Chemopreventive Role of Dietary Phytochemicals in Colorectal Cancer

CHAPTER THREE
Chemopreventive Role of
Dietary Phytochemicals in
Colorectal Cancer
Megha Bansal*,†,2, Neha Singh*,†,2, Saurabh Pal*,†,2, Indra Dev*,†,2,
Kausar Mahmood Ansari*,1
*Food Toxicology Division, Food, Drug, and Chemical Toxicology Group, CSIR-Indian Institute of
Toxicology Research (CSIR-IITR), Lucknow, Uttar Pradesh, India
†
Academy of Scientific and Innovative Research (AcSIR), CSIR-Indian Institute of Toxicology Research
Campus, (CSIR-IITR), Lucknow, Uttar Pradesh, India
1
Corresponding author: e-mail address: kmansari@iitr.res.in
Contents
1. Introduction 70
2. Dietary Phytochemicals 71
2.1 Quercetin 71
2.2 Capsaicin 75
2.3 Epigallocatechin-3-gallate 78
2.4 Resveratrol 81
2.5 Sulforaphane 84
2.6 [6]-gingerol 86
2.7 Lycopene 89
2.8 Inositol hexaphosphate 91
2.9 Curcumin 94
2.10 Folic acid 98
2.11 Organosulfur compounds of garlic 101
2.12 Genistein 104
3. Conclusion and Future Perspectives 107
Conflict of Interest 108
References 108
Further Reading 121
Abstract
Colorectal cancer is one of the leading causes of morbidity and mortality globally,
which accounts for 0.7 million deaths in 2015. Despite the fact that tremendous
advancement had been achieved in research and development in medicine, the
2
These authors contributed equally to the work.
Advances in Molecular Toxicology, Volume 12 Copyright # 2018 Elsevier B.V. 69

