Plant Polyphenols

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Chapter 8

C0040 Plant Polyphenols: RecentAdvances in EpidemiologicalResearch and Other Studieson Cancer Prevention

Athanasios Valavanidis and Thomais VlachogianniLaboratory of Organic Chemistry, Department of Chemistry, University of Athens, University

Campus Zografou, Athens, Greece

Chapter OutlineIntroduction 2

Structure–Activity Relationships,

Antioxidant, and Anticarcinogenic

Activities 3

Dietary Polyphenols and

Anticancer Properties 4

Chemical Families of Polyphenols

as Anticancer Agents 5

Flavonoids as Anticancer Agents 6

Flavonoids: In Vitro and In Vivo

Studies for Anticancer Activity 6

Epidemiological Studies for the

Association of Risk Reduction of

Tumors and Increased of Dietary

Flavonoid Intake 7

Case–Control Epidemiological

Studies 7

Prospective Epidemiological

Studies 8

Meta-Analysis Epidemiological

Studies 9

Other Polyphenolic Chemical

Families: Stilbenes,

Anthocyanins, and Chalcones 13

Phytoalexins Stilbenes and

Trans-Resveratrol as Anticancer

Agents 13

Anthocyanins as Anticancer

Agents 14

Chalcones as Anticancer Agents 15

Clinical Trials for Anticancer

Activity of the Most Promising

Plant Polyphenols 16

Curcumin: A Promising

Anticancer Agent in Clinical

Trials 16

Resveratrol: Clinical Trials as

Anticancer Agent 17

Tea (�)-Epigallocatechin-3-

Gallate in Clinical Trials 18

Genistein as a Chemopreventive

Agent 19

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© 2013 Elsevier B.V. All rights reserved. 1


Quercetin as Anticancer Agent

and Clinical Trials 20

Conclusions 21

References 21

s0005 INTRODUCTION Au4

p0005 Plants produce thousands of phenolic and polyphenolic chemical compounds

as secondary metabolites. They are essential to the physiology of plants,

because they are involved in various important functions (growth, structure,

defense, pigmentation, lignifications, etc.). The majority of polyphenols are

synthesized by the highly branched phenylpropanoid pathway, which is

responsible for the biosynthesis of a large number of chemical compounds

with considerable structural diversity [1].

p0010 Plant polyphenols, especially the families of flavonoids (flavanols, fla-

vones, flavanones, isoflavones, anthocyanins), stilbenes and chalcones, and

related compounds have been studied (chemical properties, synthesis of ana-

logues, biological activity in vitro and in vivo, epidemiological investigations,

etc.). In recent years, there is a substantial increase in the number of scientific

publications on “polyphenols.” The majority focused on their potential as

antioxidants, anti-inflammatory agents, and with antitumor activity that can

be used in new anticancer drugs [2–7]. The topic of plant polyphenols (chem-

ical properties, biological activities, and synthesis) has been presented in a

recent extensive review [8].

p0015 Plant polyphenols have attracted the attention of scientists because they are

considered among the most abundant phytochemicals present in human diets.

In the past decade, numerous epidemiological studies support the evidence that

health-promoting effects of certain polyphenols are beneficial to human health.

There is epidemiological evidence also that consistent consumption of fruit and

vegetables is associated with increased protection from premature cardiac and

vascular diseases, various forms of cancer, reduced incident of various chronic

diseases, and especially neurodegenerative diseases [9–12].

p0020 Plant polyphenols form one of the most important and extensive used clas-

ses of plant-derived therapeutics for cancer prevention and chemotherapy.

Experimental evidence suggest that these protective effects could be in part

explained by the capacity of plant polyphenols to act as antioxidants scaveng-

ing reactive oxygen species (ROS) and free radicals which are involved in

damaging mechanisms to DNA. Also, polyphenols can modulate proinflam-

matory and oncogenic signals acting as anti-invasive cancer agents. Addition-

ally, polyphenols can influence gene expression and apoptosis, intervene in

intercellular signaling, P-glycoprotein activation, modulate enzyme activities

associated with carcinogen activation, and regulate tumor suppressor genes

[13–16].


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https://www.researchgate.net/publication/298091723_Plant_Phenolics_and_Human_Health_Biochemistry_Nutrition_and_Pharmacology?el=1_x_8&enrichId=rgreq-9400f44bff885ea6bcd52afdeb4095a2-XXX&enrichSource=Y292ZXJQYWdlOzIzNjIzMDk5NjtBUzo5ODU1NDc4NTgyODg2NUAxNDAwNTA4NzAwNzg0

p0025 Recent findings suggest that polyphenols express their anticarcinogenic

effects through cellular signaling cascades regulating the activity of transcrip-

tion factors and consequently affecting the expression of genes and proteins

rather than to their direct antioxidant capacity. Gene and protein expression

modulation results in modification of different cellular processes, such as apo-

ptosis, cell cycle, or migration, that can be regulated by miRNAs [17]. Also, it

was found that dietary polyphenols play a promising role for epigenetic

mechanisms in carcinogenesis (i.e., DNA methylation and histone modifica-

tions of noncoding RNAs) [18].

s0010 STRUCTURE–ACTIVITY RELATIONSHIPS, ANTIOXIDANT,AND ANTICARCINOGENIC ACTIVITIES

p0030 A large number of scientific publications on “polyphenols” and their associated

anticancer activity have appeared over the course of the past 20 years. Such

reports and scientific papers included extraction and identification of natural

polyphenols, synthesis of polyphenol analogues with biological activity, fol-

lowed by numerous in vitro, in vivo, and epidemiological studies that have con-

firmed the potential for the prevention of age-related diseases, especially

various types of malignant neoplasms [19–22].

p0035 The so-called antioxidation ability is frequently cited to be the key property

underlying the prevention and/or reduction of oxidative stress-related chronic

diseases (cardiovascular diseases, carcinogenesis, neurodegeneration). Plant

polyphenols can act as antioxidants reducing free radicals and ROS thus

decreasing their damaging effects on DNA. Also, they have inhibitory activities

against various mechanisms of tumorigenesis and promotion of cancer malig-

nancies [23–25].

