1. No category

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
a
a
Wu-Yang Huang , Yi-Zhong Cai & Yanbo Zhang
b
a
School of Biological Sciences, University of Hong Kong, Hong Kong, PR China
b
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), 1–20
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
Downloaded by [University of Valladolid] at 04:09 11 January 2012
School of Chinese Medicine, the University of Hong Kong, Hong Kong, PR China
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.,
aflatoxins 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 sufficient consumption of fruit and vegetables and the risk of specific cancers,
Natural phenolic compounds play an important role in cancer
prevention and treatment. Phenolic compounds from medicinal
herbs and dietary plants include phenolic acids, flavonoids, 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-inflammatory 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 final 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: [email protected]
1
Downloaded by [University of Valladolid] at 04:09 11 January 2012
2
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 modified diets to prevent cancer are ongoing (17). Dietary
plant—such as fruits, vegetables, spices, cereals, and edible
tubers/roots—which also contain significant levels of bioactive
natural compounds, may provide human health benefits 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 antiinflammatory and anticell growth signaling pathways culminating in cell cycle arrest and/or cell-death (19).
Phytochemicals are defined 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, identified
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 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, 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-inflammatory activities to a greater or
lesser extent (21–24). 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 (12,25–33). Hundreds of natural phenolic compounds have been identified from
our tested medicinal herbs and dietary plants, mainly including phenolic acids, flavonoids, 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, flavonoids, 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 officinalis, Cassia auriculata,
Polygonum aviculare, Punica granatum, Rheum officinale, Rhus
chinensis, Sanguisorba officinalis, and Terminalia chebula as
well as dietary spices, for example, thyme and clove (12,28–31).
Other hydroxybenzoic acids are also ubiquitous in medicinal
herbs and dietary plants (spices, fruits, vegetables). For example,
Dolichos biflorus, Feronia elephantum, and Paeonia lactiflora
contain hydroxybenzoic acid; Cinnamomum cassia, Lawsonia
inermis, dill, grape, and star anise possess protocatechuic acid;
Foeniculum vulgare, Ipomoea turpethum, and Picrorhiza scrophulariiflora have vanillic acid; Ceratostigma willmottianum
and sugarcane straw possess syringic acid (12,28–31,35,36).
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
3
NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS
R1
COOH
R1
R
COOH
OH
HO
HO
HO
R2
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
R=H: tyrosol
R=OH: hydroxytyrosol
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
O
OH
H
N
Downloaded by [University of Valladolid] at 04:09 11 January 2012
H3CO
H3CO
O
gingerol
HO
capsaicin
OH
OH
HO
HOOC
OH
OH
O
OH
O
HO
OH
O
O
O
cynarin (1,3-dicaffeoylquinic acid)
O
OH
OH
OH
O
COOH
O
OH
O
OH
OH
chlorogenic acid
HO
O
OH
O
O
HO
HO
O
O
O
OH
HO
O
OH
HO
salvianolic acid B
O
OH
ellagic acid
O
OH
HO
OH
HO
COOH
OH
OH
O
HO
OH
O
OH
O
HO
gossypol
FIG. 1.
rosmarinic acid
Chemical structures of common phenolic acids and analogs from medicinal herbs and dietary plants.
Downloaded by [University of Valladolid] at 04:09 11 January 2012
4
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 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 bond
is saturated), flavanols (flavan-3-ols and flavan-3,4-diols; C-ring
is 1-pyran), anthocyanins (anthocyanidins; C-ring is 1-pyran,
and 1–2 and 3–4 bonds are unsaturated), chalcones (C-ring
is opened), isoflavonoids (mainly isoflavones; B ring binds to
the 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). In
nature, flavonoids 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 flavonoids are present as aglycones
(4,31). More than 80 different sugars have been discovered
bound to flavonoids, and common glycosides include glucoside,
glucuronide, galactoside, arabinoside, rhamnoside, apiosylglucoside, and malonyl (42) (Fig. 2).
