Wu-Yang Huang, Yi-Zhong Cai - Natural Phenolic Compounds From Medicinal Herbs and Dietary Plants, Use For Cancer Prevention

This article was downloaded by: [University of Valladolid] On: 11 January 2012, At: 04:09 Publisher: Routledge Informa
Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Nutrition and Cancer

Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/hnuc20
Natural Phenolic Compounds From Medicinal Herbs and Dietary Plants: Potential Use for Cancer Prevention
Wu-Yang Huang , Yi-Zhong Cai & Yanbo Zhang
a b a a b
School of Biological Sciences, University of Hong Kong, Hong Kong, PR China 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 Herbs and 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
PLEASE SCROLL DOWN FOR ARTICLE Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. The publisher does not give any warranty express or implied or make any representation that the contents will be complete or accurate or up to date. The accuracy of any instructions, formulae, and drug doses should be independently verified with primary sources. The publisher shall not be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or howsoever caused arising directly or indirectly in connection with or arising out of the use of this material.
Nutrition and Cancer, 62(1), 120 Copyright 2010, Taylor & Francis Group, LLC ISSN: 0163-5581 print / 1532-7914 online DOI: 10.1080/01635580903191585
Natural Phenolic Compounds From Medicinal Herbs and Dietary Plants: Potential Use for Cancer Prevention
Wu-Yang Huang and Yi-Zhong Cai
School of Biological Sciences, the University of Hong Kong, Hong Kong, PR China
Yanbo Zhang
School of Chinese Medicine, the University of Hong Kong, Hong Kong, PR China
Natural phenolic compounds play an important role in cancer prevention and treatment. Phenolic compounds from medicinal herbs and dietary plants include phenolic acids, avonoids, tannins, stilbenes, curcuminoids, coumarins, lignans, quinones, and others. Various bioactivities of phenolic compounds are responsible for their chemopreventive properties (e.g., antioxidant, anticarcinogenic, or antimutagenic and anti-inammatory effects) and also contribute to their inducing apoptosis by arresting cell cycle, regulating carcinogen metabolism and ontogenesis expression, inhibiting DNA binding and cell adhesion, migration, proliferation or differentiation, and blocking signaling pathways. This review covers the most recent literature to summarize structural categories and molecular anticancer mechanisms of phenolic compounds from medicinal herbs and dietary plants.
INTRODUCTION Cancer 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 Organization (WHO) (http://www.who.int/cancer/en/), from a total of 58 million deaths worldwide in 2005, cancer accounted for 13%. There are now more than 10 million cases of cancer per year worldwide, including a group of more than 100 diseases such as cancer of the liver, lung, stomach, colon, breast, and so forth (2,3). The most rational way to affect carcinogenesis is by interfering with modulation steps (initiation, promotion, and progression) as well as the associated signal transduction pathways (4). There are numerous physiological and biochemical carcinogens, for example, ultraviolet and ionizing radiation; asbestos and tobacco smoke (5); infections by virus (e.g., hepatitis B
Submitted 12 December 2008; accepted in nal form 14 April 2009. Address correspondence to Wuyang Huang, School of Biological Sciences, the University of Hong Kong, Pokfulam Road, Hong Kong, PR China. Phone: 852-22990-846. Fax: 852-25599-114. E-mail: wuyang@ualberta.ca
virus causing liver cancer and human papilloma virus causing cervical cancer) (6,7); bacteria (Helicobacter pylori causing gastric cancer) (8) and parasites (schistosomiasis causing bladder cancer) (9); and contamination of food by mycotoxins (e.g., aatoxins causing liver cancer) (10). Some kinds of cancer are due to oxygen-centered free radicals and other reactive oxygen species because overproduction of such free radicals can cause oxidative 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 effective, possess low toxicity, and have a minor environment impact. Novel natural products offer opportunities for innovation in drug discovery (12). In fact, natural products play a major role in cancer prevention and treatment. A considerable number of antitumor agents currently used in the clinic are of natural origin. For instance, over half of all anticancer prescription drugs approved internationally between the 1940s and 2006 were natural products or their derivatives (13). Among them, plants have been 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). Natural compounds isolated from medicinal plants, as rich sources of novel anticancer drugs, have been of increasing interest since then. Traditional medicinal herbs have been used for pharmaceutical and dietary therapy for several millennia in East Asia, for example, in China, Japan, India, Thailand, and are currently widely used in cancer therapy (12). During long-term folk practice, a large number of anticancer medicinal herbs and many relevant prescriptions have been screened and used for treating and preventing various cancers (15). Recently, many studies have reported medicinal plants in treatment and prevention of cancer (13). Earlier investigation showed that an average of 35% of overall human cancer-related mortality was attributed to diet (16). Substantial evidence from population as well as laboratory studies have revealed an inverse relationship between sufcient consumption of fruit and vegetables and the risk of specic cancers, 1
Downloaded by [University of Valladolid] at 04:09 11 January 2012
W.-Y. HUANG ET AL.
that is, a high dietary intake of fruits and vegetables as well as whole grains is strongly associated with reduced risk of cancer (2). Many clinical trials on the use of nutritional supplements and modied diets to prevent cancer are ongoing (17). Dietary plantsuch as fruits, vegetables, spices, cereals, and edible tubers/rootswhich also contain signicant levels of bioactive natural compounds, may provide human health benets beyond basic nutrition to reduce the risk of many chronic diseases including cancer (18). The cancer-protective effects elicited by these dietary compounds are believed to be due to the induction of cellular defense systems including the detoxifying and antioxidant enzymes system as well as the inhibition of antiinammatory and anticell growth signaling pathways culminating in cell cycle arrest and/or cell-death (19). Phytochemicals are dened as bioactive nonessential nutrients from plants (phyto is derived from the Greek word phyto, which means plant). They have a variety of human health effects such as possessing putative chemo-reventive properties (anticarcinogenic and antimutagenic) and interfering with tumor promotion and progression (2,19). The National Cancer Institute, based on numerous reports describing anticancer activity, identied about 40 edible plants possessing cancer-preventive properties (20). Moreover, there are more than 400 species of traditional Chinese medicinal herbs associated with anticancer (12). It is estimated that more than 5,000 individual phytochemicals have been identied in fruits, vegetables, grains, and other plants, mainly classied as phenolics, carotenoids, vitamins, alkaloids, nitrogen-containing compounds, and organosulfur compounds. Among the great structural diversity of phytochemicals, phenolic compounds have attracted considerable interest and the most attention for their wide variety of bioactivities (21). Phenolic compounds provide essential functions in the reproduction and growth of plants; act as defense mechanisms against pathogens, parasites, and predators; as well as contribute to the color of plants (22). In addition, phenolics abundant in vegetables and fruits are reported to play an important role as chemopreventive agents; for example, the phenolic components of apples have been linked with inhibition of colon cancer in vitro (23). Many phenolic compounds have been reported to possess potent antioxidant activity and to have anticancer or anticarcinogenic/antimutagenic, antiatherosclerotic, antibacterial, antiviral, and anti-inammatory activities to a greater or lesser extent (2124). Our recent studies have characterized a large number of natural phenolic compounds from 112 traditional Chinese medicinal herbs associated with anticancer, 133 traditional Indian medicinal herbs, and about 50 dietary plants (e.g., spices, cereals, vegetables, and fruits) and evaluated their antioxidant activity and other bioactivities (12,2533). Hundreds of natural phenolic compounds have been identied from our tested medicinal herbs and dietary plants, mainly including phenolic acids, avonoids, tannins, stilbenes, curcuminoids, coumarins, lignans, quinones, and phenolic mixtures and other phenylethanoids and phenylpropanoids. Their physiological and pharmacological functions may originate from their antioxidant
and free radical scavenging properties and function of regulating detoxifying enzymes (2). Further, these antioxidant activities are related to the structures of phenolic compounds, generally depending on the number and positions of hydroxyl groups and glycosylation or other substituents (31,34). CHEMISTRY AND OCCURRENCE OF PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS Phenolics are compounds possessing one or more aromatic rings bearing one or more hydroxyl groups with over 8,000 structural variants and generally are categorized as phenolic acids and analogs, avonoids, tannins, stilbenes, curcuminoids, coumarins, lignans, quinones, and others based on the number of phenolic rings and of the structural elements that link these rings (4). Phenolic Acids and Analogs Phenolic 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, vanillic acid, and syringic acid) and hydroxycinnamic acids (e.g., ferulic acid, caffeic acid, p-coumaric acid, chlorogenic acid, and sinapic acid) (31). Natural phenolic acids, either occurring in the free or conjugated forms, usually appear as esters or amides. Due to their structural similarity, several other polyphenols are considered as phenolic acid analogs such as capsaicin, rosmarinic acid, gingerol, gossypol, paradol, tyrosol, hydroxytyrosol, ellagic acid, cynarin, and salvianolic acid B (4,21) (Fig. 1). Gallic acid is widely distributed in medicinal herbs, such as Barringtonia racemosa, Cornus ofcinalis, Cassia auriculata, Polygonum aviculare, Punica granatum, Rheum ofcinale, Rhus chinensis, Sanguisorba ofcinalis, and Terminalia chebula as well as dietary spices, for example, thyme and clove (12,2831). Other hydroxybenzoic acids are also ubiquitous in medicinal herbs and dietary plants (spices, fruits, vegetables). For example, Dolichos biorus, Feronia elephantum, and Paeonia lactiora contain hydroxybenzoic acid; Cinnamomum cassia, Lawsonia inermis, dill, grape, and star anise possess protocatechuic acid; Foeniculum vulgare, Ipomoea turpethum, and Picrorhiza scrophulariiora have vanillic acid; Ceratostigma willmottianum and sugarcane straw possess syringic acid (12,2831,35,36). Ferulic, caffeic, and p-coumaric acid are present in many medicinal herbs and dietary spices, fruits, vegetables, and grains (12). Wheat bran is a good source of ferulic acids. Free, solubleconjugated, and bound ferulic acids in grains are present in the 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 hydroxycinnamic acids (caffeic, ferulic, p-coumaric acid) and p-hydroxybenzoic, ellagic acid, which contribute to their antioxidant activity (38). Chlorogenic acids are the ester of caffeic
NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS
R1
COOH
R1
COOH
R OH HO
HO R2
HO R2
R1=H, R 2=H: p-hydroxybenzoic acid R1=H, R 2=OH: protocatechuic acid R1=OH, R2=OH: gallic acid R1=OCH3, R 2=H: vanillic acid R1=OCH3, R 2=OCH3: syringic acid
O H3CO OH
R1=H, R 2=H: p-coumaric acid R1=H, R 2=OH: caffeic acid R1=H, R 2=OCH3: ferulic acid R1=OCH3, R 2=OCH3: sinapic acid
HO
R=H: tyrosol R=OH: hydroxytyrosol
H N H3CO O
HO
gingerol
OH
capsaicin
OH HO HOOC OH OH
O HO O
O OH O OH OH O COOH O OH O OH OH O O OH
OH
cynarin (1,3-dicaffeoylquinic acid)
chlorogenic acid
HO O OH O HO HO O O HO O HO OH O OH O
salvianolic acid B
OH O
ellagic acid
O OH HO
OH
HO
COOH
OH
O OH OH HO O O OH
HO
gossypol
FIG. 1.
rosmarinic acid
Chemical structures of common phenolic acids and analogs from medicinal herbs and dietary plants.
W.-Y. HUANG ET AL.
acids and are the substrate for enzymatic oxidation leading to browning, particularly in apples and potatoes. We also found that chlorogenic acid is a major phenolic acid from medicinal plants especially in the species of Apocynaceae and Asclepiadaceae (39). Salvianolic acid B is a major water-soluble polyphenolic acid extracted from Radix salviae miltiorrhizae, which is a common herbal medicine clinically used as antioxidant agent for thousands of years in China. There are 9 activated phenolic hydroxyl groups that may be responsible for the release of active hydrogen to block lipid peroxidation reaction (3). Rosmarinic acid is an antioxidant phenolic compound, which is found in many dietary spices such as mint, sweet basil, oregano, rosemary, sage, and thyme (28). Gossypol, a polyphenolic aldehyde, derived from the seeds of cotton plant (genus Gossypium, family Malvaceae), has contraceptive activity and can cause hypokalemia in some men (21). Gingerol, a phenolic substance, is responsible for the spicy taste of ginger (2).
Flavonoids Flavonoids are a group of more than 4,000 phenolic compounds that occur naturally in plants (40). These compounds commonly have the basic skeleton of phenylbenzopyrone structure (C6 -C3 -C6 ) consisting of 2 aromatic rings (A and B rings) linked by 3 carbons that are usually in an oxygenated central pyran ring, or C ring (12). According to the saturation level and opening of the central pyran ring, they are categorized mainly into avones (basic structure, B ring binds to the 2 position), avonols (having a hydroxyl group at the 3 position), avanones (dihydroavones) and avanonols (dihydroavonols; 23 bond is saturated), avanols (avan-3-ols and avan-3,4-diols; C-ring is 1-pyran), anthocyanins (anthocyanidins; C-ring is 1-pyran, and 12 and 34 bonds are unsaturated), chalcones (C-ring is opened), isoavonoids (mainly isoavones; B ring binds to the 3 position), neoavonoids (B ring binds to the 4-position), and biavonoids (dimer of avones, avonols, and avanones) (12,31,40,41) (main structure groups/subgroups; see Fig. 2). In nature, avonoids can occur either in the free or conjugated forms, and often in plants they are mainly present as glycosides with a sugar moiety or more sugar moieties linked through an OH group (O -glycosides) or through carbon-carbon bonds (C -glycosides); but some avonoids are present as aglycones (4,31). More than 80 different sugars have been discovered bound to avonoids, and common glycosides include glucoside, glucuronide, galactoside, arabinoside, rhamnoside, apiosylglucoside, and malonyl (42) (Fig. 2). Different kinds of avonoids are present in practically all dietary plants, like fruits and vegetables, and we also found that avonoids are the largest class of phenolics in the tested medicinal herbs and dietary spices in our previous studies (12,28 33,39). Some common different categories of avonoids from medicinal herbs and dietary plants are shown in Fig. 3. The most common avones are luteolin, apigenin, baicalein, chrysin, and
their glycosides (e.g., apigetrin, vitexin, and baicalin), mainly distributed in the Labiatae, Asteraceae, and so forth, such as roots of Scutellaria baicalensis, inorescences of Chrysanthemum morifolium, and aerial parts of Artemisia annua. Their major 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, and astragalin) are the predominant avonols. These avonols have a 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 associated with anticancer, for example, owers of Sophora japonica and Rosa chinensis, aerial parts of A. annua, rhizomes of Alpinia ofcinarum, and fruits (hawthorn) of Crataegus pinnatida (12,28). Among these common avonols, quercetin is one of the major dietary avonoids, found in a broad range of fruit, vegetables, and beverages with a daily intake in Western countries of 2530 mg (3). Flavanones such as naringenin, hesperetin, eriodictyol, and their glycosides (e.g., naringin, hesperidin, and liquiritin) and avanonols (taxifolin) are mainly found in citrus fruits (e.g., oranges, lemons, and aurantium), grape, and the medicinal herbs of Rutaceae, Rosaceae, Leguminosae, and so forth (12,40). Flavanols, such as catechin, epicatechin, epigallocatechin, epicatechin gallate (ECG), and epigallocatechin gallate (EGCG), are also widespread in the medicinal herbs and dietary plants (e.g., tea, apples, berries, cocoa, and catechu) (4,40). Anthocyanins, including anthocyanidins (e.g., cyanidin, delphinidin, malvidin, peonidin, pelargonidin, etc.) and their glycosides, are widely distributed in the medicinal herbs such as inorescences of Prunella vulgaris and owers of Rosa chinensis (12). Many dietary plants (e.g., fruits, vegetables, grains, etc.) contain anthocyanins such as grape skins, blueberries, bayberry, red cabbages, beans, red/purple rice and corn, and purple sweet potatoes (32,40). Chalcones (butein, phloretin, sappanchalcone, carthamin, etc.) are detected in medicinal herbs such as Rhus verniciua, Caesalpinia sappan, and Carthamus tinctorius (12,31). Isoavones include daidzein, genistein, glycitein, formononetin, and their glycosides (e.g., genistin, daidzin), mostly from soybeans, legumes, and red clover, and are also detected in the medicinal herbs of Leguminosae, such as roots of Astragalus mongholicus (12,31). In addition, biavonoids are avonoid dimers connected with a CC or COC bond (43) and occur in some fruits, vegetables, and medicinal plants such as Citrus fruits, Ginkgo biloba, Rhus succedanea, and Ouratea hexasperma (12,44,45). Silymarin (Fig. 3), a avonoid analog, was found in fruits of Silybum marianum (46).
Tannins Tannins are natural, water-soluble, polyphenolic compounds with molecular weight ranging from 500 to 4,000, usually classied into 2 classes: hydrolysable tannins (gallo- and ellagi-tannins) and condensed tannins (proanthocyanidins) (12)
OH O O
flavones
O
flavonols
O
isoflavones
OH O OH O
flavanones
flavanonols
+ O
flavanols
OH O
chalcones
O OH HO O
anthocyanidins
OH HO OH HO
OH
O OH HO OH HO OH
O OH HO HO
-glucoside
OH OH
-glucuronide
-galactoside
O O O O
OH
OH
O OH
OH HO CH3 HO OH S OH
-rhamnoside
-arabinoside
-malonyl
-apiosylglucoside
FIG. 2. Structures of major groups/subgroups of avonoids and their associated glycosides.
(Fig. 4). The former are complex polyphenols, which can be degraded into sugars and phenolic acids through either pH changes or enzymatic or nonenzymatic hydrolysis. The basic units of hydrolysable tannins of the polyster type are gallic acid and its derivatives (4). Tannins are commonly found combined with alkaloids, polysaccharides, and proteins, particularly the latter (21). Hydrolysable tannins contain a central core of
polyhydric alcohol such as glucose and hydroxyl groups, which are esteried either partially or wholly by gallic acid (gallotannins) or by hexahydroxy-diphenic acid or by other substituents (e.g., chebulic acid) (ellagitannins) (31). Ellagitannins differ from gallotannins in that at least 2 gallic acid units surrounding the core are linked through carbon-carbon bonds. Condensed tannins are structurally more complex and more widely spread
6
R2 R3
W.-Y. HUANG ET AL.