p0040 Polyphenols are able to chelate transition metals through their multiple

OH groups and the carbonyl moiety, when present. By chelating metal ions,

such as iron(II)/copper(I) and iron(III)/copper(II) that are involved in the con-

version of superoxide anion O2�� and H2O2 into highly reactive hydroxyl

radicals (HOl), polyphenols can act as protective DNA agents from damaging

free radicals [26–28].

p0045 Multiple lines of evidence suggest that oxidative stress induced by ROS is

closely related to multistage carcinogenesis. Dietary polyphenols can directly

bind with signaling molecules involved in carcinogenesis and regulate their

activity. The binding between the polyphenol and the target protein and enzymes

is determined by their structural relationship, which implies that different poly-

phenols have different target proteins, leading to divergent chemopreventive

effects. Src family kinase (proto-oncogenic tyrosine kinases) activated by oxida-

tive stress and proinflammatory agents is known to regulate cell proliferation,

differentiation, survival, and angiogenesis. Downstream signal cascades include

mitogen-activated protein kinase, phosphoinositol-3-kinase, NF-kB, and other

tumor biomarkers which induce cell proliferation and cause malignant


Au2Chapter 8 Plant Polyphenols 3

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neoplasms. Studies in vivo suggest that polyphenols may exert their anticancer

chemoprevention though suppressing tumor promotion and inflammation by

blocking signal transduction [29,30].

p0050 Quantitative structure–activity relationships (QSAR) analyses of substi-

tuted phenols have been used for estimating their redox potential or antioxi-

dant activities. The antioxidant potentials of different flavonoids are found

to be mainly governed by the number and location of hydroxyl groups on

the flavonoid ring system, the size and shape of molecules, as well steric

properties [31,32].

p0055 Improved QSAR models have been developed to predict the antioxidant

activity or radical scavenging activity of polyphenols and their analogues

[33]. The importance of group frontier electron density of a series of flavo-

noids was used for quantitative analysis of their radical scavenging capacity

[34]. QSAR analysis of polyphenolics based on Trolox test (TEAC, Trolox

Equivalent Antioxidant Capacity) data from literature pointed out that antiox-

idant activity of polyphenols as hydrogen-donating free radical scavengers, is

closely related to their chemical structure, especially with the number and

arrangement of free hydroxyl groups of polyphenol skeleton [35]. The density

functional theory was used for the calculation of the gas-phase bond dissocia-

tion enthalpy and ionization potential for the class of phenolic antioxidants

[36]. Similarly, QSAR studies were developed (using computational tools)

to evaluate the anticarcinogenic, antiangiogenic, and radical scavenging radi-

cal activities for various structural families of polyphenols [37,38].

p0060 Some of these QSAR studies were directed in measurements of inhibition of

cell proliferation which is very important in pathways and mechanisms of later

stage carcinogenesis [39]. Another QSAR study showed that polyphenol-

derived molecules are attractive compounds regarding anticancer activity. They

are found to be important regarding disruption of Bax/Bcl-xL interaction.

The antiapoptotic Bcl-2 family of proteins (especially Bcl-2, Bcl-xL Mcl-1) is

frequently overexpressed in cancer cells [40] (Fig Au5. 1).

s0015 DIETARY POLYPHENOLS AND ANTICANCER PROPERTIES

p0065 Plant polyphenolic compounds constitute a diverse group of secondary meta-

bolites that are present in the human diet. This group of heterogeneous com-

pounds showed in vitro and in vivo studies that have anticancer activities. In

this respect, major chemical families of polyphenols have been subjects of

anticarcinogenic studies. A number of polyphenols showed exceptional anti-

cancer potential and were tested for a wide variety of cancer chemopreventive

activities and for various types of malignant neoplasms [41,42].

p0070 Most of the studies with plant polyphenols showed that cancer-preventing

mechanisms include antioxidant activity, radical scavenging activity, inactiva-

tion of carcinogenic substances, antiproliferation, cell cycle arrest, induction

of apoptosis and differentiation, inhibition of angiogenesis, modulation of



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tumor suppression genes, blocking signal transduction and cell signaling that

promote tumorigenesis, anti-inflammatory action, anti-invasive cancer action,

and others. The diversity in the biological targets of plant polyphenols has led

during the past 20 years to an extensive research toward medicinal chemistry

of polyphenols as promising anticancer drugs. In recent years, some antican-

cer agents derived from polyphenols are emerging as major anticancer drugs

or chemosensitizers [43–45].

s0020 CHEMICAL FAMILIES OF POLYPHENOLS AS ANTICANCERAGENTS

p0075 The number Au6of scientific publications for the anticancer properties of polyphe-

nols is very large and these publications cover many fields: studies in vitro,in vivo, clinical, and epidemiological observations. In the present review,

we will focus mainly in the publications of the past 5 years. Flavonoids

(flavonols, flavones, flavanones, flavan-3-ols, isoflavones, catechins) are

presented as one group since they have certain similarities. Anthocyanins as


Flavone

Flavonol

Chalcones Anthocyanidins Stilbenes

Flavanone

Flavanonol Isoflavone

Flavanol

35

O

O

C

B

A

1

1′

3′

5′7

O

O

C

B

A

O

OH

C

B

A

B

O

O

CAO

O

OH

C

B

A

O

B

A

BO

O

OH

CA

O+

OH

C

B

A

OH

R3

OR2

OR1

FIGURE 1f0005 Chemical structures of the most important families of polyphenols. Polyphenols are

ubiquitously present in plant foods. The common structural feature of all polyphenols is the pres-

ence of phenolic hydroxyl group(s) in various positions on the aromatic rings.

Chapter 8 Plant Polyphenols 5

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a major subgroup of flavonoids are presented as a separately for their unique

properties and particular anticancer activity. Stilbenes (resveratrol) and chal-

cones are the other two polyphenol groups with substantial chemopreventive

properties.

s0025 FLAVONOIDS AS ANTICANCER AGENTS

p0080 Flavonoids are a vast group of heterogeneous polyphenols (it is estimated that

there are 9000 compounds) which are ubiquitously found in fruits, vegetables,

tea, herbs, and wine. Flavonoids are usually subdivided into six classes: (a)

flavonols (e.g., quercetin, kaempferol), (b) flavones (e.g., apigenin, luteolin),(c) flavanones (e.g., hesperidin, naringenin), (d) flavan-3-ols (e.g., catechin,

theaflavin, and gallic esters of catechin and theaflavins), (e) anthocyanidins(e.g., pelargonidin, cyanidin), and (f) isoflavones (e.g., genistein, daidzein).