Different kinds of flavonoids are present in practically all
dietary plants, like fruits and vegetables, and we also found that
flavonoids 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 flavonoids from
medicinal herbs and dietary plants are shown in Fig. 3. The most
common flavones 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, inflorescences 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 flavonols. These flavonols 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, flowers of Sophora japonica and Rosa chinensis, aerial parts of A. annua, rhizomes of
Alpinia officinarum, and fruits (hawthorn) of Crataegus pinnatifida (12,28). Among these common flavonols, quercetin is one
of the major dietary flavonoids, found in a broad range of fruit,
vegetables, and beverages with a daily intake in Western countries of 25–30 mg (3). Flavanones such as naringenin, hesperetin,
eriodictyol, and their glycosides (e.g., naringin, hesperidin, and
liquiritin) and flavanonols (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 inflorescences of Prunella vulgaris and flowers 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 verniciflua, Caesalpinia sappan, and Carthamus tinctorius (12,31).
Isoflavones 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, biflavonoids are flavonoid
dimers connected with a C–C or C–O–C 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 flavonoid 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
classified into 2 classes: hydrolysable tannins (gallo- and
ellagi-tannins) and condensed tannins (proanthocyanidins) (12)
5
NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS
O
O
O
O
OH
O
O
flavones
flavonols
O
O
isoflavones
O
OH
OH
Downloaded by [University of Valladolid] at 04:09 11 January 2012
O
O
flavanones
flavanols
flavanonols
+
O
OH
O
chalcones
OH
anthocyanidins
O
OH
HO
OH
O
OH
HO
HO
O
O
OH
HO
O
OH
OH
OH
HO
HO
HO
-glucuronide
-glucoside
-galactoside
O
OH
OH
O
OH
O
O
O
O
OH
OH
OH
HO
CH3
-rhamnoside
HO
S
OH
OH
-arabinoside
-malonyl
-apiosylglucoside
FIG. 2. Structures of major groups/subgroups of flavonoids 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 esterified 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
W.-Y. HUANG ET AL.
R2
R2
R1
R3
HO
HO
O
R1
R3
OH
+
O
HO
O
R4
R2
OH
R1
OH
OH
O
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
OH
O
OH
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
R1
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
R2
Downloaded by [University of Valladolid] at 04:09 11 January 2012
HO
HO
O
OH
O
HO
R1
R2
O
R3
OH
O
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
R1=OH, R2=OCH3: hesperetin
R1=H, R 2=OH: naringenin
R1=OH, R2=OH: eriodictyol
OH
O
OH
butein
R
OH
OH
OH
HO
O
OH
HO
O
O
HO
OH
OH
OH
OH
O
OH
OH
taxifolin
OH
OH
R=H: epicatechin
R=OH: epigallocatechin
catechin
OH
OH
HO
O
R
O
O
HO
O
OCH3
O
OH
OH
O
OH
OH
OH
R=H: epicatechin gallate
R=OH: epigallocatechin gallate
OH
OH
O
silymarin
FIG. 3. Representative compounds from different categories of flavonoids 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 flavan-3-diols (catechin or epicatechin derivatives),
also known as proanthocyanidins (47). Some authors have considered that the polymerized products of flavan-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.
