInhibit different cell cycles at different cell phases: G1,
S, S/G2, and G2; direct or indirect effect on cellcycle arrest; subsequently induce apoptosis,involving p53, the Bcl-2, and caspase families.
Phenolic acids (ferulic acid, caffeic acid andits phenethyl ester, ellagic acid, andhydroxytyrosol), flavonoids (quercetinand EGCG), tannins (proanthocyanidins,gallotannin and casuarinin), stilbenes(resveratrol), curcuminoids (curcumin),coumarins (coumarin and7-hydroxycoumarin), lignans (sesamin),quinones, and others (eugenol).
3,4,21,62, 81–84,95
Inhibition of signal transduction pathwaysNrf-KEAP1 (Kelch-like ECH-associated protein 1)
complex signaling pathways; NF-κB and AP-1signaling pathway, including c-Jun activitysuppression; the Wnt or β-catenin signaling pathway(direct inhibition of mitosis); MAPK signalingpathway; growth-factor receptor-medicatedpathways.
Phenolic acids and analogs (caffeic acid,gingerol, and capsaicin), flavonoids andanalogs (apigenin, genistein, quercetin,EGCG, and silymarin), tannins(proanthocyanidins, ellagitannins),stilbenes (resveratrol), curcuminoids(curcumin), coumarins (esculetin),lignans, quinones (emodin), and others(anethole and carnosol).
2,4,19,21,61,62,85,86,99,112
Regulation of steroid hormone and estrogen metabolismSome are important phytoestrogens; modulate the level
of hormones; inhibit androgen receptor effects inLNCaP prostate cancer cell.
Phenolic acids and analogs (gossypol),flavonoids (isoflavones: formononetin,glycitein, genistein and daidzein),stilbenes (resveratrol), coumarins(coumestans: coumestrol), and lignans(pinoresinol, lariciresinol,secoisolariciresinol, and matairesinol).
21,93,94,117
Inhibition of acrylamide, nitrosation, and nitrationInhibit formation of acrylamide and heterocyclic
amines, probable/possible human carcinogens.Phenolic acids (caffeic acid and gallic acid),
flavonoids (homoorientin, luteolin,quercetin, and EGCG), curcuminoids(curcumin), and others (eugenol).
65,89,90,113,114
Antiviral, antibacterial, and antifungal effectsDownregulate HIV expression, subsequently inhibit
liver cancer.Phenolic acids and analogs (cinnamic acid
and its esters, and hydroxytyrosol),flavonoids, tannins, stilbenes (resveratrol),curcuminoids (curcumin), coumarins,lignans, quinones, and others.
21,64,105,106
aAbbreviations are as follows: ROS, reactive oxygen species; SOD, superoxide dismutase; TNF, tumor necrosis factor; LOX, lipoxygenases;iNOS, inducible nitric oxide synthase; COX-2, cyclooxygenase-2; XO, xanthine oxidase; PKC, protein kinase C; PTK, protein tyrosine kinase;UDP, NADPH, nicotinamide adenine dinucleotide phosphate; ICAM-1, intercellular adhesion molecule-1; VCAM-1, vascular cell adhesionmolecule-1; Bcl-2, B-cell non-Hodgkin lymphoma-2; nuclear factor kappa of activated B cells; AP-1, activator protein-1; MAPK, mitogen-activated protein kinases; LNCaP, lymph node carcinoma of the prostate; EGCG, epigallocatechin gallate; ECG, epicatechin gallate.
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NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS 15
FlavonoidsFlavonoids have been linked to reducing the risk of major
chronic diseases including cancer because they have powerfulantioxidant activities in vitro, being able to scavenge a widerange of reactive species (e.g., hydroxyl radicals, peroxyl rad-icals, hypochlorous acid, and superoxide radicals) (42). Manyflavonoids chelate transition metal ions such as iron and copper,decreasing their ability to promote reactive species formation.Flavonoids also inhibit bio-molecular damage by peroxynitritein vitro, prevent carcinogen metabolic activation, induce apop-tosis by arresting cell cycle, promote differentiation, modulatemultidrug resistance, and inhibit proliferation and angiogenicprocess (42,71,72,91) (Table 1). These activities of flavonoidsare related to their structures. Flavonols containing more hy-droxyl groups exhibit very high radical scavenging activity, forexample, myricetin, quercetin, rutin, and quercitrin are well-known potent antioxidants. Flavanols with additional catecholstructure (3-galloyl group) have significantly enhanced antirad-ical activity (31). Moreover, glycosylation of hydroxyl groupsand substitution of other substituents (e.g., methoxy groups)also affects the antioxidant activity of flavonoids (34).