Various studies estimated that the average intake of flavonoids was around

25–30 mg/day but can reach 130–100 mg/day for healthy men and women,

respectively [46].

s0030 FLAVONOIDS: IN VITRO AND IN VIVO STUDIES FORANTICANCER ACTIVITY

p0085 Interest for the scientific study of anticarcinogenic effects started initially from

the vast group of flavonoid chemicals. Most of the evidence on the beneficial

effects on health and anticarcinogenic potential from dietary flavonoids emerged

from in vitro and in vivo experimental evidence and by using much higher con-

centrations than those generally attainable by humans through daily diet.

p0090 The compounds tested in these experiments are often flavonoid agly-

cones or their sugar conjugates, rather than their metabolites. It must be

emphasized that in order to reach conclusive evidence of the anticancer

potential of flavonoids or any polyphenols and constituents of the diet, it

is essential to determine their distribution in human diet, their bioavailability

and the fate of their metabolites, and then evaluate their biological activity

in target tissues.

p0095 The results of these studies in vitro and in vivo showed that flavonoids

interfere with cancer processes such as ROS-initiating DNA damage, prolifer-

ation, inflammation, angiogenesis, invasion, tumor activating proteins, proin-

flammatory factors, and metastasis. The most extensive recent reviews on the

subject referring to a great variety of experimental data have been published

[47–49].

p0100 In vitro studies showed that flavonoids have a variety of anticancer effects,

such as cell growth, kinase activity inhibition, apoptosis induction, suppression

of the secretion of matrix metalloproteinases, and suppression of tumor

invasive behavior. These studies have been extended into in vivo studies



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(experimental animals). Some structural characteristics of flavonoids were

revealed in these studies to critically influence their anticancer activities, espe-

cially the inhibition of protein kinase activity and antiproliferation. Also, it was

found that certain flavonoids target cell surface signal transduction enzymes

(protein tyrosine and focal adhesion kinases), as well as the important tumor

pathways of angiogenesis [47].

p0105 These studies and the accumulated results increase the understanding

about the preventive and therapeutic effects of flavonoid compounds. Also,

data facilitated the extrapolation of these results from animal studies to human

situations. As in many scientific studies, some experimental results were neg-

ative or inconclusive.

s0035 EPIDEMIOLOGICAL STUDIES FOR THE ASSOCIATION OF RISKREDUCTION OF TUMORS AND INCREASED OF DIETARYFLAVONOID INTAKE

p0110 Epidemiological and intervention studies suggest dietary intake of flavonoids

may reduce the risk of tumors of the breast, stomach, gastric, liver, colon,

esophageal, oral, lung, prostate, and pancreas. These anticancer effects and

reduced risk for organ malignant neoplasms are specific to certain flavonoid

subclasses and population subgroups. Not all studies are positive; some stud-

ies have reported inconclusive results or even harmful associations [50,51].

p0115 Due to the large body of scientific papers in the past decade available on

flavonoids and chemoprevention of cancer, we included in this review the

most important epidemiological studies. We are aware that not all pertinent

publications could be cited.

p0120 The most recent review of Romagnolo and Selmin [52] has a compilation

of the most important epidemiological studies (2005–2012) subdivided into

three groups: case–control epidemiological, prospective epidemiological,

and meta-analyses.

p0125 This review includes mostly studies of the past 5 years up to 2012, as an

update to previous reviews that are published already in the scientific literature.

s0040 Case–Control Epidemiological Studies

p0130 Case–control epidemiological studies are used widely in epidemiology. In

these studies, two existing groups differing in outcome are identified and

compared on the basis of some supposed causal attribute.

p0135 Most of the case–control epidemiological studies with plant polyphenols

showed reduced risk of certain cancers with increasing intake of total dietary

flavonoids. Also, some studies focused on specific groups of flavonoids, such

as flavanones, isoflavones anthocyanins, and catechins.

p0140 Oral cancer (laryngeal, pharyngeal) showed reduced riskwith increasing intake

of dietary flavonoids [53,54]. Gastrointestinal cancers (stomach, esophageal,



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gastric, pancreatic) were associated with reduced risk or protective effects in

comparison with higher diet intake of flavonoids [55–57].

p0145 Association of risk with colorectal and liver cancers with higher dietary

flavonoid intake was studied in Japan, Italy, Greece, and the United Kingdom.

All case–control studies showed reduced risk or protective effect [51,58–60].

Reproductive cancers (prostate, ovarian, endometrial) showed mixed results in

risk reduction or no association with higher flavonoid intake [61–65].

p0150 Many case–control epidemiological studies evaluated the reduction of risk

or protective effects of flavonoids on breast cancer in pre- and postmeno-

pausal women, especially with isoflavones, genistein, and lignans. Most of

the epidemiological results showed protective effects and reduced risk

[66–70]. Case–control epidemiological studies showed that lung cancer risk

was reduced with increased intake of various dietary flavonoids (isoflavones,

quercetin, epicatechin, etc.) [71–73].

s0045 Prospective Epidemiological Studies

p0155 Epidemiological evidence can only show that this risk factor is associated (cor-

related) with a higher incidence of disease in the population exposed to that risk

factor. The higher the correlation the more certain the association, but it cannot

prove the causation. Prospective epidemiological studies study over time of a

cohort of persons who share a feature of clinical or other interest.

p0160 Prospective epidemiological studies showed strong associations for higher

dietary flavonoid intake and reduced risk for various types of cancer. Gastro-

intestinal cancers (gastric and pancreatic) showed reduced risk with higher

plasma levels of certain flavonoids, or higher isoflavone intake or total flavo-

nols [74–77].