7
NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS
OH
Basic skeleton of gallotannins
OH
HO
HO
Gn O
O(H/ G)
O
Gn O
Gn O
HOH 2 C
HO
OG
O
OGn
O
O
OH
HO
O
O
C=O
OH
Gn = O-3-galloyls
G = gal loyl
HO
di-O-galloyl-β-D-glucose (gallotannins)
Basic skeleton and substituents of ellagitannins
O
Downloaded by [University of Valladolid] at 04:09 11 January 2012
R3
O
O
R 1 =H, H/CHEB/DHHDP
R 2 =HHDP/H, H
R2
O
R 1O
OG
O
O
O
O
O
HO
O
OH
OH
O
O
HO
HO
OH HO
R1
O
OH
O
OH
BC HT
HHDP
O
O
O
O
HO
R2
R 1 =OH/OG
R 2 =H, H/G, G/HHDP
R 3 =H, H/HHDP/BCHT
O
OH
O
O
O
HOOC
HO
OH
HO
O
O
O
OH
O
OH
HO
HO
O
OH
CHEB
HO
OH
OH
OH
O
OH
DHHDP
OH
OH
OH
HO
HO
HO
HO
O
HO
O
O
O
GO
HO
OH
RO
O
O
HO
OH
OH
O
O
O
OG
OG
OH
O
O
OH
complex tannins
tellimagrandin II (ellagitannins)
OH
Basic skeleton of condensed tannins
HO
OH
OH
HO
OH
O
G=
O
HO
OG
OH
n
OH
C
OH
OH
OH
HO
O
HO
OH
OH
OH
O
OH
FIG. 4.
OH
OH
oligomeric proanthocyanidins
(condensed tannins)
The basic skeletons and structures of different categories of tannins from medicinal herbs and dietary plants.
8
W.-Y. HUANG ET AL.
R1O
O
OH
OH
R1
R2
HO
OH
R3
R2O
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
Downloaded by [University of Valladolid] at 04:09 11 January 2012
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. officinalis. 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. officinalis, 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 identified 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 root
of P. multiflorum; and oxyresveratrol in fruit of Morus alba
(12,31). It was reported that dimeric stilbenes and stilbene glycosides were identified 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 identified 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 β-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 officinale (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.
9
NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS
R
R
HO
O
O
O
O
R=OH: esculetin
R=OCH3: scopoletin
R=CH3: escopoletin
R=Gluc: aesculin
O
O
O
O
R
R
R=H: xanthyletin
R=OCH3: xanthoxyletin
R=H: seselin
R=OH: khellactone
CH2OH
HO
O
O
OH
O
OH
O
O
O
H3CO
HO
psoralen
OH
OH
O
Downloaded by [University of Valladolid] at 04:09 11 January 2012
HO
O
O
O
O
O
O
OH
bergenin
bicoumarin
O
H3CO
H3CO
isopsoralen
OH
O
OH
OH
OH
O
HO
HO
OH
H3CO
O
O
OCH3
secoisolariciresinol
wedelolactone
R1
OCH3
R=OH: matairesinol
R=OCH3: arctigenin
OH
R
R2
O
O
O
O
O
O
O
O
O
O
O
O
H3CO
OCH3
R
OCH3
OCH3
R3
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: β-peltatin
R1=H, R 2=H, R3=H: bursehemin
O
R=H: morelensin
R=OCH3: yatein
anhydropodorhizol
O
O
OH
O
O
O
O
O
O
HO
O
O
sesamin
O
FIG. 6.
hinokinin
magnolol
The structures of representative coumarins and lignans from medicinal herbs and dietary plants.
Downloaded by [University of Valladolid] at 04:09 11 January 2012
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) (29–31). 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 mirifica (http://en.wikipedia.org/wiki/).
Lignans
Lignans are also derived from cis-o-hydroxycinnamic acid
and are dimers (with 2 C6-C3 units) resulting from tail–tail
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 officinalis), 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 first identified 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 identified from leaves, berries, and stalks of Piper cubeba
L. (Piperaceae), an Indonesian medicinal plant (56). Milder
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 flaxseed
(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 sunflower 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 identified in the rhizomes
and roots from P. cuspidatum (also in leaves), P. multiflorum,
and R. officinale 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., magnoflorine), Phellodendron amurense (e.g., phellodendrine and magnoflorine),
and Zanthoxylum nitidum (e.g., nitidine and dihydronitidine)
(12). Magnoflorine 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
11
NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS
OH
O
OH
O
O
OH
R2
R1
C11 H23
HO
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
O
embelin
juglone
O
O
O
OH
O
O
R1
R2
O
Downloaded by [University of Valladolid] at 04:09 11 January 2012
O
OH
R
O
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 identified 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 (filicic acids from Matteuccia
struthiopteris), and so forth. (12,28–31). Triptophenlolide has
been isolated from the roots of T. wilfordii Hook. Oleuropein
and its glycoside have been obtained from olive oil (24).