Many flavonoids possess diverse bioactivities. For exam-ple, apigenin could inhibit cell adhesion and invasion; reducethe formation of diolepoxide 2, mitochondrial proton F0F1-ATPase/ATP synthase, prostaglandin synthsis, and IL-6,8 (in-terleukin) production; block the expression of intercellular adhe-sion molecule-1 (ICAM-1), vascular cell adhesion molecule-1(VCAM-1), and E-selectin; and induce cell differentiation andinterferon-gamma gene expression (79,87). Furthermore, genis-tein, luteolin, quercetin, ECG, EGCG, and silymarin as well asapigenin show antiangiogenesis and antimutagenic properties(62). Besides these 7 flavonoids and analogs, daidzein, hes-peretin, kaempferol, and myricetin were all anti-inflammatory(21,46). In addition, apigenin, genistein, quercetin, EGCG, andsilymarin could suppress the activation of NF-κB and AP1 andblock signal transduction pathways (2,62,79,87). Silymarin alsoprevented induction of apoptosis and suppressed protein kinasesand MAPKs (46). Soy isoflavone genistein was an angiogene-sis inhibitor that could inhibit the growth of new blood vesselsand showed antitumor and antiangiogenic activity in mousemodels of melanoma and breast cancer (116). Moreover, someisoflavones (e.g., genistein and daidzein) were phytoestrogensand could mimic the biological activity of estrogens and mod-ulate steroid hormone metabolism. Therefore, they might playan important role in breast cancer prevention (117).
Some catechins (e.g., EGCG and EGC) showed significantradical scavenging ability and could chelate metal ions and pre-vent the generation of free radicals. Their specific chemicalstructures (i.e., vicinal dihydroxy or trihydroxy structure) con-tribute to their potent antioxidant activity (31). EGCG couldinhibit telomerase, LOXs, and DNA methyltransferase; reducethe expression of COX-2 (cyclooxygenase) and activation ofNF-κB and AP1; block c-Jun N-terminal kinase (JNK) andp38 MAPK-related signaling pathways; attenuate adhesion and
migration of peripheral blood CD8 T cells; increase eNOS (ni-tric oxide synthase) activity; and induce apoptosis by activatingcaspases and arresting cell growth G0/G1 phase of the cell cy-cle (2,4,21,99). Also, EGCG could induce apoptosis in humanepidermoid carcinoma cells but not in normal human epidermalkeratinocytes (99).
Quercetin is one of the most potent antioxidants and has an-tioxidant, anti-inflammatory, antiproliferative, or apoptotic ef-fects in vitro or in vivo. At molecular level, quercetin acts asan anticancer agent through modulation of cell cycle, protein,oncogenes, and antioncogenes (100). In addition, quercetin caninhibit the activity of caspases-3, protein kinases, telomerase,lymphocyte tyrosine kinase, different tyrosines, and serine-threonine kinases; increase the expression of nicotinamide ade-nine dinucleotide phosphate (NADPH):quinine oxidereductaseand activity of SOD, CAT, GSH; decrease lipoperoxidation,NO production and iNOS (inducible nitric oxide synthase) pro-tein expression, and levels of some oxidative metabolites; pre-vent lactate dehydrogenase (LDH) leakage; interact with theβ-catenin pathway; block c-Jun N-terminal kinase (JNK) andp38 MAPK-related signaling pathway; enhance Nrf2-mediated(NF-E2-related factor-2, a basic region-leucine zipper transcrip-tion factor to regulate transactivation of antioxidant genes) tran-scription activity; suppress angiogenesis, colorectal crypt cellproliferation; and induce apoptosis in different cell lines by ar-resting cell cycle (4,21,62,100).