R2 R1 R3 R1 OH
HO
HO
O R4
HO
+ O R2
R1 OH O OH O
OH OH
OH
R1=H, R 2=H, R3=H: chrysin R1=H, R 2=H, R3=OH: apigenin R1=H, R 2=OH, R 3=OH: luteolin R1=OH, R 2=H, R 3=H: baicalein
R1 R2
R1=H, R 2=H, R3=H, R4=H: galangin R1=H, R 2=H, R3=OH, R4=H: kaempferol R1=H, R 2=OH, R 3=OH, R4=H: quercetin R1=OH, R2=H, R 3=OH, R4=H: morin R1=H, R 2=OH, R 3=OH, R4=OH: myricetin
HO O
R1=H, R 2=H: pelargonidin R1=OH, R 2=H: cyanidin R1=OCH3, R 2=H: peonidin R1=OH, R 2=OH: delphinidin R1=OCH3, R 2=OCH3: malvidin
OH OH
HO
O R1 R2 OH O O R3 HO
R1=OH, R2=OCH3: hesperetin R1=H, R 2=OH: naringenin R1=OH, R2=OH: eriodictyol

OH
R1=H, R 2=H, R3=OCH3: formononetin R1=H, R 2=H, R3=OH: daidzein R1=H, R 2=OH, R 3=OH: genistein R1=OCH3, R 2=H, R3=OH: glycitein
OH
OH
butein
R OH
OH HO O OH HO OH OH O OH OH OH OH OH OH HO O R O OH O HO O OH
taxifolin
catechin
R=H: epicatechin R=OH: epigallocatechin
O OH O OH
HO
O O
OCH3
OH OH
OH
R=H: epicatechin gallate R=OH: epigallocatechin gallate
OH OH
silymarin
FIG. 3. Representative compounds from different categories of avonoids from medicinal herbs and dietary plants.
among the plants than hydrolysable tannins. They are mainly the oligomers and polymers (e.g., monomers, dimmers, and trimers) of avan-3-diols (catechin or epicatechin derivatives), also known as proanthocyanidins (47). Some authors have considered that the polymerized products of avan-3,4-diols also
belong to the category of condensed tannins called leucoanthocyanidins (31). Complex tannins are constructed of catechin units linked glucosidically to gallotannin or ellagitannin; at least 2 gallic acid units surrounding the core are linked through carbon-carbon.
OH HO
Basic skeleton of gallotannins

O(H/ G ) Gn O O Gn O Gn O O Gn HO OG O HO
OH HOH 2 C HO O O OH O O OH
C=O G = gal loyl
Gn = O-3-galloyls
HO
Basic skeleton and substituents of ellagitannins

O O O R2 R 1O O HO O R1 O O O O HOOC HO O O OH OH O HO HO OH O OH O HO OH HO
OH
di-O-galloyl- -D-glucose (gallotannins)
R3
O O
R 1 =H, H/CHEB/DHHDP R 2 =HHDP/H, H

OG O O O OH HO OH
HO O O
OH
R2 R 1 =OH/OG R 2 =H, H/G, G/HHDP R 3 =H, H/HHDP/BCHT
OH
HHDP
O
BC HT
O
O HO OH OH OH O
OH
OH
CHEB
OH HO
DHHDP
OH
HO
HO HO O HO O O GO HO O O OG OG
HO
RO O
OH OH OH O O O O OH OH OH
HO
tellimagrandin II (ellagitannins) Basic skeleton of condensed tannins

OH OH HO O
complex tannins
HO
OH
OH HO O
OH OH OH
OG OH OH
n
HO HO
OH OH
G=
C O OH
OH
OH
oligomeric proanthocyanidins (condensed tannins)
FIG. 4.
The basic skeletons and structures of different categories of tannins from medicinal herbs and dietary plants.
8
R1O OH
W.-Y. HUANG ET AL.