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-
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 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 (4,19,21,61–114,117,118).
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 detoxification. And some phenolic acids
and analogs also exhibit antibacterial, antifungal, antiviral, antimutagenic, and anti-inflammatory activities (21,64,67,74,82)
(Table 1).
Gallic acid as a natural antioxidant had significant 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
W.-Y. HUANG ET AL.
H3CO
OH
OH
HO
HO
N+
OH
HO
O
HO
O
COOH
HO
O
O
OH
H3CO
magnoflorine
carnosol
carnosic acid
epirosmanol
R1
OH
OCH3
OCH3
R2
R1
R1
Downloaded by [University of Valladolid] at 04:09 11 January 2012
R2
OH
R2
O
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
anethole
paeonol
COOCH3
H3CO
O
OCH3
O
HO
O
HO
O
OH
O
H3CO
HO
OCH3
syringaresinol
OC6H11 O5
oleuropein
OCH3
O
H3CO
O
N
O
H3CO
dihydronitidine
FIG. 8.
triptophenolide
O
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 (96–98). Many phenolic acids and analogs possess anti-inflammatory 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-κB 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-α) 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
NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS
TABLE 1
Cancer prevention and possible mechanisms of phenolic compounds from medicinal herbs and dietary plantsa
Downloaded by [University of Valladolid] at 04:09 11 January 2012
Mechanisms of Action
Phenolic Compounds
(Representative Phenolics)
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), flavonoids (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), flavonoids 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 flavonoids and
flavones), stilbenes (resveratrol),
curcuminoids (curcumin), and quinones.
Enhancement of immune functions and surveillance
Suppress production of TNF, a pro-inflammatory
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), flavonoids and analogs
inflammatory 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), flavonoids 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 detoxification
Phase II enzymes, such as UDP-glucuronosyl
Phenolic acids and analogs (protocatechuic
transferase and quinine reductases; glutathione
acid and ellagic acid), flavonoids
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
flavonoids (baicalein, apigenin, and citrus
through Matrigel, cell migration, and cell
flavonoids), stilbenes (resveratrol),
proliferation.
curcuminoids (curcumin), and lignans.
References
4,19,21,29,31,
34,63,95,108, 111
4,21,101,103, 110,118
91,92
4,19,21,61, 66–70
4,19,21, 74–78,100
4,71–73
4,87,88, 96–97
(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
Downloaded by [University of Valladolid] at 04:09 11 January 2012
Induction of cell differentiation
Phenolic Compounds
(Representative Phenolics)
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), flavonoids (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-κB and AP-1
gingerol, and capsaicin), flavonoids and
signaling pathway, including c-Jun activity
analogs (apigenin, genistein, quercetin,
suppression; the Wnt or β-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
flavonoids (isoflavones: 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.
flavonoids (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),
flavonoids, tannins, stilbenes (resveratrol),
curcuminoids (curcumin), coumarins,
lignans, quinones, and others.
References
79,80
3,4,21,62, 81–84,95
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.
Downloaded by [University of Valladolid] at 04:09 11 January 2012
NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS
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
flavonoids 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 flavonoids
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 significantly enhanced antiradical activity (31). Moreover, glycosylation of hydroxyl groups
and substitution of other substituents (e.g., methoxy groups)
also affects the antioxidant activity of flavonoids (34).