p0165 Epidemiological prospective studies frommany countries showed reduced risk

of proximal colorectal tumors and adenomas with increased dietary intake of iso-

flavones, flavonols and catechins, quercetin, catechin, and procyanidins [78–81].

p0170 But there were also negative prospective epidemiologic studies, the most

important was from a large prospective in the United States (Nurses’ Health

Study, with 71,976 women from the Nurses’ Health Study and 35,425 men

from the Health Professionals Follow-Up Study). This study showed that

higher intakes of individual flavonols, including quercetin, myricetin, and

kaempferol, were not related to a lower risk of colorectal cancer. These data

provide little support for the hypothesis of an association between flavonoid

intake and colorectal cancer risk, at least within the ranges of intakes con-

sumed in the populations studied [82]. A recent large collection of epidemio-

logical studies showed that there is insufficient or conflicting evidence

regarding flavonoid intake and the prevention of colorectal neoplasms [83].

p0175 Prospective studies with tumors of reproductive organs (prostate, ovary,

endometrium) showed reduced risk with higher intake of certain flavonoids

(e.g., kaempferol, luteolin, genistein) or with high levels of urinary or plasma



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flavonoids [84–87]. Breast cancer is of course a very important neoplasm for

women and partly connected to changes in diet in the developed countries.

There were at least 10 prospective epidemiological studies on breast cancer

and flavonoid intake in the 2005–2010 period. Almost half of them showed

reduced risk with increased intake of flavonoid, soy food, catechins, or indi-

vidual flavonoids, but the other half showed no association. We record here

the most recent and important studies [88–92].

p0180 Lung cancer risk reduction and increased flavonoid intake were studied in

relation with smoking (which is the main cause of 80–85% of this deadly

malignant neoplasm), applied to current or past smokers. Studies showed that

there is reduction of risk with increased intake of flavanols, flavanones,

flavan-3-ols, proanthocyanidins, and isoflavones [93,94]. In a large-scale,

population-based, prospective study in Japan, isoflavone intake was associated

with a decreased risk of lung cancer in never smokers [95].

s0050 META-ANALYSIS EPIDEMIOLOGICAL STUDIES

p0185 A meta-analysis for epidemiological studies refers to methods focused on con-

trasting and combining results from different studies, in the hope of identify-

ing patterns among study results, sources of disagreement among those

results, or other interesting relationships that may come to light in the context

of multiple studies, especially, when results of different studies are inconsis-

tent, because they use different methodology, or number of subjects, or did

not counted confounders. The random-effects model is used normally in

meta-analysis to estimate the pooled relative risk.

p0190 Meta-analysis epidemiological studies for prostate cancer showed that

increased flavonoid intake has protective effect or lower risk for this type of

cancer [96–98]. Similarly, all meta-analysis studies for breast cancer in asso-

ciation with soy isoflavones, soy (whole), and green tea consumption, showed

reduced risk or trends for reduced risk [99–103].

p0195 Meta-analysis studies for reduction in ovarian and endometrial cancers with

increased intake of flavonoids gave mixed results. Some studies found no asso-

ciation or only a trend for a protective effect [104–107]. A meta-analysis study

showed positive results for the protective role of green tea consumption for

ovarian and endometrial cancers [108]. Reduced risk for lung cancer and flavo-

noid consumption was established by two meta-analysis studies [109,110].

p0200 Gastric, stomach, and liver cancers were other types of malignant neo-

plasms that it was hoped to show reduced risk with increasing intake of flavo-

noids. Meta-analysis studies gave mixed results. Some studies showed

protective effect with green tea [111–113], while others did not show any

association or preventive effect [114,115].

p0205 Epidemiological results for case–control, prospective, and meta-analyses

studies on the effects of dietary flavonoids and cancer risk are presented in

a systematic way in Table 1.



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TABLE 1t0005 Summary of Case–Control, Prospective, and Meta-Analyses Epidemiological Studies on the Effects of Dietary

Flavonoids on Cancer Risk

Type of Malignant Neoplasm

Dietary Flavonoid

(Higher Dietary Intake)

Outcome (Reduced Risk,

Protective Effect, No

Association, Weak Support)

References [No. in the List of

References] (First Author,

Year)

Case–control epidemiological studies

Oral cancer (laryngeal,pharyngeal)

Increased flavonoid intake Reduced risk [53] (Rossi et al., 2011)[54] (Garavello et al., 2007)

Gastrointestinal cancer(stomach, esophageal, gastric,pancreatic)

Increased dietary intake Reduced risk and protective effect [55] (Rossi et al., 2010)[56] (Ekstrom et al., 2011)[57] (Rossi et al., 2011)

Colorectal cancer and livercancer

Increased dietary intake Reduced risk and protective effect [51] (Rossi et al., 2010)[58] (Budhathoki et al., 2011)[59] (Kyle et al., 2010)[60] (Lagiou et al., 2008)

Reproductive system cancers(prostate, ovarian, endometrial)

Higher intake of flavoinoids, soyfoods, and isoflavones

Reduced risk, weak reduced risk, andno association with isoflavone intake

[61] (Jackson et al., 2010)[63] (Gates et al., 2009)[64] (Rossi et al., 2008)[65] (Bandera et al., 2009)[62] (Bandera et al., 2011)

Breast cancer (pre- andpostmenopausal women)

Increased falavonoid intake,isoflavones, genistein, lignans,etc.)Au1

Reduced risk [66] (Wang et al., 2011)[67] (Cho et al., 2010)[68] (Iwasaki et al., 2009)[69] (Fink et al., 2007)[70] (Lampe et al., 2007)

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Lung cancer (smokers,nonsmokers)

Increased flavonoid intake,isoflavones, quercetin,epicatechin, etc.)Au1

Reduced risk [71] (Cui et al., 2008)[72] (Garcia-Tirando et al., 2012)[73] (Shimazu et al., 2011)

Prospective epidemiological studies

Gastrointestinal cancers (gastric,pancreatic)

Higher flavonoid intake(measurements in plasma levels)

Reduced risk [74] (Sasazuki et al., 2008)[75] (Hara et al., 2012)[76] (Bobe et al., 2008)[77] (Ekstrom et al., 2011)

Proximal colorectal tumors andadenomas

Increased flavonoid intake Negative studies, insufficient, orconflicting evidence

[82] (Lin et al., 2006)[83] (Jin et al., 2012)

Reproductive organ cancer(prostate, ovary, endometrium)

Higher intake (kaempferol,luteolin, genistein)

Reduced risk [84] (Park et al., 2008)[85] (Travis et al., 2009)[86] (Gates et al., 2007)[87] (Ollberding et al., 2012)

Breast cancer Higher intake (soy food,catechins)

Reduced risk (1/2 of studies) and noassociation (1/2 of studies)

[88] (Guha et al., 2009)[89] (Iwasaki et al., 2010)[90] (Luo et al., 2010)[91] (Boggs et al., 2010)[92] (Shu et al., 2009)

Lung cancer (smokers,nonsmokers, past smokers)

Higher intake (flavonols,isoflavones, proanthocyanidins,etc.)