O R1 OH R2
R3 HO R2O OH
R1=H, R 2=H, R3=H: trans-resveratrol R1=H, R 2=Gluc, R3=H: trans-piceid R1=CH3, R2=CH3, R3=H: trans-pterostilbene R1=H, R 2=H, R3=OH: trans-piceatannol
FIG. 5.
R1=OCH3, R 2=OCH3: curcumin R1=H, R 2=OCH3: demethoxycurcumin R1=H, R 2=H: bisdemethoxycurcumin
The structures of typical stilbenes and curcuminoids from medicinal herbs and dietary plants.
Tannins are a large class of polyphenolics in dietary plants and medicinal herbs. Oligomeric proanthocyanidins, which are widely distributed in grape seed and skin and pine bark, are considered to be the most potent antioxidants and frequently used in health care and cancer treatment (48). Many fruits (e.g., apple juice, 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 proanthocyanidins or ellagitannins (21,28). More than 32 species in 112 tested traditional Chinese medicinal plants associated with anticancer contain tannin constituents (e.g., gallotannins, ellagitannins, and proanthocyanidins) (12). Of these, 19 species contained particularly high proportions of tannins such as Chinese Galls, catechu, P. granatum, and S. ofcinalis. Ten of 126 Indian medicinal herbs also possess high levels of hydrolysable tannins (29). Some gallotannins were detected in Euphorbia hirta, Glycyrrhiza glabra, and Rhus succedanea. Several ellagitannins (e.g., corilagin, casuarictin) were isolated from fruits of T. chebula and peels of P. granatum. Camellia sinensis and Areca catechu contained proanthocyanidins and leucoanthocyanidins, respectively. Some plant species (e.g., Acacia catechu, S. ofcinalis, Rosa chinensis, and P. granatum) may produce complex mixtures containing both hydrolysable and condensed tannins (12,29,31). Stilbenes Stilbenes are phenolic compounds displaying 2 aromatic rings linked by an ethane bridge, structurally characterized by the presence of a 1,2-diarylethene nucleus with hydroxyls substituted on the aromatic rings (4) (Fig. 5). They are distributed in higher plants and exist in the form of oligomers and in monomeric form (e.g., resveratrol, oxyresveratrol) and as dimeric, trimeric, and polymeric stilbenes or as glycosides. The well-known compound, trans-resveratrol, a phytoalexin produced by plants, is the member of this chemical family more abundant in the human diet (especially rich in the skin of red grapes), possessing a trihydroxystilben skeleton (21). We identied the monomeric stilbenes in 4 species of medicinal herbs, that is, trans-resveratrol in root of Polygonum cuspidatum,
Polygonum multiorum, and P. lactiora; piceatannol in root of P. multiorum; and oxyresveratrol in fruit of Morus alba (12,31). It was reported that dimeric stilbenes and stilbene glycosides were identied from these species (33,49). In addition, 40 stilbene oligomers were isolated from 6 medicinal plant species (Shorea hemsleyana, Vatica rassak, Vatica indica, Hopea utilis, Gnetum parvifolium, and Kobresia nepalensis) (50). Other stilbenes that have recently been identied in dietary source, such as piceatannol and its glucoside (usually named astringin) and pterostilbene, are also considered as potential chemopreventive agents (4). These and other in vitro and in vivo studies provide a rationale in support of the use of stilbenes as phytoestrogens to protect against hormone-dependent tumors (51). Curcuminoids Curcuminoids are ferulic acid derivatives, which contain 2 ferulic acid molecules linked by a methylene with a -diketone structure in a highly conjugated system. Curcuminoids and ginerol analogues are natural phenolic compounds from plants of the family Zingiberaceae (12). Curcuminoids include 3 main chemical compounds: curcumin, demethoxycurcumin, and bisdemethoxycurcumin (31) (Fig. 5). All 3 curcuminoids impart the characteristic yellow color to turmeric, particularly to its rhizome, and are also major yellow pigments of mustard (3). Curcuminoids containing Curcuma longa (turmeric) and ginerol analogues containing Zingiber ofcinale (ginger) are not only used as Chinese traditional medicines but also as natural color agents or ordinary spices (12). In addition, curcuminoids with antioxidant properties were isolated from various Curcuma or Zingiber species, such as Indian medicinal herb Curcuma xanthorrhiza, the spice Curcuma domestica, Curcuma zedoaria grown in Brazil, and Zingiber cassumunar from tropic regions (29,52,53). Coumarins Coumarins are lactones obtained by cyclization of cisortho-hydroxycinnamic acid, belonging to the phenolics with the basic skeleton of C6 + C3 (12) (Fig. 6). This precursor is formed through isomerization and hydroxylation of the structural analogs trans-hydroxycinnamic acid and derivatives.
HO
R=OH: esculetin R=OCH3: scopoletin R=CH3: escopoletin R=Gluc: aesculin
O R
R=H: seselin R=OH: khellactone

O O
R=H: xanthyletin R=OCH3: xanthoxyletin

CH2OH
HO
OH OH O O O HO O
H3CO OH OH O HO
psoralen
O O O O
OH
bicoumarin
H3CO OH OH
bergenin
O H3CO
isopsoralen
OH O HO
O OH HO
OH
H3CO
OCH3
OCH3
wedelolactone
R1 R2
secoisolariciresinol
OH
R=OH: matairesinol R=OCH3: arctigenin

O O
O O
O O
O O O O O O
H3CO R3 OCH3 OCH3 OCH3
OCH3
OCH3
OCH3
R1=H, R 2=H, R3=OCH3:deoxypodophyllotoxin R1=H, R 2=OH, R 3=OCH3: podophyllotoxin R1=OH, R2=H, R3=OCH3: -peltatin R1=H, R 2=H, R3=H: bursehemin O
O O O O
anhydropodorhizol
R=H: morelensin R=OCH3: yatein
O OH
O O O
HO
sesamin
FIG. 6.
hinokinin
magnolol
The structures of representative coumarins and lignans from medicinal herbs and dietary plants.
10
W.-Y. HUANG ET AL.
Coumarins are present in plants in the free form and as glycosides. In general, coumarins are characterized by great chemical diversity, mainly differing in the degree of oxygenation of their benzopyrane moiety. In nature, most coumarins are C7 -hydroxylated (4,31). Major coumarin constituents included simple hydroxylcoumarins (e.g., aesculin, esculetin, scopoletin, and escopoletin), furocoumarins and isofurocoumarin (e.g., psoralen and isopsoralen from Psoralea corylifolia), pyranocoumarins (e.g., xanthyletin, xanthoxyletin, seselin, khellactone, praeuptorin A), bicoumarins, dihydro-isocoumarins (e.g., bergenin), and others (e.g., wedelolactone from Eclipta prostrata) (2931). Plants, fruits, vegetables, olive oil, and beverages (coffee, wine, and tea) are all dietary sources of coumarins; for example, seselin from fruit of Seseli indicum, khellactone from fruit of Ammi visnaga, and praeuptorin A from Peucedanum praeruptorum (4,54). In our previous studies, we found coumarins occurred in the medicinal herbs Umbelliferae, Asteraceae, Convolvulaceae, Leguminosae, Magnoliaceae, Oleaceae, Rutaceae, and Ranunculaceae, such as simple coumarins from A. annua, furocoumarins (5-methoxyfuranocoumarin) from Angelica sinensis, pyranocoumarins from Citrus aurantium, and isocoumarins from Agrimonia pilosa (12). Some Indian medicinal plants (e.g., Toddalia aculeata, Murraya exotica, Foeniculum vulgare, and Carum copticum) and dietary spices (e.g., cumin and caraway) are also detected to possess coumarins (28,29). In addition, coumestans, derivatives of coumarin, including coumestrol, a phytoestrogen, are found in a variety of medicinal and dietary plants such as soybeans and Pueraria mirica (http://en.wikipedia.org/wiki/).
et al. (57) established a lignan database from Dutch plant foods by quantifying lariciresinol, pinoresinol, secoisolariciresinol, and matairesinol in 83 solid foods and 26 beverages commonly consumed in The Netherlands (57). They reported that axseed (mainly secoisolariciresinol), sesame seeds, and Brassica vegetables (mainly pinoresinol and lariciresinol) contained unexpectedly high levels of lignans. Sesamol, sesamin, and their glucosides are also good examples of this type of compound, which come from sesame oil and sunower oil (4). Quinones Natural quinones in the medicinal plants fall into 4 categories, that is, anthraquinones, phenanthraquinones, naphthoquinones, and benzoquinones (12) (Fig. 7). Anthraquinones are the largest class of natural quinones and occur more widely in the medicinal and dietary plants than other natural quinones (31). The hydroxyanthraquinones normally have 1 to 3 hydroxyl groups on the anthraquinone structure. Our previous investigation found that quinones were distributed in 12 species of medicinal herbs from 9 families such as Polygalaceae, Rubiaceae, Boraginaceae, Labiatae, Leguminosae, Myrsinaceae, and so forth (12,29). For example, high content benzoquinones and derivatives (embelin, embelinol, embeliaribyl ester, embeliol) are found in Indian medicinal herbs Embelia ribes; naphthoquinones (shikonin, alkannan, and acetylshikonin) come from Lithospermum erythrorhizon and juglone comes from Juglans regia; phenanthraquinones (tanshinone I, IIA , and IIB ) were detected in Salvia miltiorrhiza; denbinobin was detected in Dendrobium nobile; and many anthraquinones and their glycosides (e.g., rhein, emodin, chrysophanol, aloe-emodin, physcion, purpurin, pseudopurpurin, alizarin, munjistin, emodin-glucoside, emodin-malonyl-glucoside, etc.) were identied in the rhizomes and roots from P. cuspidatum (also in leaves), P. multiorum, and R. ofcinale in the Polygalaceae and Rubia cordifolia in the Rubiaceae (12,29,33). In addition, some naphthoquinones were isolated from maize (Zea mays L.) roots (58). Others Because phenolic alkaloids, phenolic terpenoids (including aromatic volatile oils), special phenolic glycosides, and mbenzo-triphenol derivatives contain one or more aromatic rings bearing one or more hydroxy groups (Fig. 8), they also structurally belong to phenolic compounds and are widely distributed in medicinal herbs and dietary plants. There are different phenolic alkaloids detected in our previously investigated traditional Chinese medicinal plants such as Aconitum carmichaeli (e.g., demethylsalsoline), Coptis chinensis (e.g., magnoorine), Phellodendron amurense (e.g., phellodendrine and magnoorine), and Zanthoxylum nitidum (e.g., nitidine and dihydronitidine) (12). Magnoorine was also found in the traditional medical herbal tea, Toddalia asiatica Lam. in Okinawa (59). Some Chinese and Indian medicinal herbs and many spices contain high levels of various aromatic volatile oils or phenolic terpenoids
Lignans Lignans are also derived from cis-o-hydroxycinnamic acid and are dimers (with 2 C6-C3 units) resulting from tailtail linkage of 2 coniferl or sinapyl alcohol units (31) (Fig. 6). Lignans are mainly present in plants in the free form and as glycosides in a few (4). Main lignan constituents are lignanolides (e.g., arctigenin, arctiin, secoisolariciresinol, and matairesinol from Arctium lappa), cyclolignanolides (e.g., chinensin from Polygala tenuifolia), bisepoxylignans (e.g., forsythigenol and forsythin from Forsythia suspensa), neolignans (e.g., magnolol from Cedrus deodara and Magnolia ofcinalis), and others (e.g., schizandrins, schizatherins, and wulignan from Schisandra chinensis; pinoresinol from Pulsatilla chinensis; and furofuran lignans from Cuscuta chinensis) (12,29). The famous tumor therapy drug podophyllotoxin (cyclolignanolide) was rst identied in Podophyllum peltatum, which Native Americans used to treat warts, and also found in a traditional medicinal plant Podophyllum emodi var. chinense (13). Two new lignans (podophyllotoxin glycosides) were isolated from the Chinese medicinal plant, Sinopodophyllum emodi (55). Different lignans (e.g., cubebin, hinokinin, yatein, and isoyatein) were identied from leaves, berries, and stalks of Piper cubeba L. (Piperaceae), an Indonesian medicinal plant (56). Milder

OH O OH
11
O OH
R2 O
R1 HO C11 H23 O
R1=CH3, R2=H: chrysophanol R1=CH3, R2=OH: emodin R1=CH2OH, R2=H: aloe-emodin R1=COOH, R2=H: rhein R1=CH3, R2=OCH3: physcion
OH O R1 R2
OH
juglone
O
embelin
O O
O O
OH
R1=H, R 2=OH: alkannan R1=OH, R 2=H: shikonin R1=COCH3, R2=H: acetylshikonin