TanninsHydrolysable tannins and condensed tannins are powerful an-
tioxidant agents because they have many hydroxyl groups, espe-cially many ortho-dihydroxyl or galloyl groups. Bigger tanninmolecules possess more galloy and ortho-dihydroxyl groups,and their activities are stronger (31). In addition, these tanninsalso exhibit strong antibacterial, antiulcer, anti-inflammatory,antileishmanial, antimutagenic, enzyme regulating, signal trans-duction pathways blocking, and apoptotic activities; thus, theyhave attracted wide attention for cancer treatment (68,75,82,85)(Table 1). For example, gallotannin showed anticarcinogenicactivities in several animal models including colon cancer, andthe hydrolysable tannin-containing fraction from Sweet Charliestrawberries was most effective at inhibiting mutation (101). Inaddition, 4 ellagitannins and 2 chromone gallates significantlyblocked epidermal growth factor-induced cell transformationby attenuating AP-1 and phosphoinositide 3-kinases (PI3K)signaling pathways activation, and by inhibiting phosphoryla-tion of extracellular-signal regulated protein kinases and p38kinases (85). Chebulinic acid had an inhibitory effect on dif-ferentiation of human leukemia K562 cells through regulatingtranscriptional activation of erythroid related genes includinggamma-globin, and NF-E2 genes, and through inhibiting acetyl-cholinesterase and hemoglobin synthesis (79). Casuarinin, a hy-drolysable tannin isolated from the bark of Terminalia arjuna L.(Combretaceae), could inhibit the proliferation by blocking cell
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cycle progression in the G0/G1 phase and by inducing apoptosisin human breast adenocarcinoma cells (81).
StilbenesStilbenes, especially resveratrol, possess potential antioxi-
dant, antibacterial, antiviral, anti-inflammatory, and anticanceractivities (2,4,21,62,94) (Table 1). Resveratrol has increased inimportance as a cancer preventive agent since 1997 (51). Resver-atrol can affect the processes underlying all 3 stages of carcino-genesis, namely, tumor initiation, promotion, and progression.It had also been shown to suppress angiogenesis and metastasis.Extensive data in human cell cultures indicated that resvera-trol could modulate multiple pathways involved in cell growth,apoptosis, and inflammation; and resveratrol and its hydroxy-lated analogues also possess antileishmanial activity (102,103).For molecular mechanisms of cancer prevention, resveratrol andits analogs could retard tumor progression by triggering numer-ous intracellular pathways leading to cell growth arrest such asinhibition of protein kinase C (PKC) activation; downregula-tion of β-catenin expression; counteraction of reactive oxygenspecies (ROS) production; activation of caspases; induction ofgenes for oxidative phosphorylation and mitochondrial biogen-esis; and blocking NF-κB and AP1 mediated signal transductionpathways (51,94,102,103). Furthermore, resveratrol can inhibitthe expression and function of the androgen receptor effects inLNCaP prostate cancer cell line by repressing androgen recep-tor upregulated genes (94). In addition, 40 stilbene oligomerspossessed inhibitory activity against DNA topoisomerase II(50).
CurcuminoidsOngoing laboratory and clinical studies have indicated that
curcuminoids possess unique antioxidant, anti-inflammatory,anticarcinogenic/antimutagenic, antithrombotic, hepatoprotec-tective, antifibrosis, antimicrobial, antiviral, and antiparasiticproperties and play important roles in cancer chemotherapy(88,92,104) (Table 1). In particular, curcumin can suppress tu-mor promotion, proliferation, angiogenesis, and inflammatorysignaling; decrease oxidatively modified DNA and the level ofNOS mRNA and protein; modulate AP-1 signaling pathways;block phosphorylation and subsequent degradation of IκB ki-nase β activity; inhibit NF-κB-regulated gene products (cyclinD1, Bcl-2, Bcl-xL, COX-2); sustain phosphorylation of JNK andp38 MAPK; activate caspase-8, BID cleavage, and cytochromec release; downregulate iNOS expression; upregulate Map ki-nase phosphates-5; and also has proapoptotic and antimetastaticactivities (4,88,92). Tetrahydrocurcuminoid is a colorless hy-drogenated product derived from the yellow curcuminoids andcan be used as an efficient superior antioxidant mixture of com-pounds for use in achromatic foods and cosmetics (105). Inaddition, the ginerol analogues in ginger also had antioxidantactivity (2).