Many flavonoids 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 flavonoids and analogs, daidzein, hesperetin, kaempferol, and myricetin were all anti-inflammatory
(21,46). In addition, apigenin, genistein, quercetin, EGCG, and
silymarin could suppress the activation of NF-κB 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 isoflavone 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
isoflavones (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 significant
radical scavenging ability and could chelate metal ions and prevent the generation of free radicals. Their specific 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-κB and AP1; block c-Jun N-terminal kinase (JNK) and
p38 MAPK-related signaling pathways; attenuate adhesion and
15
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-inflammatory, 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
β-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-inflammatory,
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 significantly
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.
Downloaded by [University of Valladolid] at 04:09 11 January 2012
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-inflammatory, 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 inflammation; 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 β-catenin expression; counteraction of reactive oxygen
species (ROS) production; activation of caspases; induction of
genes for oxidative phosphorylation and mitochondrial biogenesis; and blocking NF-κB 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).
Curcuminoids
Ongoing laboratory and clinical studies have indicated that
curcuminoids possess unique antioxidant, anti-inflammatory,
anticarcinogenic/antimutagenic, antithrombotic, hepatoprotectective, antifibrosis, 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 inflammatory
signaling; decrease oxidatively modified DNA and the level of
NOS mRNA and protein; modulate AP-1 signaling pathways;
block phosphorylation and subsequent degradation of IκB kinase β activity; inhibit NF-κB-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 efficient 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).
Coumarins
Coumarins and derivatives possess diverse bioactivities, such
as antioxidant, antitubercular, antimalarial, anti-HIV-1, antiangiogenesis, antimutagenic, anti-inflammatory, 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 significant negative influence 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 beneficial 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-inflammatory, antibacterial, antiviral, antiallodynic,
antiangiogenesis, and antimutagenic properties; regulate expression of enzymes, signal transduction pathways, and hormone
metabolism; enhance detoxification; 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-inflammatory 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
NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS
Downloaded by [University of Valladolid] at 04:09 11 January 2012
structure in the hydroxyanthraquinone molecules played a
significant 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-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 transduction
pathways (13,66,78,84). Therefore, certain quinones can play
an important role as biomarkers for cancer chemoprevention.
Others
Other phenolic compounds also present a wide range of
bioactivities (Table 1). For example, magnoflorine from T. asiatica had anti-HIV activity; dihydronitidine possessed tumor specific 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-inflammatory 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 classified 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 fish 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 classified 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,
17
chokeberry, grape, and cherry), spices (e.g., thyme, marjoram,
rosemary, sage, and garlic), soy, tea, and pine bark have significant 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 beneficial 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 benefits and the possible risks of dietary
supplement or herbal medicines is needed to ensure their efficacy
and safety. In fact, toxic flavonoids 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 confirmatory
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, 1–13, 2003.
2. Surh Y-J: Cancer chemoprevention with dietary phytochemicals. Nat Rev
Cancer 3, 768–780, 2003.
Downloaded by [University of Valladolid] at 04:09 11 January 2012
18
W.-Y. HUANG ET AL.
3. Luk JM, Wang XL, Liu P, Wong K-F, Chan K-L, et al.: Traditional
Chinese herbal medicines for treatment of liver fibrosis and cancer:
from laboratory discovery to clinical evaluation. Liver Int 27, 879–890,
2007.
4. Fresco P, Borges F, Diniz C, and Marques MPM: New insights on the
anticancer properties of dietary polyphenols. Med Res Rev 26, 747–766,
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, 390–396, 2007.
6. Tabor E: Pathogenesis of hepatitis B virus-associated hepatocellular carcinoma. Hepatol Res 37, S110–S114, 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, 8083–8089, 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,
581–587, 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, 153–157, 2007.
10. Groopman JD, Wang JS, and Scholl P: Molecular biomarkers for aflatoxins: from adducts to gene mutations to human liver cancer. Can J Physiol
Pharm 74, 203–209, 1996.
11. Poulson HE, Prieme H, and Loft S: Role of oxidative DNA damage in
cancer initiation and promotion. Eur J Cancer Prev 71, 9–16, 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, 2157–2184, 2004.