ISSN 1872-0854 All rights reserved.
https://doi.org/10.1016/B978-0-444-64199-1.00004-X
70 Megha Bansal et al.
colorectal cancer-related deaths are ascending continuously thus, the research commu-
nity has come up with chemoprevention, a novel and innovative way to reduce colo-
rectal cancer. Chemoprevention therapies use several pharmacological agents having
negative influences on human health and to overcome this natural products are used
now-a-days, as being reported. Various epidemiological studies have associated the
consumption of some dietary phytochemicals with lower risk of colorectal cancer devel-
opment. Here in this chapter, we summarize the chemopreventive effect of dietary phy-
tochemicals, their availability, in vitro and in vivo effects on colorectal cancer, and clinical
studies. This review describes the promising effect of dietary phytochemicals in colorec-
tal cancer intervention.
1. INTRODUCTION
Colorectal cancer is the one of the leading causes of death worldwide,
and it was ranked as the second major factor of cancer-related deaths after
lung cancer [1]. Colorectal cancer is a complex multistep disease which
begins with polyps. Polyps are the small, localized growths on the inner
lining of colon or rectum, dispersed all the way through the colon.
A majority of these polyps are not cancerous, but a few of these polyps have
the malignant potential and can convert into cancer over the period of time.
The American Society of Cancer estimates 97,220 and 43,030 new cases of
colon and rectal cancer, respectively, in the year 2018 [2]. Colorectal cancer
continues to be a worldwide killer, despite the fact that the past decade has
witnessed plenty of research and rapid development; nonetheless, 50,630
deaths are expected by colorectal cancer during 2018 in the United States
alone [2]. Similarly, the frequency of colorectal cancer in several countries,
which are at low risk, is promptly rising [3]. Epidemiological studies have
shown strong evidence that, apart from the factors that cannot be changed
like age, heredity, inflammatory bowel syndrome, race and ethnicity, etc.,
diet and lifestyle are the major risk factors for development of colorectal can-
cer [4]. Diets high in red meats and processed meats, cooking food at very
high temperatures can increase the risk associated with colorectal cancer [4].
Recently, there has been a lot of research in understanding of colorectal
cancer and it has been found that most of the colorectal cancer cases occur
due to lifestyle [3]. This leads to the new mode of cancer prevention known
as “chemoprevention.” Chemoprevention is the intake of agents in order to
inhibit, prevent, or delay the occurrence of carcinogenesis [5]. Now-a-days
natural products from plants have gained importance for their role as
anticancer agents and have been explored for their chemopreventive effects
against cancers. Several epidemiologic studies have demonstrated that the
Chemopreventive Role of Dietary Phytochemicals 71
oral consumption of fruits and vegetables is inversely associated with the risk
of cancer development [6]. Furthermore, recent research has shown that
almost 70% of all the sporadic cases of colorectal cancer might be reduced
with changes in dietary habits [7]. Therefore, change in dietary habits
are potentially one of the best ways for alleviating the risk of developing
colon cancer.
2. DIETARY PHYTOCHEMICALS
Although there is remarkable progress in the research and develop-
ment in medicine, the cases of colorectal cancer are still rising. This led
researchers to move to use natural products as chemopreventive agents to
improve cancer survival. Various pharmacologic or dietary agents have been
evaluated for their chemopreventive effects against cancer. Phytochemicals
are biologically active compounds, classified by chemical structures, found in
plants. These include polyphenols, alkaloids, carotenoids, and nitrogen
compounds [8]. Phytochemicals that are naturally present in different
fruits, vegetables, grains, and other plant products are dietary phytochemi-
cals. These foods contain substances such as carotenoids, chlorophyll,
flavonoids, indole, isothiocyanate, polyphenolic compounds, protease
inhibitors, sulfides, and terpenes. The presence of these potent antic-
arcinogenic substances might be the reason for the inverse association of
plant foods with cancer [9]. A diet, rich in fruits, vegetables, spices, and
grains, is considered beneficial to human health, it possesses positive effects
especially on the colon part of the intestines. These dietary foods contain
different phytochemicals that can prevent colorectal cancer. Various phyto-
chemicals, having chemopreventing activity, have been extracted and
characterized from different fruits, vegetables, spices, and grains. Intestine
is perfect target organ for the diet-related chemoprevention due to its direct
contact with the food taken. In this review, some major dietary phytochem-
icals that are known to cause chemopreventive effects in colorectal cancer
have been summarized.
2.1 Quercetin
Quercetin is a plant polyphenol from the flavonoid group, diversified in
nature and is a naturally occurring polar auxin transport inhibitor [10]. It
is derived from quercetum (oak forest), after Quercus. Quercetin is also
termed as Bioflavonoid, Bioflavonoid Complex, Bioflavonoid Concentrate,
Citrus Bioflavones, Citrus Bioflavonoid, Citrus Bioflavonoids, Citrus
Bioflavonoid Extract, Citrus Flavones, and Citrus Flavonoids. Quercetin is

extensively found in many plants and fruits such as red grapes, citrus fruit,
tomato, broccoli, and other leafy green vegetables, and a number of berries,
including raspberries and cranberries [11]. It is used for treating conditions
of the heart and blood vessels including “hardening of the arteries” (athero-
sclerosis), high cholesterol, heart disease, and circulation problems. It is
also used for diabetes, cataracts, hay fever, peptic ulcer, schizophrenia,
inflammation, asthma, gout, viral infections, chronic fatigue syndrome,
preventing cancer, and for treating chronic infections of the prostate. It is
also used to increase endurance and improve athletic performance. Due
to its antioxidant and antiinflammatory effects, it helps reduce prostate
inflammation [12]. Besides being as an antioxidant, it is also antiatherogenic,
anticarcinogenic properties, and neuroactive, with some of the same abilities
as caffeine but less potent [13]. Dosages of quercetin used are in the range of
12.5–25 mg/kg body weight, which translates to a range of 1136–2272 mg
daily consumption of quercetin when in isolation.
After ingestion, quercetin glycosides are converted to phenolic acids as
they pass through the gastrointestinal tract [14]. However, quercetin has
neither been confirmed scientifically as a specific therapeutic for any condi-
tion nor been approved by any regulatory agency. The U.S. Food and Drug
Administration has not approved any health claims for quercetin. Neverthe-
less, the interest in dietary flavonoids has grown after the publication of
several epidemiological studies showing an inverse correlation between
dietary consumption of flavonols and flavones and reduced incidence and
mortality from cardiovascular disease and several types of cancer. In recent
years, a large amount of experimental and some clinical data have accumu-
lated regarding the effects of flavonoids on the endothelium cells under
physiological and pathological conditions [15]. The meta-analysis of seven
prospective cohort studies concluded that the individuals in the top third of
dietary flavonol intake are associated with a reduced risk of mortality
from coronary heart disease as compared with those in the bottom third,
after adjustment for known risk factors and other dietary components.
A limited number of intervention studies with flavonoids and flavonoid-
containing foods and extracts have been performed in several pathological
conditions.
2.1.1 Chemical composition and molecular structure