FIG. 7.
tanshinone I
R=H: tanshinone IIA R=OH: tanshinone IIB
The structures of representative quinones from medicinal herbs and dietary plants.
such as carnosic acid in Andrographis paniculata, Nerium oleander, Xanthium sibiricum, sweet basil, and sage; carnosol and epirosmanol in rosemary; carvacrol in oregano, sweet basil, and rosemary; anethole in star anise; menthol in mint; thymol in thyme; eugenol in clove; estragole and xanthoxylin in Chinese prickly ash; cinnamaldehyde in cinnamon; and triptophenolide and its methyl ether in Tripterygium wilfordii (12,28,29,60). Additionally, simple phenols (only C6 skeleton) are identied in the aromatic volatiles of some medicinal herbs such as vanillin and p-cresol from A. sinensis (12). Other phenolics also include syringaresinol (Clematis chinensis), paeonol (Paeonia suffruticosa), m-benzo-triphenols (agrimol A, B from A. pilosa) and their derivatives (licic acids from Matteuccia struthiopteris), and so forth. (12,2831). Triptophenlolide has been isolated from the roots of T. wilfordii Hook. Oleuropein and its glycoside have been obtained from olive oil (24).
chain-enhancer of activated B cells (NF- B), activator protein-1 (AP-1), mitogen-activated protein kinases (MAPK), and others; modulation of enzyme activities in detoxication, oxidation, and reduction; anti-inammatory properties by stimulation of the immune system; regulation of hormone metabolism; suppression of angiogenesis; antiatherosclerosis by inhibition proliferation and migration of vascular cells; neuroprotective effects on antiaging; antibacterial and antiviral effects; and action on other possible targets (4,19,21,61114,117,118).
CANCER PREVENTION AND POSSIBLE MECHANISMS OF PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS Phenolic compounds from medicinal herbs and dietary plants possess a range of bioactivities and play an important role in prevention of cancer (Table 1). They have complementary and overlapping mechanisms of action including antioxidant activity and scavenging free radicals; modulation of carcinogen metabolism; regulation of gene expression on oncogenes and tumor suppressor genes in cell proliferation and differentiation; induction of cell-cycle arrest and apoptosis; inhibition of signal transduction pathways including nuclear factor kappa-light-
Phenolic Acids and Analogs Phenolic acids and analogs possess broad bioactivities, some of which can play a role in cancer prevention. Most phenolic acids have antioxidant capacity, and the radical scavenging ability of phenolic acids depends on the number and position of hydroxyl groups and methoxy substituents in the molecules (31). In addition, phenolic acids and analogs can inhibit tumor cells and induce apoptosis by inducing cell cycle arrest; regulating signal transduction pathways; inducing or inhibiting some enzymes, and enhancing detoxication. And some phenolic acids and analogs also exhibit antibacterial, antifungal, antiviral, antimutagenic, and anti-inammatory activities (21,64,67,74,82) (Table 1). Gallic acid as a natural antioxidant had signicant inhibitory effects on cell proliferation, induced apoptosis in a series of cancer cell lines, and showed selective cytotoxicity against tumor cells with higher sensitivity than normal cells (95). Cinnamic, caffeic, and ferulic acids and their esters inhibited the growth of bacteria and fungi, and hydroxytyrosol (an analog
12
H3CO HO
W.-Y. HUANG ET AL.