Reduced risk [93] (Mursu et al., 2008)[94] (Cutler et al., 2008)[95] (Shimazu et al., 2010)

Meta-analysis epidemiological studies

Prostate cancer Increased flavonoid intake Protective effect or lower risk [96] (Boehm et al., 2009)[97] (Hwang et al., 2009)[98] (Zheng et al., 2011)

Continued

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TABLE 1 Summary of Case–Control, Prospective, and Meta-Analyses Epidemiological Studies on the Effects of Dietary

Flavonoids on Cancer Risk—Cont’d

Type of Malignant Neoplasm

Dietary Flavonoid

(Higher Dietary Intake)

Outcome (Reduced Risk,

Protective Effect, No

Association, Weak Support)

References [No. in the List of

References] (First Author,

Year)

Breast cancer Increased intake of soyisoflavones, soy food, and greentea

Reduced risk [99] (Dong and Qin, 2011)[100] (Hooper et al., 2010)[101] (Wu et al., 2008)[102] (Sun et al., 2006)[103] (Zhou et al., 2011)

Ovarian, endothelial cancers Increased intake of flavonoid Mixed results, no association, orprotective effect

[104] (Nagle et al., 2010)[105] (Braem et al., 2012)[106] (Zhou et al., 2007)[107] (Steevens et al., 2007)[108] (Butler et al., 2011)

Lung cancer Increased flavonoid consumption Reduced risk [109] (Tang et al., 2009)[110] (Tang et al., 2009)

Gastric, stomach, and livercancers

Increased flavonoid intake, greentea

Protective effect, mixed results, andno association or protective effect

[111] (Sing et al., 2011)[112] (Jin et al., 2008)[113] (Kang et al., 2010)[114] (Zhou et al., 2008)[115] (Myung et al., 2009)

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s0055 OTHER POLYPHENOLIC CHEMICAL FAMILIES: STILBENES,ANTHOCYANINS, AND CHALCONES

p0210 The natural flavonoid’s family contains substantial number of chemical sub-

stances with anticarcinogenic potential. There is also a substantial number

of studies for stilbenes (especially for trans-resveratrol and its analogues)

and chalcones. Although anthocyanins are flavonoids, in this review we pres-

ent separate results for these compounds since they have interesting anticancer

properties.

s0060 PHYTOALEXINS STILBENES AND TRANS-RESVERATROL ASANTICANCER AGENTS

p0215 Stilbenes occur naturally in various families of plants. Especially, grapes and

related products are considered the most important dietary sources of these

substances. The synthesis of these phytoalexins in grapevine is stimulated

by stresses such as ultraviolet light and fungal infection, particularly in leaves

and berry skins [116,117].

p0220 Trans-resveratrol (3,40,5-trihydroxystilbene) in the past decade has made a

great name as chemopreventive substance for cardiovascular diseases and sev-

eral malignant neoplasms. However, despite the identification of numerous

molecular targets, the underlying mechanisms involved in the anticancer

activities of resveratrol are not completely understood. Trans-resveratrol ispostulated to function as a potential signaling pathway modulator and, as

such, is demonstrated to affect a multitude of signal transduction pathways

associated with tumorigenesis. As a result, researchers have increasingly

searched for possible targets of resveratrol, specifically transcription factors

which are related to inhibition of carcinogenic activation, induction of carcin-

ogen detoxification, and induction of growth [118]. Trans-resveratrol provedto be effective for the prevention and treatment of colorectal cancer and

hematologic malignancies [119,120].

Resveratrol

OH

HO

OH

p0225 Trans-resveratrol’s chemopreventive action became a highly popular subjects

in scientific literature especially in connection with its presence in the red

wine and grape skins. Resveratrol is believed to work as a chemopreventive

agent by producing its effect on cell apoptosis, antiproliferation, and anti-

inflammation. Also, it has been found that trans-resveratrol has synergistic

effects with other anticancer drugs in vitro [121].



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p0230 Also, many studies showed that trans-resveratrol impacts on the mitochon-

drial functions (respiratory chain, oncoproteins, gene expression, etc.), in

which p53 protein can be involved and its acetylated or phosphorylated forms.

Also, trans-resveratrol affects death receptor distribution in ceramide-

enriched membrane platforms which serve to trap and cluster receptor

molecules and facilitates the formation of a death-inducing signaling complex

in the cell. To induce apoptosis, resveratrol also activates the ceramide/sphin-

gomyelin pathway, which promotes ceramide generation and the downstream

activation of kinase cascades. Trans-resveratrol can activate alternative path-

ways to cell death such as those leading to autophagy, senescence, or mitotic

catastrophe [122–125].

p0235 However, the potential use of resveratrol in cancer chemoprevention has

been hindered by its short half-life and low bioavailability. The limitations

of resveratrol accompanied with its structural simplicity and low toxicity have

prompted interest in designing novel resveratrol analogues with superior anti-

cancer activity to that of the parent compound [126,127].

s0065 ANTHOCYANINS AS ANTICANCER AGENTS

p0240 Anthocyanins are polyphenols which are found in plants as red pigments.