CoumarinsCoumarins and derivatives possess diverse bioactivities, such
as antioxidant, antitubercular, antimalarial, anti-HIV-1, antian-giogenesis, antimutagenic, anti-inflammatory, cell differenti-ation inducing, xanthine oxidase inhibiting, and cytotoxicityagainst human cancer cell lines (69,76,106) (Table 1). For exam-ple, coumarin and 7-hydroxycoumarin show antitumor actionsin vitro and in vivo on human lung carcinoma cell lines by in-hibiting cell proliferation, arresting cell cycle in the G phase, andinducing apoptosis (83). Esculetin (6,7-dihydroxycoumarin)showed lipoxygenase inhibitory effect on the proliferation re-sponse of cultured rabbit vascular smooth muscle cells by modu-lating P signal transduction pathway (86). The structure-activityrelationship of esculetin and 8 other coumarin derivatives indi-cated that 2 adjacent phenolic hydroxyl groups at the C-6 andC-7 positions in the coumarin skeleton were necessary for thepotent antiproliferative and antioxidant effect. Therefore, glyco-sylation and damage of the catechol structure (ortho-dihydroxygroups) had significant negative influence on the activity ofthe coumarins, for example, it considerably reduced the radicalscavenging level (31).
LignansSome authors have reported that there was a beneficial ef-
fect of the hydroxyl group in the lignan molecules on theantioxidant activity and anticancer activity, but most of thelignans did not exhibit strong activity in scavenging radicals(31,63,107). Many reports also have shown that lignans couldhave anti-inflammatory, antibacterial, antiviral, antiallodynic,antiangiogenesis, and antimutagenic properties; regulate expres-sion of enzymes, signal transduction pathways, and hormonemetabolism; enhance detoxification; induce apoptosis by cellcycle arresting; and reduce human breast cancer cell adhesion,invasion, and migration in vitro (70,77,93) (Table 1). For exam-ple, sesamin had been reported to possess antioxidant, inductionof apoptosis, cell cycle arresting, and anti-inflammatory effectsand could be used in killing human leukemia, stomach, breast,and skin cancer cells (4). And podophyllotoxin was used in thetreatment of cancer as a DNA topoisomerase II (topo II) in-hibitor, because topo II induced DNA double-strand breaks andthus reduced torsion tension in DNA during replication and thecondensation of chromosomes in the nucleus during cell divi-sion (13). In addition, lignans (e.g., pinoresinol, lariciresinol,secoisolariciresinol, and matairesinol) are also important phy-toestrogens (118).
QuinonesQuinones (especially hydroxyanthraquinones) are natural
phenolic antioxidants. Among the hydroxyanthraquinones,purpurin, pseudopurpurin, and alizarin were most effective, andmany others (e.g., emodin, chrysazine, rhein, chrysophanol, andaloe-emondin), without the ortho-dihydroxy structure, werefar less effective (31). This indicated that the ortho-dihydroxy
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structure in the hydroxyanthraquinone molecules played asignificant role in improving the radical scavenging capacitylike the catechol structure in other phenolic molecules. Inaddition, glycosylation of hydroxyanthraquinones markedlydiminished their radical scavenging activity (108). Quinonemetabolites perform a variety of key functions in plants includ-ing pathogen protection, oxidative phosphorylation, and redoxsignaling. Many of these structurally diverse compounds exhibitpotent antimicrobial, anticancer, antitumor, antiangiogenesis,antimutagenic, and anti-inflammatory properties (109,110).Many studies have reported that some quinones (e.g., emodin)can prevent DNA binding, inhibit casein kinase-2 and urease,induce pRb-preventable G2/M cell cycle arrest and apoptosis,modulate the function of kinases, and block signal transductionpathways (13,66,78,84). Therefore, certain quinones can playan important role as biomarkers for cancer chemoprevention.