OH HO O COOH O OH HO OH
N+ HO HO
O OH
H3CO
magnoflorine
OH R1
carnosic acid
R1 R2
carnosol
OCH3 R1
epirosmanol
OCH3
R2
OH
R2
R1=OCH3, R2=CHO: vanillin R1=OH, R2=OCH3: eugenol R1=OH, R2=H: carvacrol R1=H, R2=CH3: p-cresol R1=OCH3, R2=H: estragole R1=H, R2=OH: thymol
H3CO O HO
paeonol
anethole
COOCH3
OCH3 HO O OH O HO OCH3 OCH3 O
H3CO
syringaresinol
oleuropein
OC6H11 O5
H3CO
O N O
H3CO
dihydronitidine
FIG. 8.
triptophenolide
The structures of some other typical phenolic compounds from medicinal herbs and dietary plants.
of phenolic acid) showed antimycoplasmal activity against Mycoplasma pneumoniae, Mycoplasma hominis, and Mycoplasma fermentans (64). In addition, hydroxytyrosol could inhibit cell proliferation and the activities of lipoxygenases (LOXs), increase catalase (CAT) and superoxide dismutase (SOD) activities, reduce leukotriene B4 production, decrease vascular cell adhesion molecule-1 (VCAM-1) mRNA and protein, slow the lipid peroxidation process, attenuate Fe2+ and NO-induced cytotoxicity, and induce apoptosis by arresting the cells in the G0/G1 phase (9698). Many phenolic acids and analogs possess anti-inammatory effects and enhance immune function such as cinnamic acids, rosmarinic acid, gingerol, paradol, and hydroxytyrosol (4). Both chlorogenic acid and caffeic acids are antioxidants and inhibit the formation of mutagenic and carcinogenic N -nitroso compounds in vitro (21). Chlorogenic acid
could also inhibit the formation of DNA single strand breaks and prevent the formation of dinitrogen trioxide by scavenging nitrogen dioxide generated in the human oral cavity (89). Furthermore, caffeic acids, capsaicin, and gingerol (an analog of phenolic acids) modulate the ceramide-induced signal transduction pathway, suppress the activation of NF- B and AP1, and inhibit protein tyrosine kinase (PTK) activity (2,21,62). Gingerol could also inhibit tumor promotion, epidermal growth factor, tumor necrosis factor-alpha (TNF- ) production, and phorbol-12-myristate-13-acetate (PMA)-induced ornithine decarboxylase activity (2). Moreover, some phenolic acids (caffeic acid, ferulic acid, gallic acid, protocatechuic acid, etc.) in grape extracts and wine contribute to their activity against various types of cancer such as breast, lung, and gastric cancer (36).
13
TABLE 1 Cancer prevention and possible mechanisms of phenolic compounds from medicinal herbs and dietary plantsa Mechanisms of Action Phenolic Compounds (Representative Phenolics) References 4,19,21,29,31, 34,63,95,108, 111
Antioxidant and antiaging activity Scavenge free radicals and ROS, such as superoxide Phenolic acids and analogs (caffeic acid, anion, singlet oxygen, hydroxyl radical, peroxyl gallic acid, chlorogenic acid, and ellagic radical, nitric oxide, nitrogen dioxide and acid), avonoids (catechin and quercetin), peroxynitrite; increase SOD activities; decrease tannins (proanthocyanidins, corilagin), lipoperoxidation. stilbenes (resveratrol), curcuminoids, coumarins, lignans, quinones, and others. Antiangiogenesis and antimutagenic properties Inhibit cell proliferation; inhibit oncogene expression; Phenolic acids and analogs (chlorogenic acid induce tumor suppressor gene expression; inhibit and hydroxytyrosol), avonoids and vascular endothelial growth factor. analogs (apigenin, daidzein, hesperetin, luteolin, kaempferol, myricetin, quercetin, EGCG, genistein, and silymarin), tannins (proanthocyanidins), stilbenes (resveratrol), curcuminoids (curcumin), coumarins, lignans, quinones, and others. DNA binding prevention Flavonoids (methoxylated avonoids and avones), stilbenes (resveratrol), curcuminoids (curcumin), and quinones. Enhancement of immune functions and surveillance Suppress production of TNF, a pro-inammatory Phenolic acids and analogs (cinnamic acids, cytokine and growth factor for most tumor cells; rosmarinic acid, gingerol, paradol, and suppress LOXs, iNOS, chemokines, and other hydroxytyrosol), avonoids and analogs inammatory molecules. (apigenin, genistein, luteolin, quercetin, ECG, EGCG, and silymarin), tannins (proanthocyanidins, tannic acid), stilbenes (resveratrol), curcuminoids (curcumin), coumarins (coumarin), lignans (sesamol), quinones, and others. Enzyme inhibition Phase I enzyme (block activation of carcinogens); Phenolic acids and analogs (chlorogenic COX-2; iNOS; XO; signal transduction enzymes, acid, caffeic acid, ellagic acid, and such as PKC and PTK; topoisomerase I and II; hydroxytyrosol), avonoids and analogs telomerase; urease; lipase; angiotensin I-converting (apigenin, luteolin, quercetin, and EGCG), enzyme; DNA methytransferases (consequent tannins (proanthocyanidins, corilagin), reactivation of key tumor suppressor gene p16). stilbenes (resveratrol), curcuminoids (curcumin), coumarins, lignans (podophyllotoxin), and quinones. Enzyme induction and enhancing detoxication Phase II enzymes, such as UDP-glucuronosyl Phenolic acids and analogs (protocatechuic transferase and quinine reductases; glutathione acid and ellagic acid), avonoids peroxidase; catalase; SOD; cytochrome P450 (hesperidin and anthocyanins), tannins, epoxide hydrolase; NADPH:quinone reductase. stilbenes (resveratrol), curcuminoids (curcumin), lignans, and quinones. Inhibition of cell adhesion and invasion Inhibit expression of cell-adhesion molecules, namely Phenolic acids and analogs (hydroxytyrosol), ICAM-1 and VCAM-1; inhibit tumor cell invasion avonoids (baicalein, apigenin, and citrus through Matrigel, cell migration, and cell avonoids), stilbenes (resveratrol), proliferation. curcuminoids (curcumin), and lignans.
4,21,101,103, 110,118
91,92
4,19,21,61, 6670
4,19,21, 7478,100
4,7173
4,87,88, 9697
(Continued on next page)
14
W.-Y. HUANG ET AL.
TABLE 1 Cancer prevention and possible mechanisms of phenolic compounds from medicinal herbs and dietary plantsa (Continued) Mechanisms of Action Induction of cell differentiation Phenolic Compounds (Representative Phenolics) References 79,80
Flavonoids (apigenin), tannins (chebulinic acid), and coumarins. Induction of cell-cycle arrest and induction of apoptosis Inhibit different cell cycles at different cell phases: G1, Phenolic acids (ferulic acid, caffeic acid and S, S/G2, and G2; direct or indirect effect on cell its phenethyl ester, ellagic acid, and cycle arrest; subsequently induce apoptosis, hydroxytyrosol), avonoids (quercetin involving p53, the Bcl-2, and caspase families. and EGCG), tannins (proanthocyanidins, gallotannin and casuarinin), stilbenes (resveratrol), curcuminoids (curcumin), coumarins (coumarin and 7-hydroxycoumarin), lignans (sesamin), quinones, and others (eugenol). Inhibition of signal transduction pathways Nrf-KEAP1 (Kelch-like ECH-associated protein 1) Phenolic acids and analogs (caffeic acid, complex signaling pathways; NF- B and AP-1 gingerol, and capsaicin), avonoids and signaling pathway, including c-Jun activity analogs (apigenin, genistein, quercetin, suppression; the Wnt or -catenin signaling pathway EGCG, and silymarin), tannins (direct inhibition of mitosis); MAPK signaling (proanthocyanidins, ellagitannins), pathway; growth-factor receptor-medicated stilbenes (resveratrol), curcuminoids pathways. (curcumin), coumarins (esculetin), lignans, quinones (emodin), and others (anethole and carnosol). Regulation of steroid hormone and estrogen metabolism Some are important phytoestrogens; modulate the level Phenolic acids and analogs (gossypol), of hormones; inhibit androgen receptor effects in avonoids (isoavones: formononetin, LNCaP prostate cancer cell. glycitein, genistein and daidzein), stilbenes (resveratrol), coumarins (coumestans: coumestrol), and lignans (pinoresinol, lariciresinol, secoisolariciresinol, and matairesinol). Inhibition of acrylamide, nitrosation, and nitration Inhibit formation of acrylamide and heterocyclic Phenolic acids (caffeic acid and gallic acid), amines, probable/possible human carcinogens. avonoids (homoorientin, luteolin, quercetin, and EGCG), curcuminoids (curcumin), and others (eugenol). Antiviral, antibacterial, and antifungal effects Downregulate HIV expression, subsequently inhibit Phenolic acids and analogs (cinnamic acid liver cancer. and its esters, and hydroxytyrosol), avonoids, tannins, stilbenes (resveratrol), curcuminoids (curcumin), coumarins, lignans, quinones, and others.
3,4,21,62, 8184,95
2,4,19,21,61, 62,85,86,99,112
21,93,94,117
65,89,90,113,114
21,64,105,106
a Abbreviations 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 adhesion molecule-1; Bcl-2, B-cell non-Hodgkin lymphoma-2; nuclear factor kappa of activated B cells; AP-1, activator protein-1; MAPK, mitogenactivated protein kinases; LNCaP, lymph node carcinoma of the prostate; EGCG, epigallocatechin gallate; ECG, epicatechin gallate.
15
Flavonoids Flavonoids have been linked to reducing the risk of major chronic diseases including cancer because they have powerful antioxidant activities in vitro, being able to scavenge a wide range of reactive species (e.g., hydroxyl radicals, peroxyl radicals, hypochlorous acid, and superoxide radicals) (42). Many avonoids chelate transition metal ions such as iron and copper, decreasing their ability to promote reactive species formation. Flavonoids also inhibit bio-molecular damage by peroxynitrite in vitro, prevent carcinogen metabolic activation, induce apoptosis by arresting cell cycle, promote differentiation, modulate multidrug resistance, and inhibit proliferation and angiogenic process (42,71,72,91) (Table 1). These activities of avonoids are related to their structures. Flavonols containing more hydroxyl groups exhibit very high radical scavenging activity, for example, myricetin, quercetin, rutin, and quercitrin are wellknown potent antioxidants. Flavanols with additional catechol structure (3-galloyl group) have signicantly enhanced antiradical activity (31). Moreover, glycosylation of hydroxyl groups and substitution of other substituents (e.g., methoxy groups) also affects the antioxidant activity of avonoids (34). Many avonoids possess diverse bioactivities. For example, apigenin could inhibit cell adhesion and invasion; reduce the formation of diolepoxide 2, mitochondrial proton F0F1ATPase/ATP synthase, prostaglandin synthsis, and IL-6,8 (interleukin) production; block the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin; and induce cell differentiation and interferon-gamma gene expression (79,87). Furthermore, genistein, luteolin, quercetin, ECG, EGCG, and silymarin as well as apigenin show antiangiogenesis and antimutagenic properties (62). Besides these 7 avonoids and analogs, daidzein, hesperetin, kaempferol, and myricetin were all anti-inammatory (21,46). In addition, apigenin, genistein, quercetin, EGCG, and silymarin could suppress the activation of NF- B and AP1 and block signal transduction pathways (2,62,79,87). Silymarin also prevented induction of apoptosis and suppressed protein kinases and MAPKs (46). Soy isoavone genistein was an angiogenesis inhibitor that could inhibit the growth of new blood vessels and showed antitumor and antiangiogenic activity in mouse models of melanoma and breast cancer (116). Moreover, some isoavones (e.g., genistein and daidzein) were phytoestrogens and could mimic the biological activity of estrogens and modulate steroid hormone metabolism. Therefore, they might play an important role in breast cancer prevention (117). Some catechins (e.g., EGCG and EGC) showed signicant radical scavenging ability and could chelate metal ions and prevent the generation of free radicals. Their specic chemical structures (i.e., vicinal dihydroxy or trihydroxy structure) contribute to their potent antioxidant activity (31). EGCG could inhibit telomerase, LOXs, and DNA methyltransferase; reduce the expression of COX-2 (cyclooxygenase) and activation of NF- B and AP1; block c-Jun N-terminal kinase (JNK) and p38 MAPK-related signaling pathways; attenuate adhesion and
migration of peripheral blood CD8 T cells; increase eNOS (nitric oxide synthase) activity; and induce apoptosis by activating caspases and arresting cell growth G0/G1 phase of the cell cycle (2,4,21,99). Also, EGCG could induce apoptosis in human epidermoid carcinoma cells but not in normal human epidermal keratinocytes (99). Quercetin is one of the most potent antioxidants and has antioxidant, anti-inammatory, antiproliferative, or apoptotic effects in vitro or in vivo. At molecular level, quercetin acts as an anticancer agent through modulation of cell cycle, protein, oncogenes, and antioncogenes (100). In addition, quercetin can inhibit the activity of caspases-3, protein kinases, telomerase, lymphocyte tyrosine kinase, different tyrosines, and serinethreonine kinases; increase the expression of nicotinamide adenine dinucleotide phosphate (NADPH):quinine oxidereductase and activity of SOD, CAT, GSH; decrease lipoperoxidation, NO production and iNOS (inducible nitric oxide synthase) protein expression, and levels of some oxidative metabolites; prevent lactate dehydrogenase (LDH) leakage; interact with the -catenin pathway; block c-Jun N-terminal kinase (JNK) and p38 MAPK-related signaling pathway; enhance Nrf2-mediated (NF-E2-related factor-2, a basic region-leucine zipper transcription factor to regulate transactivation of antioxidant genes) transcription activity; suppress angiogenesis, colorectal crypt cell proliferation; and induce apoptosis in different cell lines by arresting cell cycle (4,21,62,100).
Tannins Hydrolysable tannins and condensed tannins are powerful antioxidant agents because they have many hydroxyl groups, especially many ortho-dihydroxyl or galloyl groups. Bigger tannin molecules possess more galloy and ortho-dihydroxyl groups, and their activities are stronger (31). In addition, these tannins also exhibit strong antibacterial, antiulcer, anti-inammatory, antileishmanial, antimutagenic, enzyme regulating, signal transduction pathways blocking, and apoptotic activities; thus, they have attracted wide attention for cancer treatment (68,75,82,85) (Table 1). For example, gallotannin showed anticarcinogenic activities in several animal models including colon cancer, and the hydrolysable tannin-containing fraction from Sweet Charlie strawberries was most effective at inhibiting mutation (101). In addition, 4 ellagitannins and 2 chromone gallates signicantly blocked epidermal growth factor-induced cell transformation by attenuating AP-1 and phosphoinositide 3-kinases (PI3K) signaling pathways activation, and by inhibiting phosphorylation of extracellular-signal regulated protein kinases and p38 kinases (85). Chebulinic acid had an inhibitory effect on differentiation of human leukemia K562 cells through regulating transcriptional activation of erythroid related genes including gamma-globin, and NF-E2 genes, and through inhibiting acetylcholinesterase and hemoglobin synthesis (79). Casuarinin, a hydrolysable tannin isolated from the bark of Terminalia arjuna L. (Combretaceae), could inhibit the proliferation by blocking cell
16
W.-Y. HUANG ET AL.
cycle progression in the G0/G1 phase and by inducing apoptosis in human breast adenocarcinoma cells (81).