Anthocyanins are responsible for the blue, purple, red, and intermediate colors

of many flowers, leaves, vegetables, and fruits. Nearly one thousand anthocya-

nins, and more than 15 anthocyanidins, exist in the vegetal kingdom. The term

anthocyanin was initially coined to indicate the substance responsible for the

color of cornflower. Anthocyanidins are present in low quantity in fresh bil-

berry fruits and are anthocyanins without the sugar moiety and should be con-

sidered as anthocyanin degradation products. Dietary intake of anthocyanins

has been estimated at up to 200 mg/day, which is higher than other flavonoids.

From various studies, it is found that some plants or their parts containing

anthocyanins have anticancer property and their analogues may be helpful in

synthesizing newer effective anticancer agents in future. Structure–activity

analysis reveals that the number of hydroxyl groups and presence of sugar moi-

ety are crucial for the specific modulatory actions of anthocyanins [128].

OH

OH

Basic chemical structure of anthocyanins

HO

A C

O+ B

R2

R3

R1

p0245 Numerous in vitro and in vivo studies showed that anthocyanins can affect

basic cell functions related to cancer development. They may inhibit the for-

mation and growth of tumors by induction of cell cycle arrest and apoptosis.



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The regulation of cell cycle is altered in tumorigenic cells. Also, anthocyanins

can interfere in basic cellular functions. Experiments showed that anthocya-

nins can induce cell apoptosis thus eliminating damaged cells or tumor cells.

Berry fruits which have very high concentrations of anthocyanins have been

used in animal tests [129–131].

p0250 Recent papers on polyphenols explore the significance of anthocyanins as

chemopreventive agents and the promising possibilities for development as

potential anticancer drugs [132,133]. Also, two recent books on neutrachem-

icals in cancer and apoptotic regulators in carcinogenesis devote chapters on

anthocyanins and on the latest developments regarding anticarcinogenic

effects in cell cultures and in animal model systems [134,135].

s0070 CHALCONES AS ANTICANCER AGENTS

p0255 Chalcones are a group of plant-derived polyphenolic compounds belonging to

the flavonoids family. Studies showed that some chalcones possess a wide

variety of cytoprotective and modulatory functions, which may have therapeu-

tic potential for multiple diseases. Their physicochemical properties seem to

define the extent of their biological activity [136].

O

OH

OH

OHO

Basic structure of chalcones and on the right with hydroxyl groups

HO

p0260 Chalcones, aromatic ketones and enones, are known for their anticancer

effects. Although parent chalcones consist of two aromatic rings joined by a

three-carbon a,b-unsaturated carbonyl system, various synthetic compounds

possessing heterocyclic rings like pyrazole, indole, etc., are well known and

proved to be effective anticancer agents. In addition to their use as anticancer

agents in cancer cell lines, heterocyclic analogues are reported to be effective

even against resistant cell lines [136,137].

p0265 Some of the most significant chalcones identified from these plants include

flavokawin, butein, xanthoangelol, 4-hydroxyderricin, cardamonin, 20,40-dihydroxychalcone, isoliquiritigenin, isosalipurposide, and naringenin chalcone.

These chalcones have been linked with immunomodulation, antibacterial,

antiviral, anti-inflammatory, antioxidant, and anticancer activities [138].

p0270 A comprehensive synopsis of recent patent literature (2005–2011) for

chalcones and their derivatives on selected activities (e.g., anti-inflammatory,

antimitotic, cytotoxic, antioxidant, and anticarcinogenic) has been provided in



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https://www.researchgate.net/publication/233905959_Novel_Apoptotic_Regulators_in_Carcinogenesis?el=1_x_8&enrichId=rgreq-9400f44bff885ea6bcd52afdeb4095a2-XXX&enrichSource=Y292ZXJQYWdlOzIzNjIzMDk5NjtBUzo5ODU1NDc4NTgyODg2NUAxNDAwNTA4NzAwNzg0

a 2011 review. The reviewers have collected most of the recent papers and

patents on natural and synthetic chalcones and their derivatives that showed

promising anti-inflammatory and anticancer activities. Some of the most

promising chalcones are going to be tested in future clinical trials for their

anticancer therapeutic utility [139]. The anticancer activity of chalcones has

been evaluated in association with special features of their chemical structures

in QSAR studies [140].

s0075 CLINICAL TRIALS FOR ANTICANCER ACTIVITY OF THE MOSTPROMISING PLANT POLYPHENOLS

p0275 Progress in cancer prevention by polyphenols has been accelerated in the past

decade as prevention clinical trials are completed and reported. A promising

strategy is the identification of cancer risk factors through epidemiologic

and experimental research with lifestyle and medical approaches that allow

translation of clinical trial results to clinical practice.

p0280 Amajor focus of cancer prevention in clinical trials has been on breast, colon,

gastric, reproductive, head and neck, and prostate cancers by using plant polyphe-

nols of their synthetic analogues. Among the most promising bioactive food com-

ponents being investigated in prevention clinical trials are: tea polyphenols

(especially epigallocatechin-3-gallate), curcumin, resveratrol and synthetic ana-

logues, genistein, quercetin, isoflavones, pomegranate supplements, and individ-

ual polyphenols in combinations with other anticancer drugs [141,142].

p0285 Scientists suggest that future prevention clinical trials will rely on multidis-

ciplinary medical approaches that bring together expertise in many fields to

address disease across the cancer spectrum. Nutritional science can play an

important role in this effort through the use of new and emerging technologies

to better understand the influence of bioactive food components on the genes,

proteins, and cellular processes that are associated with cancer risk. In this

review, we focus on certain clinical trials, phase I, II, and III in the past 5 years.

s0080 Curcumin: A Promising Anticancer Agent in Clinical Trials

p0290 Curcumin has been traditionally used for centuries for treating numerous

diseases. Over the past few years, a number of studies uncovered several phar-

macological properties of curcumin.

O O

Curcumin

O

HO

H3CO

CH3

OH

p0295 For the past decade, curcumin has been tested in clinical trials for its antican-

cer potential with very promising results. Curcumin has been shown to



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interfere with multiple cell signaling pathways, including apoptosis (activa-

tion of caspases and downregulation of antiapoptotic gene products), prolifer-

ation (HER-2, EGFR, and AP-1), angiogenesis (VEGF), and inflammation

(NF-kB, TNF, IL-6, IL-1, COX-2, and 5-LOX). Various synthetic analogues

have been prepared and evaluated for anticancer activity in clinical trials.