OthersOther phenolic compounds also present a wide range of
bioactivities (Table 1). For example, magnoflorine from T. asiat-ica had anti-HIV activity; dihydronitidine possessed tumor spe-cific cytotoxicity effects; triptophenlolide had clear inhibitoryeffects on lymphocyte and IgG and Mn(III)-based oxidativeradical cyclization reactions (111); oleuropein and its glyco-side and carnosol had antioxidant, induction of apoptosis, cellcycle arresting, and anti-inflammatory effects; and anetholeand carnosol suppressed AP-1 activation (59,61). Furthermore,eugenol exhibited potent antiproliferation activity at differentstages of progression; induced apoptosis by blocking cells inthe S phase of progression; inhibited E2F1 transcriptional ac-tivity in melanoma cells; and has been used as an antiseptic,antibacterial, analgesic agent in traditional medical practices inAsia (112).
Interestingly, natural phenolic compounds also suppress theformation of mutagenic and carcinogenic acrylamide and het-erocyclic amines (65). High levels of acrylamide have beenfound after frying or baking of carbohydrate-rich foods such aspotatoes and cereal products (113). Acrylamide has been classi-fied as “probably carcinogenic to humans” by the InternationalAgency for Research on Cancer. In earlier toxicological stud-ies, acrylamide was genotoxic and carcinogenic to test animalsand caused reproductive and developmental problems (65). Ad-ditionally, a series of heterocyclic amines (HCAs) have beenisolated as mutagens from various kinds of thermally processedmaterials including cooked meat and fish and pyrolysis prod-ucts of amino acids and proteins (113). Many HCAs have beendemonstrated to be capable of forming DNA adducts to induceDNA damage, and some of them have been classified by the In-ternational Agency for Research on Cancer as probable/possiblehuman carcinogens (113). Plant-derived extracts such as bam-boo leaves, ginkgo, tea, grape seed extracts, and so forth, canreduce acrylamide in various heat-treated foods to varying ex-tents (114). In addition, extracts from berries (e.g., blackberry,
chokeberry, grape, and cherry), spices (e.g., thyme, marjoram,rosemary, sage, and garlic), soy, tea, and pine bark have signifi-cant effects on suppressing formation of both polar and nonpolarHCAs (90). Results showed that different antioxidant phenoliccompounds in these plant extracts may play roles in reductionor inhibition of acrylamide and HCAs, subsequently reducingpotential mutagenic/carcinogenic harm of certain cooked foods(113,114).
CONCLUSIONPhenolic compounds are ubiquitous and rich in medicinal
herbs and dietary plants (e.g., fruits, vegetables, spices, cereals,and beverages). Various phenolic compounds possess a diverserange of beneficial biological activities, which contribute to theirpotent effects on inhibiting carcinogenesis. Extensive researchhas been conducted in vitro or in vivo on antioxidant and anti-cancer activities of phenolic compounds from medicinal herbsand dietary plants. Overwhelming clinical evidence has shownthat chemoprevention by phenolic phytochemicals is an inex-pensive, readily applicable, acceptable, and accessible approachto cancer control and management (3). However, more informa-tion about the health benefits and the possible risks of dietarysupplement or herbal medicines is needed to ensure their efficacyand safety. In fact, toxic flavonoids and drug interactions, liverfailure, dermatitis, and anemia were reported for some cases ofpolyphenol chemopreventive use (115). These potential toxiceffects of phenolic compounds are strongly dependent on theirconcentration and chemical environment, which must be thor-oughly understood before any preventive or therapeutic use isconsidered (4). However, information on safety assessment ofnatural phenolic compounds is still lacking.
In general, medicinal herbs and dietary plants are a goodresource of bioactive phenolic compounds in cancer prevention,and only limited aspects have been investigated. There is stillmuch work needed to search for novel and effective anticancerphenolic compounds from more medicinal and dietary plants, tofurther reveal mechanistic process, and to conduct confirmatoryhuman clinical trials of these phenolic compounds in cancerprevention and treatment.
ACKNOWLEDGMENTSThis research was supported by grants from the University of
Hong Kong (Seed Funding for Basic Research). We are gratefulto Dr. Harold Corke and Dr. Mei Sun (School of BiologicalSciences, The University of Hong Kong) for their revision andcomments on this manuscript.
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