Stilbenes Stilbenes, especially resveratrol, possess potential antioxidant, antibacterial, antiviral, anti-inammatory, and anticancer activities (2,4,21,62,94) (Table 1). Resveratrol has increased in importance as a cancer preventive agent since 1997 (51). Resveratrol can affect the processes underlying all 3 stages of carcinogenesis, namely, tumor initiation, promotion, and progression. It had also been shown to suppress angiogenesis and metastasis. Extensive data in human cell cultures indicated that resveratrol could modulate multiple pathways involved in cell growth, apoptosis, and inammation; and resveratrol and its hydroxylated analogues also possess antileishmanial activity (102,103). For molecular mechanisms of cancer prevention, resveratrol and its analogs could retard tumor progression by triggering numerous intracellular pathways leading to cell growth arrest such as inhibition of protein kinase C (PKC) activation; downregulation of -catenin expression; counteraction of reactive oxygen species (ROS) production; activation of caspases; induction of genes for oxidative phosphorylation and mitochondrial biogenesis; and blocking NF- B and AP1 mediated signal transduction pathways (51,94,102,103). Furthermore, resveratrol can inhibit the expression and function of the androgen receptor effects in LNCaP prostate cancer cell line by repressing androgen receptor upregulated genes (94). In addition, 40 stilbene oligomers possessed inhibitory activity against DNA topoisomerase II (50).
Coumarins Coumarins and derivatives possess diverse bioactivities, such as antioxidant, antitubercular, antimalarial, anti-HIV-1, antiangiogenesis, antimutagenic, anti-inammatory, cell differentiation inducing, xanthine oxidase inhibiting, and cytotoxicity against human cancer cell lines (69,76,106) (Table 1). For example, coumarin and 7-hydroxycoumarin show antitumor actions in vitro and in vivo on human lung carcinoma cell lines by inhibiting cell proliferation, arresting cell cycle in the G phase, and inducing apoptosis (83). Esculetin (6,7-dihydroxycoumarin) showed lipoxygenase inhibitory effect on the proliferation response of cultured rabbit vascular smooth muscle cells by modulating P signal transduction pathway (86). The structure-activity relationship of esculetin and 8 other coumarin derivatives indicated that 2 adjacent phenolic hydroxyl groups at the C-6 and C-7 positions in the coumarin skeleton were necessary for the potent antiproliferative and antioxidant effect. Therefore, glycosylation and damage of the catechol structure (ortho-dihydroxy groups) had signicant negative inuence on the activity of the coumarins, for example, it considerably reduced the radical scavenging level (31). Lignans Some authors have reported that there was a benecial effect of the hydroxyl group in the lignan molecules on the antioxidant activity and anticancer activity, but most of the lignans did not exhibit strong activity in scavenging radicals (31,63,107). Many reports also have shown that lignans could have anti-inammatory, antibacterial, antiviral, antiallodynic, antiangiogenesis, and antimutagenic properties; regulate expression of enzymes, signal transduction pathways, and hormone metabolism; enhance detoxication; induce apoptosis by cell cycle arresting; and reduce human breast cancer cell adhesion, invasion, and migration in vitro (70,77,93) (Table 1). For example, sesamin had been reported to possess antioxidant, induction of apoptosis, cell cycle arresting, and anti-inammatory effects and could be used in killing human leukemia, stomach, breast, and skin cancer cells (4). And podophyllotoxin was used in the treatment of cancer as a DNA topoisomerase II (topo II) inhibitor, because topo II induced DNA double-strand breaks and thus reduced torsion tension in DNA during replication and the condensation of chromosomes in the nucleus during cell division (13). In addition, lignans (e.g., pinoresinol, lariciresinol, secoisolariciresinol, and matairesinol) are also important phytoestrogens (118). Quinones Quinones (especially hydroxyanthraquinones) are natural phenolic antioxidants. Among the hydroxyanthraquinones, purpurin, pseudopurpurin, and alizarin were most effective, and many others (e.g., emodin, chrysazine, rhein, chrysophanol, and aloe-emondin), without the ortho-dihydroxy structure, were far less effective (31). This indicated that the ortho-dihydroxy
Curcuminoids Ongoing laboratory and clinical studies have indicated that curcuminoids possess unique antioxidant, anti-inammatory, anticarcinogenic/antimutagenic, antithrombotic, hepatoprotectective, antibrosis, antimicrobial, antiviral, and antiparasitic properties and play important roles in cancer chemotherapy (88,92,104) (Table 1). In particular, curcumin can suppress tumor promotion, proliferation, angiogenesis, and inammatory signaling; decrease oxidatively modied DNA and the level of NOS mRNA and protein; modulate AP-1 signaling pathways; block phosphorylation and subsequent degradation of I B kinase activity; inhibit NF- B-regulated gene products (cyclin D1, Bcl-2, Bcl-xL, COX-2); sustain phosphorylation of JNK and p38 MAPK; activate caspase-8, BID cleavage, and cytochrome c release; downregulate iNOS expression; upregulate Map kinase phosphates-5; and also has proapoptotic and antimetastatic activities (4,88,92). Tetrahydrocurcuminoid is a colorless hydrogenated product derived from the yellow curcuminoids and can be used as an efcient superior antioxidant mixture of compounds for use in achromatic foods and cosmetics (105). In addition, the ginerol analogues in ginger also had antioxidant activity (2).
17
structure in the hydroxyanthraquinone molecules played a signicant role in improving the radical scavenging capacity like the catechol structure in other phenolic molecules. In addition, glycosylation of hydroxyanthraquinones markedly diminished their radical scavenging activity (108). Quinone metabolites perform a variety of key functions in plants including pathogen protection, oxidative phosphorylation, and redox signaling. Many of these structurally diverse compounds exhibit potent antimicrobial, anticancer, antitumor, antiangiogenesis, antimutagenic, and anti-inammatory 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 transduction pathways (13,66,78,84). Therefore, certain quinones can play an important role as biomarkers for cancer chemoprevention.
chokeberry, grape, and cherry), spices (e.g., thyme, marjoram, rosemary, sage, and garlic), soy, tea, and pine bark have signicant effects on suppressing formation of both polar and nonpolar HCAs (90). Results showed that different antioxidant phenolic compounds in these plant extracts may play roles in reduction or inhibition of acrylamide and HCAs, subsequently reducing potential mutagenic/carcinogenic harm of certain cooked foods (113,114). CONCLUSION Phenolic compounds are ubiquitous and rich in medicinal herbs and dietary plants (e.g., fruits, vegetables, spices, cereals, and beverages). Various phenolic compounds possess a diverse range of benecial biological activities, which contribute to their potent effects on inhibiting carcinogenesis. Extensive research has been conducted in vitro or in vivo on antioxidant and anticancer activities of phenolic compounds from medicinal herbs and dietary plants. Overwhelming clinical evidence has shown that chemoprevention by phenolic phytochemicals is an inexpensive, readily applicable, acceptable, and accessible approach to cancer control and management (3). However, more information about the health benets and the possible risks of dietary supplement or herbal medicines is needed to ensure their efcacy and safety. In fact, toxic avonoids and drug interactions, liver failure, dermatitis, and anemia were reported for some cases of polyphenol chemopreventive use (115). These potential toxic effects of phenolic compounds are strongly dependent on their concentration and chemical environment, which must be thoroughly understood before any preventive or therapeutic use is considered (4). However, information on safety assessment of natural phenolic compounds is still lacking. In general, medicinal herbs and dietary plants are a good resource of bioactive phenolic compounds in cancer prevention, and only limited aspects have been investigated. There is still much work needed to search for novel and effective anticancer phenolic compounds from more medicinal and dietary plants, to further reveal mechanistic process, and to conduct conrmatory human clinical trials of these phenolic compounds in cancer prevention and treatment. ACKNOWLEDGMENTS This research was supported by grants from the University of Hong Kong (Seed Funding for Basic Research). We are grateful to Dr. Harold Corke and Dr. Mei Sun (School of Biological Sciences, The University of Hong Kong) for their revision and comments on this manuscript. REFERENCES
1. Reddy L, Odhav B, and Bhoola KD: Natural products for cancer prevention: a global perspective. Pharmacol Ther 99, 113, 2003. 2. Surh Y-J: Cancer chemoprevention with dietary phytochemicals. Nat Rev Cancer 3, 768780, 2003.
Others Other phenolic compounds also present a wide range of bioactivities (Table 1). For example, magnoorine from T. asiatica had anti-HIV activity; dihydronitidine possessed tumor specic cytotoxicity effects; triptophenlolide had clear inhibitory effects on lymphocyte and IgG and Mn(III)-based oxidative radical cyclization reactions (111); oleuropein and its glycoside and carnosol had antioxidant, induction of apoptosis, cell cycle arresting, and anti-inammatory effects; and anethole and carnosol suppressed AP-1 activation (59,61). Furthermore, eugenol exhibited potent antiproliferation activity at different stages of progression; induced apoptosis by blocking cells in the S phase of progression; inhibited E2F1 transcriptional activity in melanoma cells; and has been used as an antiseptic, antibacterial, analgesic agent in traditional medical practices in Asia (112). Interestingly, natural phenolic compounds also suppress the formation of mutagenic and carcinogenic acrylamide and heterocyclic amines (65). High levels of acrylamide have been found after frying or baking of carbohydrate-rich foods such as potatoes and cereal products (113). Acrylamide has been classied as probably carcinogenic to humans by the International Agency for Research on Cancer. In earlier toxicological studies, acrylamide was genotoxic and carcinogenic to test animals and caused reproductive and developmental problems (65). Additionally, a series of heterocyclic amines (HCAs) have been isolated as mutagens from various kinds of thermally processed materials including cooked meat and sh and pyrolysis products of amino acids and proteins (113). Many HCAs have been demonstrated to be capable of forming DNA adducts to induce DNA damage, and some of them have been classied by the International Agency for Research on Cancer as probable/possible human carcinogens (113). Plant-derived extracts such as bamboo leaves, ginkgo, tea, grape seed extracts, and so forth, can reduce acrylamide in various heat-treated foods to varying extents (114). In addition, extracts from berries (e.g., blackberry,
18
W.-Y. HUANG ET AL. 25. Hu C, Cai YZ, Li WD, Corke H, and Kitts DD: Anthocyanin characterization and bioactivity assessment of a dark blue grained wheat (Triticum aestivum L. cv. Hedong Wumai) extract. Food Chem 104, 955961, 2007. 26. Shan B, Cai YZ, Brooks JD, and Corke H: Antibacterial properties and major bioactive components of cinnamon stick (Cinnamomum burmannii): activity against foodborne pathogenic bacteria. J Agric Food Chem 55, 54845490, 2007. 27. Shan B, Cai YZ, Brooks JD, and Corke H: The in vitro antibacterial activity of dietary spice and medicinal herb extracts. Int J Food Microbiol 117, 112119, 2007. 28. Shan B, Cai YZ, Sun M, and Corke H: Antioxidant capacity of 26 spice extracts and characterization of their phenolic constituents. J Agric Food Chem 53, 77497759, 2005. 29. Surveswaran S, Cai YZ, Corke H, and Sun M: Systematic evaluation of natural phenolic antioxidants from 133 Indian medicinal plants. Food Chem 102, 938953, 2007. 30. Cai YZ, Sun M, and Corke H; Antioxidant activity of betalains from plants of the Amaranthaceae. J Agric Food Chem 51, 22882294, 2003. 31. Cai YZ, Sun M, Xing J, Luo Q, and Corke H: Structure-radical scavenging activity relationships of phenolic compounds from traditional Chinese medicinal plants. Life Sci 78, 28722888, 2006. 32. Bao JS, Cai YZ, Sun M, Wang GY, and Corke H: Anthocyanins, avonols, and free radical scavenging activity of Chinese bayberry (Myrica rubra) extracts and their color properties and stability. J Agric Food Chem 53, 23272332, 2005. 33. Huang WY, Cai YZ, Xing J, Corke H, and Sun M: Comparative analysis of bioactivities of four Polygonum species. Planta Med 74, 4349, 2008. 34. Heim KE, Tagliaferro AR, and Bobilya DJ: Flavonoid antioxidants: chemistry, metabolism, and structure-activity relationships. J Nutr Biochem 13, 572584, 2002. 35. Sampietro DA and Vattuone MA: Sugarcane straw and its phytochemicals as growth regulators of weed and crop plants. Plant Growth Regul 48, 2127, 2006. 36. Stagos D, Kazantzoglou G, Theofanidou D, Kakalopoulou G, Magiatis P, et al.: Activity of grape extracts from Greek varieties of Vitis vinifera against mutagenicity induced by bleomycin and hydrogen peroxide in Salmonella typhimurium strain TA102. Mutat Res-Gen Tox En 609, 165 175, 2006. 37. Adom KK and Liu RH: Antioxidant activity of grains. J Agric Food Chem 50, 61826187, 2002. 38. Jakobek L, Seruga M, Novak I, and Medvidovic-Kosanovic M: Flavonols, phenolic acids, and antioxidant activity of some red fruits. Deut LebensmRunsch 103, 369378, 2007. 39. Huang WY, Cai YZ, Xing J, Corke H, and Sun M: A potential antioxidant resource: endophytic fungi isolated from traditional Chinese medicinal plants. Econ Bot 61, 1430, 2007. 40. Ren WY, Qiao ZH, Wang HW, Zhu L, and Zhang L: Flavonoids: promising anticancer agents. Med Res Rev 23, 519534, 2003. 41. Iwashina T: The structure and distribution of the avonoids in plants. J Plant Res 113, 287299, 2000. 42. Hollman PCH and Katan MB: Flavonols, avones, and avanolsnature, occurrence, and dietary burden. J Sci Food Agric 80, 10811093, 2000. 43. Chen JJ, Chang HW, Kim HP, and Park H: Synthesis of phospholipase A2 inhibitory biavonoids. Bioorg Med Chem Lett 16, 23732375, 2006. 44. Lin YM, Anderson H, Flavin MT, Pai YH, Mata-Greenwood E, et al.: In vitro anti-HIV activity of biavonoids isolated from Rhus succedanea and Garcinia multiora. J Nat Prod 60, 884888, 1997. 45. Grynberg NF, Carvalho MG, Velandia JR, Oliveira MC, Moreira IC, et al.: DNA topoisomerase inhibitors: biavonoids from Ouratea species. Braz J Med Biol Res 35, 819822, 2002. 46. Singh RP, Tyagi AK, Zhao J, and Agarwal R: Silymarin inhibits growth and causes regression of established skin tumors in SENCAR mice via modulation of mitogen-activated protein kinases and induction of apoptosis. Carcinogenesis 23, 99510, 2002.