Few analogues have shown very potent results and may be considered as clin-

ical candidates for future anticancer drugs [143,144].

p0300 Recent studies showed substantial evidence that curcumin inhibited prolif-

eration, migration, invasion and metastasis, and induced apoptosis via modu-

lating multiple signaling pathways in head and neck cancer. Curcumin also

suppressed the growth of xenograft derived from head and neck cancer

in vivo in animal models. Although curcumin has been shown to be safe at

doses of 8 g/day in both phase I and phase II clinical trials, its bioavailability

is poor. Overcoming the poor bioavailability of curcumin in the near future

would facilitate its clinical use [145].

p0305 Clinical trials with curcumin have demonstrated it to be safe and well tol-

erated. However, bioavailability is limited and efficacious doses have not yet

been determined. Evidence of efficacy has been derived from animal models

or small clinical trials. There is only finite data supporting the use of curcu-

min in phase III trials with specific diseases (e.g., ulcerative colitis). However,

for the vast majority of conditions additional early-phase studies are required

to justify larger trials determining efficacy [146].

p0310 Although curcumin’s poor absorption and low bioavailability limits the

access of adequate concentrations for pharmacological effects in certain tissues,

active levels in the gastrointestinal tract have been found in animal and human

pharmacokinetic studies. In the past years, sufficient data have been shown to

advocate phase II and phase III clinical trials of curcumin for a variety of cancer

conditions including multiple myeloma, pancreatic, and colon cancer [147].

p0315 Curcumin has been used in clinical trials as a chemoprevention agent in

colon and pancreatic cancer, cervical neoplasia, and Barrett’s metaplasia.

Some clinical experiments were performed with curcumin, along with the

antimetabolite gemcitabine in the treatment of patients with advanced pancre-

atic carcinoma, produced an objective response in less than 10% of patients,

with a minor effect on survival. However, the safety of this combination

was proved. Curcumin’s potent antiproliferative activity interacting with sev-

eral intracellular signal transduction pathways may potentiate the antitumor

effect of gemcitabine. The preclinical data lead to various, but still scarce,

clinical studies (some ongoing) that demonstrated the possible efficacy of this

treatment as a chemopreventive or chemotherapeutic agent [148].

s0085 Resveratrol: Clinical Trials as Anticancer Agent

p0320 All anticancer studies showed that resveratrol affects all three discrete stages

of carcinogenesis (initiation, promotion, and progression) by modulating



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signal transduction pathways that control cell division and growth, apoptosis,

inflammation, angiogenesis, and metastasis. These anticancer data have led to

numerous preclinical animal studies to evaluate this drug for cancer chemo-

prevention and chemotherapy. A 2009 review provided concise, comprehen-

sive data from preclinical in vivo studies in various rodent models of human

cancers, highlighting the related mechanisms of action. Also, human and

on-going interventional clinical trials were presented [149].

p0325 A review in 2011 described the available clinical trials data that supported the

continuation of efforts for the development of resveratrols as an anticancer drug

in humans. Despite the promising results, the authors emphasized the need for

larger and more systematic studies with resveratrol in future clinical trials [150].

p0330 Another review on trans-resveratrol presented the studies conducted in vitrowhich show that the protective activity takes place by inhibition of proliferation

and induction of apoptosis. Also, the review describes the chemopreventive

activity of resveratrol in animal models of colon carcinogenesis. Lastly, the

review analyzes the available data on clinical trials. The authors concluded that

the present findings support the hypothesis that the oral administration of trans-resveratrol might contribute to the prevention of colon carcinogenesis [119].

s0090 Tea (�)-Epigallocatechin-3-Gallate in Clinical Trials

p0335 Among the numerous polyphenols isolated from green tea, the (�)-

epigallocateching-3-gallate (EGCG) predominates and, in the past decade, is

the target of intensive anticancer research. But studies suggest that EGCG and

other catechins are poorly absorbed and undergo substantial biotransformation

to species that include glucuronides, sulfates, and methylated compounds.

Numerous studies relate the antioxidant properties of the catechins with anti-

cancer effects, but recent research proposes other mechanisms of action. How-

ever, preclinical research data in recent studies show promising results. The

EGCG appears to be ready for further study in phase II and III trials [151].

(-)-Epigallocateching-3-gallate (EGCG)

O

OH

OH

OH

OH

OH

B

CA

D

Gallate group

OHOOH

OH

O

p0340 A review in 2011 presented various clinical studies that have revealed that

treatment by EGCG inhibits tumor incidence and multiplicity in different



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organ sites such as liver, stomach, skin, lung, mammary gland, and colon.

EGCG has great potential in cancer prevention because of its safety, low cost,

and bioavailability. EGCG could be useful either alone or in combination with

conventional therapeutics for the prevention of tumor progression and/or

treatment of human malignancies [152].

s0095 Genistein as a Chemopreventive Agent

p0345 Genistein is a naturally occurring isoflavone in soy. The concentration of

genistein in most soy food materials ranges from 1 to 2 mg/g. Chronic use

of genistein as a chemopreventive agent has many advantages. It could be

delivered either in a purified state as a pill (concentrated in purified form)

or in the form of soy foods or soy-containing foods which is more economical

and better suited for clinical trials. Several biotechnological firms in Japan,

Australia, and in the United States (e.g., Nutrilite) manufacture genistein as

a natural supplement under quality controlled and assured conditions [153].