13. Efferth T, Li PCH, Konkimalla VSB, and Kaina B: From traditional Chinese medicine to rational cancer therapy. Trends Mol Med 13, 353–361,
2007.
14. Monks NR, Bordignon SAL, Ferraz A, Machado KR, Faria DH, et al.:
Anti-tumor screening of Brazilian plants. Pharm Biol 40, 603–616, 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,
1191–1308, 1981.
17. Greenwald P: Chemoprevention of cancer. Sci Am 275, 96–99, 1996.
18. Liu RH: Health benefits 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, 1409–1421, 2007.
20. Aggarwal BB and Shishodia S: Molecular targets of dietary agents for
prevention and therapy of cancer. Biochem Pharmacol 71, 1397–1421,
2006.
21. Han XZ, Shen T, and Lou HX: Dietary polyphenols and their biological
significance. Int J Mol Sci 8, 950–988, 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, 3373–3377, 2007.
23. Veeriah S, Kautenburger T, Habermann N, Sauer J, Dietrich H, et al.: Apple
flavonoids inhibit growth of HT29 human colon cancer cells and modulate
expression of genes involved in the biotransformation of xenobiotics. Mol
Carcinogen 45, 164–174, 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, 1235–1247, 2000.
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, 955–961,
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,
5484–5490, 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, 112–119, 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, 7749–7759, 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, 938–953, 2007.
30. Cai YZ, Sun M, and Corke H; Antioxidant activity of betalains from plants
of the Amaranthaceae. J Agric Food Chem 51, 2288–2294, 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, 2872–2888, 2006.
32. Bao JS, Cai YZ, Sun M, Wang GY, and Corke H: Anthocyanins, flavonols,
and free radical scavenging activity of Chinese bayberry (Myrica rubra)
extracts and their color properties and stability. J Agric Food Chem 53,
2327–2332, 2005.
33. Huang WY, Cai YZ, Xing J, Corke H, and Sun M: Comparative analysis
of bioactivities of four Polygonum species. Planta Med 74, 43–49, 2008.
34. Heim KE, Tagliaferro AR, and Bobilya DJ: Flavonoid antioxidants: chemistry, metabolism, and structure-activity relationships. J Nutr Biochem 13,
572–584, 2002.
35. Sampietro DA and Vattuone MA: Sugarcane straw and its phytochemicals
as growth regulators of weed and crop plants. Plant Growth Regul 48,
21–27, 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, 6182–6187, 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, 369–378, 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, 14–30, 2007.
40. Ren WY, Qiao ZH, Wang HW, Zhu L, and Zhang L: Flavonoids: promising
anticancer agents. Med Res Rev 23, 519–534, 2003.
41. Iwashina T: The structure and distribution of the flavonoids in plants.
J Plant Res 113, 287–299, 2000.
42. Hollman PCH and Katan MB: Flavonols, flavones, and flavanols—nature,
occurrence, and dietary burden. J Sci Food Agric 80, 1081–1093, 2000.
43. Chen JJ, Chang HW, Kim HP, and Park H: Synthesis of phospholipase A2
inhibitory biflavonoids. Bioorg Med Chem Lett 16, 2373–2375, 2006.
44. Lin YM, Anderson H, Flavin MT, Pai YH, Mata-Greenwood E, et al.: In
vitro anti-HIV activity of biflavonoids isolated from Rhus succedanea and
Garcinia multiflora. J Nat Prod 60, 884–888, 1997.
45. Grynberg NF, Carvalho MG, Velandia JR, Oliveira MC, Moreira IC, et al.:
DNA topoisomerase inhibitors: biflavonoids from Ouratea species. Braz
J Med Biol Res 35, 819–822, 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, 99–510, 2002.