3. Luk JM, Wang XL, Liu P, Wong K-F, Chan K-L, et al.: Traditional Chinese herbal medicines for treatment of liver brosis and cancer: from laboratory discovery to clinical evaluation. Liver Int 27, 879890, 2007. 4. Fresco P, Borges F, Diniz C, and Marques MPM: New insights on the anticancer properties of dietary polyphenols. Med Res Rev 26, 747766, 2006. 5. Raposo CG, Carpeno JD, and Baron MG: Causes of lung cancer: smoking, environmental tobacco smoke exposure, occupational and environmental exposures, and genetic predisposition. Med Clin 128, 390396, 2007. 6. Tabor E: Pathogenesis of hepatitis B virus-associated hepatocellular carcinoma. Hepatol Res 37, S110S114, 2007. 7. Lee JY, Li JW, and Yeung ES: Single-molecule detection of surfacehybridized human papillorna virus DNA for quantitative clinical screening. Anal Chem 79, 80838089, 2007. 8. Shiotani A, Iishi H, Uedo N, Ishiguro S, Tatsuta M, et al.: Evidence that loss of sonic hedgehog is an indicator of Helicobater pylori-induced atrophic gastritis progressing to gastric cancer. Am J Gasteroenterol 100, 581587, 2005. 9. Vauhkonen H, Bohling T, Eissa S, Shoman S, and Knuutila S: Can bladder adenocarcinomas be distinguished from schistosomiasis-associated bladder cancers by using array comparative genomic hybridization analysis? Cancer Genet Cytogen 177, 153157, 2007. 10. Groopman JD, Wang JS, and Scholl P: Molecular biomarkers for aatoxins: from adducts to gene mutations to human liver cancer. Can J Physiol Pharm 74, 203209, 1996. 11. Poulson HE, Prieme H, and Loft S: Role of oxidative DNA damage in cancer initiation and promotion. Eur J Cancer Prev 71, 916, 1998. 12. Cai YZ, Luo Q, Sun M, and Corke H: Antioxidant activity and phenolic compounds of 112 traditional Chinese medicinal plants associated with anticancer. Life Sci 74, 21572184, 2004. 13. Efferth T, Li PCH, Konkimalla VSB, and Kaina B: From traditional Chinese medicine to rational cancer therapy. Trends Mol Med 13, 353361, 2007. 14. Monks NR, Bordignon SAL, Ferraz A, Machado KR, Faria DH, et al.: Anti-tumor screening of Brazilian plants. Pharm Biol 40, 603616, 2002. 15. Bo QM, Wu ZY, Shun QS, Bao XS, Mao ZS, et al.: A Selection of the Illustrated Chinese Anti-Cancer Herbal Medicines. Shanghai: Shanghai Science and Technology Literature Press, 2002. 16. Doll R and Peto R: The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst 66, 11911308, 1981. 17. Greenwald P: Chemoprevention of cancer. Sci Am 275, 9699, 1996. 18. Liu RH: Health benets of fruits and vegetables are from additive and synergistic combination of phytochemicals. Am J Clin Nutr 78, 517S 520S, 2003. 19. Kwon KH, Barve A, Yu S, Huang MT, and Kong ANT: Cancer chemoprevention by phytochemicals: potential molecular targets, biomarkers, and animal models. Acta Pharmacol Sin 28, 14091421, 2007. 20. Aggarwal BB and Shishodia S: Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol 71, 13971421, 2006. 21. Han XZ, Shen T, and Lou HX: Dietary polyphenols and their biological signicance. Int J Mol Sci 8, 950988, 2007. 22. Baidez AG, Gomez P, Del Rio JA, and Ortuno A: Dysfunctionality of the xylem in Olea europaea L. plants associated with the infection process by Verticillium dahliae Kleb. Role of phenolic compounds in plant defense mechanism. J Agric Food Chem 55, 33733377, 2007. 23. Veeriah S, Kautenburger T, Habermann N, Sauer J, Dietrich H, et al.: Apple avonoids inhibit growth of HT29 human colon cancer cells and modulate expression of genes involved in the biotransformation of xenobiotics. Mol Carcinogen 45, 164174, 2006. 24. Owen RW, Giacosa A, Hull WE, Haubner R, Spiegelhalder B, et al.: The antioxidant/anticancer potential of phenolic compounds isolated from olive oil. Eur J Cancer 36, 12351247, 2000.
NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS 47. Schoeld DM, Mbugua DM, and Pell AN: Analysis of condensed tannins: a review. Anim Feed Sci Tech 91, 2140, 2001. 48. Huh YS, Hong TH, and Hong WH: Effective extraction of oligomeric proanthocyanidin (OPC) from wild grape seeds. Biotechnol Bioproc E 9, 471475, 2004. 49. Xiao K, Xuan LJ, Xu YM, Bai DL, Zhong DX, et al.: Dimeric stilbene glycosides from Polygonum cuspidatum. Eur J Org Chem 3, 564568, 2002. 50. Yamada M, Hayashi KI, Ikeda S, Tsutsui K, Tsutsui K, et al.: Inhibitory activity of plant stilbene oligomers against DNA topoisomerase II. Biol Pharm Bull 29, 15041507, 2006. 51. Athar M, Back JH, Tang XW, Kim KH, Kopelovich L, et al.: Resveratrol: a review of preclinical studies for human cancer prevention. Toxicol Appl Pharm224, 274283, 2007. 52. Navarro DD, de Souza MM, Neto RA, Golin V, Niero R, et al.: Phytochemical analysis and analgesic properties of Curcuma zedoaria grown in Brazil. Phytomedicine 9, 427432, 2002. 53. Masuda T: Anti-inammatory antioxidants from tropical Zingiberaceae plantsisolation and synthesis of new curcuminoids. ACS Symp Ser 660, 219233, 1997. 54. Sonnenberg H, Kaloga M, Eisenbach N, and Fromming KK: Isolation and characterization of an angular-type dihydropyranocoumaringlycoside from the fruits of Ammi visnaga (L) Lam (Apiaceae). Zeitschrift Natur C-A J BioSci 50, 729731, 1995. 55. Zhao C, Nagatsu A, Hatano K, Shirai N, Kato S, et al.: New lignan glycosides from Chinese medicinal plant, Sinopodophyllum emodi. Chem Pharm Bull 51, 255261, 2003. 56. Elfahmi, Ruslan K, Batterman S, Bos R, Kayser O, et al.: Lignan prole of Piper cubeba, an Indonesian medicinal plant. Biochem Syst Ecol 35, 397402, 2007. 57. Milder IEJ, Arts ICW, van de Putte B, Venema DP, and Hollman PCH: Lignan contents of Dutch plant foods: a database including lariciresinol, pinoresinol, secoisolariciresinol and matairesinol. Brit J Nutr 93, 393402, 2005. 58. Luthje S, Van Gestelen P, Cordoba-Pedregosa MC, Gonzalez-Reyes JA, Asard H, et al.: Quinones in plant plasma membranesa missing link? Protoplasma 205, 4351, 1998. 59. Iwasaki H, Oku H, Takara R, Miyahira H, Hanashiro K, et al.: The tumor specic cytotoxicity of dihydronitidine from Toddalia asiatica Lam. Cancer Chemoth Pharm 58, 451459, 2006. 60. Huang WY, Cai YZ, Hyde KD, Corke H, and Sun M: Endophytic fungi from Nerium oleander L (Apocynaceae): main constituents and antioxidant activity. World J Microb Biot 23, 12531263, 2007. 61. Lo AH, Liang YC, Lin-Shiau SY, and Lin JK: Carnosol, an antioxidant in rosemary, suppresses inducible nitric oxide synthase through downregulating nuclear factor-kappa B and c-Jun. Biochem Pharmacol 69, 221232, 2005. 62. Johnson IT: Phytochemicals and cancer. Proc Nutr Soc 66, 207215, 2007. 63. Yamauchi S, Hayashi Y, Kirikihira T, and Masuda T: Synthesis and antioxidant activity of olivil-type lignans. Biosci Biotech Biochem 69, 113122, 2005. 64. Silici S, Unlu M, and Vardar-Unlu G: Antibacterial activity and phytochemical evidence for the plant origin of Turkish propolis from different regions. World J Microb Biot 23, 17971803, 2007. 65. Zhang Y and Zhang Y: Formation and reduction of acrylamide in Maillard reaction: a review based on the current state of knowledge. Crit Rev Food Sci 47, 521542, 2007. 66. Motti CA, Bourguet-Kondracki ML, Longeon A, Doyle JR, Llewellyn LE, et al.: Comparison of the biological properties of several marine sponge-derived sesquiterpenoid quinones. Molecules 12, 13761388, 2007. 67. Chaubal R, Mujumdar AM, Misar A, and Deshpande NR: Isolation of phenolic compounds from Acacia nilotica with topical antiinammatory activity. Asian J Chem 17, 15951599, 2005.
19
68. Souza SMC, Aquino LCM, Milach AC, Bandeira MAM, Nobre MEP, et al.: Antiinammatory and antiulcer properties of tannins from Myracrodruon urundeuva Allemao (Anacardiaceae) in rodents. Phytother Res 21, 220225, 2007. 69. Fylaktakidou KC, Hadjipavlou-Litina DJ, Litinas KE, and Nicolaides DN. Natural and synthetic coumarin derivatives with antiinammatory/antioxidant activities. Curr Pharm Design 10, 38133833, 2004. 70. Kassuya CAL, Silvestre A, Menezes-de-Lima O, Marotta DM, Rehder VLG, et al.: Antiinammatory and antiallodynic actions of the lignan niranthin isolated from Phyllanthus amarusevidence for interaction with platelet activating factor receptor. Eur J Pharmacol 546, 182188, 2006. 71. Shih PH, Yeh CT, and Yen GC: Anthocyanins induce the activation of phase II enzymes through the antioxidant response element pathway against oxidative stress-induced apoptosis. J Agric Food Chem 55, 9427 9435, 2007. 72. Ahmad H, Li JX, Polson M, Mackie K, Quiroga W, et al.: Citrus limonoids and avonoids: enhancement of phase II detoxication enzymes and their potential in chemoprevention. Poten Health Citrus ACS Sym Ser 936, 130143, 2006. 73. Shimada T: Xenobiotic-metabolizing enzymes involved in activation and detoxication of carcinogenic polycyclic aromatic hydrocarbons. Drug Metab Phamacokin 21, 257276, 2006. 74. Raghavendra MP, Kumar PR, and Prakash V: Mechanism of inhibition of rice bran lipase by polyphenolsa case study with chlorogenic acid and caffeic acid. J Food Sci 72, E412E419, 2007. 75. Joanisse GD, Bradley RL, Preston CM, and Munson AD: Soil enzyme inhibition by condensed litter tannins may drive ecosystem structure and processes: the case of Kalmia angustifolia. New Phytol 175, 535546, 2007. 76. Ferrari AM, Sgobba M, Gamberini MC, and Rastelli G: Relationship between quantum-chemical descriptors of proton dissociation and experimental acidity constants of various hydroxylated coumarins. Identication of the biologically active species for xanthine oxidase inhibition. Eur J Med Chem 42, 10281031, 2007. 77. Hung TM, Na M, Min BS, Ngoc TM, Lee I, et al.: Acetylcholinesterase inhibitory effect of lignans isolated from Schizandra chinensis. Arch Pharm Res 30, 685690, 2007. 78. Zaborska W, Krajewska B, Kot M, and Karcz W: Quinone-induced inhibition of urease: elucidation of its mechanisms by probing thiol groups of the enzyme. Bioorg Chem 35, 233242, 2007. 79. Noel S, Kasinathan M, and Rath SK: Evaluation of apigenin using in vitro cytochalasin blocked micronucleus assay. Toxicol In Vitro 20, 11681172, 2006. 80. Yi ZC, Wang Z, Li HX, Liu MJ, Wu RC, et al.: Effects of chebulinic acid on differentiation of human leukemia K562 cells. ACTA Pharmacol Sin 25, 231238, 2004. 81. Kuo PL, Hsu YL, Lin TC, Lin LT, Chang JK, et al.: Casuarinin from the bark of Terminalia arjuna induces apoptosis and cell cycle arrest in human breast adenocarcinoma MCF-7 cells. Planta Med 71, 237243, 2005. 82. Larrosa M, Tomas-Barberan FA, and Espin JC: The dietary hydrolysable tannin punicalagin releases ellagic acid that induces apoptosis in human colon adenocarcinoma Caco-2 cells by using the mitochondrial pathway. J Nutr Biochem 17, 611625, 2006. 83. Lopez-Gonzalez JS, Prado-Garcia H, Aguilar-Cazares D, MolinaGuarneros JA, Morales-Fuentes J, et al.: Apoptosis and cell cycle disturbances induced by coumarin and 7-hydroxycoumarin on human lung carcinoma cell lines. Lung Cancer 43, 275283, 2004. 84. Qiu XB, Schonthal AH, and Cadenas E: Anticancer quinones induce pRbpreventable G(2)/M cell cycle arrest and apoptosis. Free Radical Bio Med 24, 848854, 1998.
20
W.-Y. HUANG ET AL. 101. Smith SH, Tate PL, Huang G, Magee JB, Meepagala KM, et al.: Antimutagenic activity of berry extracts. J Med Food 7, 450455, 2004. 102. Kedzierski L, Curtis JM, Kaminska M, Jodynis-Liebert J, and Murias M: In vitro antileishmanial activity of resveratrol and its hydroxylated analogues against Leishmania major promastigotes and amastigotes. Parasitol Res 102, 9197, 2007. 103. Chillemi R, Sciuto S, Spatafora C, and Tringali C: Anti-tumor properties of stilbene-based resveratrol analogues: Recent results. Nat Prod Comm 2, 499513, 2007. 104. Sharma RA, Gescher AJ, and Steward WP: curcumin: the story so far. Eur J Cancer 41, 19551968, 2005. 105. Venkateswarlu S, Rambabu M, Subbaraju GV, and Satyanarayana S: Synthesis and antibacterial activity of tetrahydrocurcuminoids. Asian J Chem 12, 141144, 2000. 106. Ishikawa T: Anti HIV-1 active Calophyllum coumarins: distribution, chemistry, and activity. Heterocycles 53, 453, 2000. 107. Chattopadhyay SK, Kumar TRS, Maulik PR, Srivastava S, Garga A, et al.: Absolute conguration and anticancer activity of taxiresinol and related lignans of Taxus wallichiana. Bioorgan Med Chem 11, 49454948, 2003. 108. Demirezer LO, Kuru uz um-Uz A, Bergere I, Schiewe H-J, and Zeeck A: The structures of antioxidant and cytotoxic agents from natural source: anthraquinones and tannins from roots of Rumex patientia. Phytochemistry 58, 12131217, 2001. 109. Garuti L, Roberti M, and Pizzirani D: Nitrogen-containing heterocyclic quinones: a class of potential selective antitumor agents. Mini-Rev Med Chem 7, 481489, 2005. 110. Asche C: Antitumour quinones. Mini-Rev Med Chem 5, 449467, 2005. 111. Yang D, Ye XY, Gu S, and Xu M: Lanthanide triates catalyze Mn(III)based oxidative radical cyclization reactions. Enantioselective synthesis of (-)-triptolide, (-)-triptonide, and (+)-triptophenolide. J Am Chem Soc 121, 55795580, 1999. 112. Ghosh R, Nadiminty N, Fitzpatrick JE, Alworth WL, Slaga TJ, et al.: Eugenol causes melanoma growth suppression through inhibition of E2F1 transcriptional activity. J Biol Chem 280, 58125819, 2005. 113. Cheng K-W, Chen F, and Wang MF: Heterocyclic amines: chemistry and health. Mol Nutr Food Res 50, 11501170, 2006. 114. Zhang Y, Chen J, Zhang XL, Wu XQ, and Zhang Y: Addition of antioxidant of bamboo leaves (AOB) effectively reduces acrylamide formation in potato crisps and french fries. J Agric Food Chem 55, 523528, 2007. 115. Galati G and OBrien P: Potential toxicity of avonoids and other dietary phenolics: signicance for their chemopreventive and anticancer properties. Free Radic Biol Med 37, 287303, 2004. 116. Farina HG, Pomies M, Alonso DF, and Gomez DE: Antitumor and antiangiogenic activity of soy isoavone genistein in mouse models of melanoma and breast cancer. Oncol Rep 16, 885891, 2006. 117. Mense SM, Hei TK, Ganju RK, and Bhat HK: Phytoestrogens and breast cancer prevention: Possible mechanisms of action. Environ Health Persp 116, 426433, 2008. 118. Thompson LU, Boucher BA, Cotterchio M, Kreiger N, and Liu Z: Dietary phytoestrogens, including isoavones, lignans, and coumestrol, in nonvitamin, nonmineral supplements commonly consumed by women in Canada. Nutr Cancer 59, 176184, 2007.
85. Nomura M, Tsukada H, Ichimatsu D, Ito H, Yoshida T, et al.: Inhibition of epidermal growth factor-induced cell transformation by tannins. Phytochemistry 66, 20382046, 2005. 86. Huang HC, Lai MW, Wang HR, Chung YL, Hsieh LM, et al.: Antiproliferative effect of esculetin on vascular smooth-muscle cellspossible roles of signal-transduction pathways. Eur J Pharmacol 237, 3944, 1993. 87. Lindenmeyer F, Li H, Menashi S, Soria C, and Lu H: Apigenin acts on the tumor cell invasion process and regulates protease production. Nutr Cancer 39, 139147, 2001. 88. Mitra A, Chakrabarti J, Banerji A, Chatterjee A, and Das BR: Curcumin, a potential inhibitor of MMP-2 in human laryngeal squamous carcinoma cells HEp2. J Environ Pathol Tox 25, 679689, 2006. 89. Takahama U, Ryu K, and Hirota S: Chlorogenic acid in coffee can prevent the formation of dinitrogen trioxide by scavenging nitrogen dioxide generated in the human oral cavity. J Agric Food Chem 55, 92519258, 2007. 90. Ahn J and Gr un IU: Heterocyclic amines: 2. inhibitory effects of natural extracts on the formation of polar and nonpolar heterocyclic amines in cooked beef. J Food Sci 70, C263C268, 2005. 91. Tsuji PA and Walle T: Inhibition of benzo(a)pyrene-activating enzymes and DNA binding in human bronchial epithelial BEAS-2B cells by methoxylated avonoids. Carcinogenesis 27, 15791585, 2006. 92. Jung KK, Lee HS, Cho JY, Shin WC, Rhee MH, et al.: Inhibitory effect of curcumin on nitric oxide production from lipopolysaccharide-activated primary microglia. Life Sci 79, 20222031, 2006. 93. Jacobs MN, Nolan GT, and Hood SR: Lignans, bacteriocides and organochlorine compounds activate the human pregnane X receptor (PXR). Toxicol Appl Pharm 209, 123133, 2005. 94. Mitchell SH, Zhu W, and Young CY: Resveratrol inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Cancer Res 59, 58925895, 1999. 95. Faried A, Kurnia D, Faried LS, Usman N, Miyazaki T, et al.: Anticancer effects of gallic acid isolated from Indonesian herbal medicine, Phaleria macrocarpa (Scheff.) Boerl, on human cancer cell lines. Int J Oncol 30, 605613, 2007. 96. Fki I, Sahnoun Z, and Sayadi S: Hypocholesterolemic effects of phenolic extracts and puried hydroxytyrosol recovered from olive mill wastewater in rats fed a cholesterol-rich diet. J Agric Food Chem 55, 624631, 2007. 97. Schaffer S, Podstawa M, Visioli F, Bogani P, M uller WE, et al.: Hydroxytyrosol-rich olive mill wastewater extract protects brain cells in vitro and ex vivo. J Agric Food Chem 55, 50435049, 2007. 98. Fabiani R, De Bartolomeo A, Rosignoli P, Servili M, Montedoro GF, et al.: Cancer chemoprevention by hydroxytyrosol isolated from virgin olive oil through G1 cell cycle arrest and apoptosis. Eur J Cancer Prev 11, 351358, 2002. 99. Chen C, Yu R, Owuer ED, and Kong AN: Activation of antioxidant response element (ARE), mitogen-activated protein kinases (MAPKs) and caspases by major green tea polyphenol compounds during cell survival and death. Arch Pharm Res 23, 605612, 2000. 100. Levy J, Teuerstein I, Marbach M, Radian S, and Sharoni Y: Tyrosine protein kinase activity in the DMBA-induced rat mammary tumor: inhibition by quercetin. Biochem Biophys Res Commun 123, 12271233, 1984.