Genistein chemical structure

O

OHO

OHOH

p0350 Since 1995, investigators have begun chemoprevention trials using a soy bev-

erage product based on SUPROTM, an isolated soy protein manufactured by

Protein Technologies International of St. Louis, MO. These investigators

examined the effect of the soy beverage on surrogate intermediate endpoint

biomarkers (SIEBs) in patients at risk for breast and colon cancer, defining

potential SIEBs in patients at risk for prostate cancer, and determining

whether the soy beverage reduces the incidence of cancer recurrence. These

studies, it is hoped (with the approval of FDA), will provide the basis for for-

mal phase I, phase II, and phase III clinical trials of genistein and soy food

products [154].

p0355 Also, recent studies have been shown that genistein inhibits the activation

of NF-kB and Akt signaling pathways, both of which are known to maintain a

homeostatic balance between cell survival and apoptosis. Moreover, genistein

antagonizes estrogen- and androgen-mediated signaling pathways in the

processes of carcinogenesis. Furthermore, genistein has been found to have

antioxidant properties and shown to be a potent inhibitor of angiogenesis

and metastasis. Taken together, both in vivo and in vitro studies have clearly

shown that genistein is a promising agent for cancer chemoprevention. Cancer

specialists suggest that genistein could be an adjunct to cancer therapy by vir-

tue of its effects on reversing radioresistance and chemoresistance. These

results are promoted for clinical trials [155].



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p0360 A recent review described more than 30 clinical trials of genistein with

various diseases. These studies have been conducted to evaluate its clinical

efficacy. Based on many animals and human pharmacokinetic studies, it is

well known that the most challenging issue for developing genistein as a che-

moprevention agent is the low oral bioavailability, producing large interindi-

vidual variations in clinical trials [156].

s0100 Quercetin as Anticancer Agent and Clinical Trials

p0365 Quercetin (3,30,40,5,7-pentahydroxyflavone) is emerging as prospective anti-

cancer drug candidates and its prodrug QC12 (a water-soluble glycine carba-

mate prodrug) of quercetin derivative has entered in phase I clinical studies.

In a recent review, authors have tried to cover in brief but comprehensive

way, the chemistry related to synthesis and uses of quercetin and its deriva-

tives with special emphasis on the anticancer properties [157,158].

Quercetin Q12

OH

OH

O

O

NH

O

OHHO

OH

O

O

A

OH

OH

OHHO

OH

O

C

OB

p0370 From 1996, investigators have performed a phase I clinical trial with the

naturally occurring flavonoid quercetin (3,30,40,5,7-pentahydroxyflavone).They initiated these studies because quercetin was found previously to have

antiproliferative activity in vitro and is known to inhibit signal transduction

targets including tyrosine kinases, protein kinase C, and phosphatidyl

inositol-3 kinase. The results in patients showed that the plasma levels

achieved inhibited lymphocyte tyrosine kinase activity, and additionally, there

was evidence of strong antitumor activity [159].

p0375 In a small clinical trial, a combination of curcumin and quercetin was used

to treat adenomas in familial adenomatous polyposis (FAP). The results

showed that the combination of curcumin and quercetin appears to reduce

the number and size of ileal and rectal adenomas in patients with FAP without

appreciable toxicity. The investigators suggest that randomized controlled

trials are needed to validate these findings [160].

p0380 The anti-inflammatory, anticarcinogenic, and chemopreventive properties

of quercetin and its derivatives have been reviewed [161,162]. The investiga-

tors emphasize that several critical points must be taken into account when

considering the potential therapeutic use of quercetin and clinical trials in

the future. The design of specific clinical trials is extremely warranted to

depict possible applications of quercetin in adjuvant cancer therapy [163,164].



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s0105 CONCLUSIONS

p0385 In the past decades, interest in dietary phytochemicals, especially plant poly-

phenols, for potential cancer chemoprevention has increased substantially.

Scientists for the past three decades screened thousands of dietary compounds

and tested in vitro and in vivo large number of natural chemicals for their anti-

cancer activity. The most prominent of these compounds, mainly from the

family of flavonoids, showed promising results and were advanced into

clinical trials. The data until now are very impressive as to the numbers of

experimental results and the promising effects for cancer prevention in gen-

eral or reduction of various malignancies in humans. In this review, we pre-

sented a vast number of studies and reviews until 2012 for the use of

natural phytochemicals as pharmaceuticals for cancer reduction, inhibition

of certain carcinogenic mechanisms, and chemopreventive action. We pre-

sented the most important polyphenol families in relation to their anticancer

properties, the in vitro and in vivo studies for chemopreventive effects and

the numerous epidemiological studies for the decrease of risk for certain

malignancies, and lastly, clinical trials taking place in the past decade of the

most important and promising polyphenols.

p0390 During the past 10 years, an International Conference on “Polyphenolsand Health” has been organized to present and discuss the recent advances

in this topic. During the 5th International Conference on Polyphenols and

Health that was held in Sitges (Spain) in October 2011, the latest advances

in this area of active research were presented. The highlights of this confer-

ence and the most important paper were published in a recent issue of Journalof Agricultural Food Chemistry (May 2012, http://pubs.acs.org/doi/full/

10.1021/jf300671j) Au7[165].

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Non-Print Items

AbstractPlant polyphenols are considered among the most abundant phytochemicals

that are present in human diets, and their regular consumption has been asso-

ciated with reduced risk of a number of chronic diseases, including cancer,

and cardiovascular and neurodegenerative disorders. In the past decades, plant

polyphenols have drawn increasing scientific attention due to their potent

antioxidant and other properties and their marked effects in the prevention

of various oxidative stress-associated diseases. Recently, the polyphenolic

extracts from different plants have become a major area of health- and

medical-related research. This review provides an update and comprehensive

overview of various plant polyphenolic compounds, and the quantification of

their antioxidant properties, anticancer activities, and therapeutic effects.

Also, the review Au3discusses the current scientific knowledge of various plant

polyphenols to inhibit tumorigenesis in animal models and to modulate cell

signaling pathways involved in inflammation and the development of malig-

nant tumors, and related biochemical interventions in cell function under both

normal and pathological conditions. We present in vitro and in vivo studies (in

experimental animals) in which polyphenols showed increased anticancer

potential. Also, numerous epidemiological research data and findings from

human intervention studies, as well preclinical studies supporting cancer pre-

vention mechanisms. Lastly, we present recent clinical trials for anticancer

action of certain polyphenols that showed promising anticancer and therapeu-

tic properties.

Keywords: Plant polyphenols; Flavonoids; Anticancer activity; Epidemiolog-

ical studies; Clinical trials


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Plant Polyphenols

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Transcript of Plant Polyphenols