Downloaded by [University of Valladolid] at 04:09 11 January 2012
NATURAL PHENOLIC COMPOUNDS FROM MEDICINAL HERBS AND DIETARY PLANTS
47. Schofield DM, Mbugua DM, and Pell AN: Analysis of condensed tannins:
a review. Anim Feed Sci Tech 91, 21–40, 2001.
48. Huh YS, Hong TH, and Hong WH: Effective extraction of oligomeric
proanthocyanidin (OPC) from wild grape seeds. Biotechnol Bioproc E 9,
471–475, 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, 564–568,
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, 1504–1507, 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, 274–283, 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, 427–432, 2002.
53. Masuda T: Anti-inflammatory antioxidants from tropical Zingiberaceae
plants—isolation and synthesis of new curcuminoids. ACS Symp Ser 660,
219–233, 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, 729–731, 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, 255–261, 2003.
56. Elfahmi, Ruslan K, Batterman S, Bos R, Kayser O, et al.: Lignan profile
of Piper cubeba, an Indonesian medicinal plant. Biochem Syst Ecol 35,
397–402, 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, 393–402,
2005.
58. Luthje S, Van Gestelen P, Cordoba-Pedregosa MC, Gonzalez-Reyes JA,
Asard H, et al.: Quinones in plant plasma membranes—a missing link?
Protoplasma 205, 43–51, 1998.
59. Iwasaki H, Oku H, Takara R, Miyahira H, Hanashiro K, et al.: The tumor specific cytotoxicity of dihydronitidine from Toddalia asiatica Lam.
Cancer Chemoth Pharm 58, 451–459, 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, 1253–1263, 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,
221–232, 2005.
62. Johnson IT: Phytochemicals and cancer. Proc Nutr Soc 66, 207–215, 2007.
63. Yamauchi S, Hayashi Y, Kirikihira T, and Masuda T: Synthesis and antioxidant activity of olivil-type lignans. Biosci Biotech Biochem 69, 113–122,
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, 1797–1803, 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, 521–542, 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, 1376–1388,
2007.
67. Chaubal R, Mujumdar AM, Misar A, and Deshpande NR: Isolation of
phenolic compounds from Acacia nilotica with topical antiinflammatory
activity. Asian J Chem 17, 1595–1599, 2005.
19
68. Souza SMC, Aquino LCM, Milach AC, Bandeira MAM, Nobre MEP, et
al.: Antiinflammatory and antiulcer properties of tannins from Myracrodruon urundeuva Allemao (Anacardiaceae) in rodents. Phytother Res 21,
220–225, 2007.
69. Fylaktakidou KC, Hadjipavlou-Litina DJ, Litinas KE, and Nicolaides DN. Natural and synthetic coumarin derivatives with antiinflammatory/antioxidant activities. Curr Pharm Design 10, 3813–3833,
2004.
70. Kassuya CAL, Silvestre A, Menezes-de-Lima O, Marotta DM, Rehder
VLG, et al.: Antiinflammatory and antiallodynic actions of the lignan
niranthin isolated from Phyllanthus amarus—evidence for interaction
with platelet activating factor receptor. Eur J Pharmacol 546, 182–188,
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 flavonoids: enhancement of phase II detoxification enzymes and their
potential in chemoprevention. Poten Health Citrus ACS Sym Ser 936,
130–143, 2006.
73. Shimada T: Xenobiotic-metabolizing enzymes involved in activation and
detoxification of carcinogenic polycyclic aromatic hydrocarbons. Drug
Metab Phamacokin 21, 257–276, 2006.
74. Raghavendra MP, Kumar PR, and Prakash V: Mechanism of inhibition of
rice bran lipase by polyphenols—a case study with chlorogenic acid and
caffeic acid. J Food Sci 72, E412–E419, 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, 535–546,
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. Identification
of the biologically active species for xanthine oxidase inhibition. Eur J
Med Chem 42, 1028–1031, 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, 685–690, 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, 233–242, 2007.