Wu-Yang Huang, Yi-Zhong Cai - Natural Phenolic Compounds From Medicinal Herbs and Dietary Plants, Use For Cancer Prevention

Hochgeladen von

Dokumentinformationen

Originalbeschreibung:

Originaltitel

Copyright

Verfügbare Formate

Dieses Dokument teilen

Dokument teilen oder einbetten

Freigabeoptionen

Stufen Sie dieses Dokument als nützlich ein?

Sind diese Inhalte unangemessen?

Copyright:

Verfügbare Formate

Wu-Yang Huang, Yi-Zhong Cai - Natural Phenolic Compounds From Medicinal Herbs and Dietary Plants, Use For Cancer Prevention

Hochgeladen von

Copyright:

Verfügbare Formate

This article was downloaded by: [University of Valladolid] On: 11 January 2012, At: 04:09 Publisher: Routledge Informa

Nutrition and Cancer

Available online: 29 Dec 2009

Downloaded by [University of Valladolid] at 04:09 11 January 2012

W.-Y. HUANG ET AL.

Downloaded by [University of Valladolid] at 04:09 11 January 2012

NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS

R=H: tyrosol R=OH: hydroxytyrosol

Downloaded by [University of Valladolid] at 04:09 11 January 2012

cynarin (1,3-dicaffeoylquinic acid)

W.-Y. HUANG ET AL.

Downloaded by [University of Valladolid] at 04:09 11 January 2012

NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS

Downloaded by [University of Valladolid] at 04:09 11 January 2012

FIG. 2. Structures of major groups/subgroups of avonoids and their associated glycosides.

W.-Y. HUANG ET AL.

Downloaded by [University of Valladolid] at 04:09 11 January 2012

R1=OH, R2=OCH3: hesperetin R1=H, R 2=OH: naringenin R1=OH, R2=OH: eriodictyol

R=H: epicatechin R=OH: epigallocatechin

R=H: epicatechin gallate R=OH: epigallocatechin gallate

NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS

Basic skeleton of gallotannins

C=O G = gal loyl

Basic skeleton and substituents of ellagitannins

di-O-galloyl- -D-glucose (gallotannins)

R 1 =H, H/CHEB/DHHDP R 2 =HHDP/H, H

Downloaded by [University of Valladolid] at 04:09 11 January 2012

R2 R 1 =OH/OG R 2 =H, H/G, G/HHDP R 3 =H, H/HHDP/BCHT

tellimagrandin II (ellagitannins) Basic skeleton of condensed tannins

oligomeric proanthocyanidins (condensed tannins)

W.-Y. HUANG ET AL.

R1=OCH3, R 2=OCH3: curcumin R1=H, R 2=OCH3: demethoxycurcumin R1=H, R 2=H: bisdemethoxycurcumin

Downloaded by [University of Valladolid] at 04:09 11 January 2012

NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS

R=OH: esculetin R=OCH3: scopoletin R=CH3: escopoletin R=Gluc: aesculin

R=H: seselin R=OH: khellactone

R=H: xanthyletin R=OCH3: xanthoxyletin

Downloaded by [University of Valladolid] at 04:09 11 January 2012

R=OH: matairesinol R=OCH3: arctigenin

H3CO R3 OCH3 OCH3 OCH3

R=H: morelensin R=OCH3: yatein

W.-Y. HUANG ET AL.

Downloaded by [University of Valladolid] at 04:09 11 January 2012

NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS

Downloaded by [University of Valladolid] at 04:09 11 January 2012

R1=H, R 2=OH: alkannan R1=OH, R 2=H: shikonin R1=COCH3, R2=H: acetylshikonin

R=H: tanshinone IIA R=OH: tanshinone IIB

W.-Y. HUANG ET AL.

Downloaded by [University of Valladolid] at 04:09 11 January 2012

OCH3 HO O OH O HO OCH3 OCH3 O

NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS

Downloaded by [University of Valladolid] at 04:09 11 January 2012

(Continued on next page)

W.-Y. HUANG ET AL.

Downloaded by [University of Valladolid] at 04:09 11 January 2012

NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS

Downloaded by [University of Valladolid] at 04:09 11 January 2012

W.-Y. HUANG ET AL.

Downloaded by [University of Valladolid] at 04:09 11 January 2012

NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS

Downloaded by [University of Valladolid] at 04:09 11 January 2012

Downloaded by [University of Valladolid] at 04:09 11 January 2012