79. Noel S, Kasinathan M, and Rath SK: Evaluation of apigenin using in vitro
cytochalasin blocked micronucleus assay. Toxicol In Vitro 20, 1168–1172,
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, 231–238, 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, 237–243,
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, 611–625, 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, 275–283,
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, 848–854, 1998.
Downloaded by [University of Valladolid] at 04:09 11 January 2012
20
W.-Y. HUANG ET AL.
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, 2038–2046, 2005.
86. Huang HC, Lai MW, Wang HR, Chung YL, Hsieh LM, et al.: Antiproliferative effect of esculetin on vascular smooth-muscle cells—possible roles
of signal-transduction pathways. Eur J Pharmacol 237, 39–44, 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, 139–147, 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, 679–689, 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, 9251–9258,
2007.
90. Ahn J and Grün 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, C263–C268, 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 flavonoids. Carcinogenesis 27, 1579–1585, 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, 2022–2031, 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, 123–133, 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, 5892–5895, 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,
605–613, 2007.
96. Fki I, Sahnoun Z, and Sayadi S: Hypocholesterolemic effects of phenolic
extracts and purified hydroxytyrosol recovered from olive mill wastewater in rats fed a cholesterol-rich diet. J Agric Food Chem 55, 624–631,
2007.
97. Schaffer S, Podstawa M, Visioli F, Bogani P, Müller WE, et al.:
Hydroxytyrosol-rich olive mill wastewater extract protects brain cells
in vitro and ex vivo. J Agric Food Chem 55, 5043–5049, 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, 351–358, 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, 605–612, 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, 1227–1233, 1984.
101. Smith SH, Tate PL, Huang G, Magee JB, Meepagala KM, et al.: Antimutagenic activity of berry extracts. J Med Food 7, 450–455, 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, 91–97, 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, 499–513, 2007.
104. Sharma RA, Gescher AJ, and Steward WP: curcumin: the story so far. Eur
J Cancer 41, 1955–1968, 2005.
105. Venkateswarlu S, Rambabu M, Subbaraju GV, and Satyanarayana S: Synthesis and antibacterial activity of tetrahydrocurcuminoids. Asian J Chem
12, 141–144, 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 configuration and anticancer activity of taxiresinol and
related lignans of Taxus wallichiana. Bioorgan Med Chem 11, 4945–4948,
2003.
108. Demirezer LO, Kuruüzüm-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, 1213–1217, 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, 481–489, 2005.
110. Asche C: Antitumour quinones. Mini-Rev Med Chem 5, 449–467, 2005.
111. Yang D, Ye XY, Gu S, and Xu M: Lanthanide triflates catalyze Mn(III)based oxidative radical cyclization reactions. Enantioselective synthesis
of (-)-triptolide, (-)-triptonide, and (+)-triptophenolide. J Am Chem Soc
121, 5579–5580, 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, 5812–5819, 2005.
113. Cheng K-W, Chen F, and Wang MF: Heterocyclic amines: chemistry and
health. Mol Nutr Food Res 50, 1150–1170, 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, 523–528, 2007.
115. Galati G and O’Brien P: Potential toxicity of flavonoids and other dietary
phenolics: significance for their chemopreventive and anticancer properties. Free Radic Biol Med 37, 287–303, 2004.
116. Farina HG, Pomies M, Alonso DF, and Gomez DE: Antitumor and antiangiogenic activity of soy isoflavone genistein in mouse models of melanoma
and breast cancer. Oncol Rep 16, 885–891, 2006.
117. Mense SM, Hei TK, Ganju RK, and Bhat HK: Phytoestrogens and breast
cancer prevention: Possible mechanisms of action. Environ Health Persp
116, 426–433, 2008.
118. Thompson LU, Boucher BA, Cotterchio M, Kreiger N, and Liu Z: Dietary phytoestrogens, including isoflavones, lignans, and coumestrol, in
nonvitamin, nonmineral supplements commonly consumed by women in
Canada. Nutr Cancer 59, 176–184, 2007.