Quercetin [2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one] is
a crystalline solid with a molecular weight about 302.238 g/mol and has
HO
OH
OH O
OH
OH O
Querecetin
Fig. 3.1 Structure of quercetin.
a melting point of 601–603°F with molecular formula as C15H10O7. Quer-

cetin is soluble in organic solvents such as ethanol, DMSO, and dimethyl
formamide (DMF), and its solubility in these solvents is approximately
2 mg/mL in ethanol and 30 mg/mL in DMSO and DMF. It is sparingly
soluble in aqueous buffers. Quercetin should first be dissolved in DMSO
and then diluted with the aqueous buffer of choice for maximum solubility
in aqueous buffers; quercetin has a solubility of approximately 1 mg/mL in a
1:4 solution of DMSO:PBS (pH 7.2) (Fig. 3.1).
2.1.2 Sources
Quercetin is extensively found in all types of tasty red, green, and purple-
pigmented plants, for example, red wine, blueberries, apples, red onion,
and even green tea are some of the best sources of quercetin [16]. The
amount of quercetin found in plant foods can vary a lot depending on
where they are grown, how fresh they are, how they are prepared, and
so on. Quercetin can be delivered in either free form or one of its glycosides.
Popular or particularly good sources of quercetin include: Herbs that are
generally rich in all polyphenolics, such as Euonymus alatus (115 mg/100 g
quercetin in ethanolic extract), Nelumbo nucifera (where quercetin consists
of 25%–30% of the total flavonoids in flowers and 67.25%–90.66% in the
leaves and seeds), Ginkgo biloba, and Morus alba (Moraceae).
Along with a GRAS (Generally Recognized as Safe) status identification,
it has no side effects in doses of a few grams a day in either humans or animals.
But there have been some studies which have reported that quercetin can
act as a thyroid disruptor. It has also been reported in rat that higher
concentrations of quercetin cause nerve cell damage with equal chances of

apoptosis and necrosis. It is also seen in human liver cancer cell culture that
quercetin significantly increased extracellular homocysteine levels, due to
increased methylation, which automatically links to heart strokes.
2.1.3 Molecular targets

Considering the adequate amount of intake, quercetin may prevent cancer.
It lowers TNF-alpha that encourages the growth and spreading of most
tumor cells. Also, it slows tumor growth in leukemia cell studies [17].
Quercetin induces the death of leukemia cells in by inhibiting Cox-2
expression and regulating the expression of biological processes involved
in apoptosis (cell death) [18,19]. It has been reported that quercetin readily
halts the cancerous cells, when they are in an early, nonproductive phase of
the cell replication cycle [20]. This freezes tumor growth and also initiates
mitochondrial pathways of apoptosis (cell death) as seen in human colon
cancer cells by inhibiting the NF-κB pathway. Several pieces of evidence
have suggested that quercetin negatively regulates the numerous crucial
signaling pathways including NF-κB, MAPK, PI3K-AKT, and mTOR
associated with life-threatening diseases [21].
2.1.4 Clinical trials

In order to investigate the clinical relevance and impact of quercetin,
M.D. Anderson Cancer Center conducted a study on early phase I cancer
patients to assess its use in changing chemotherapy-induced Neuropathic
Pain. While Stephen Kritchevsky concluded that combinatorial dose of
dasatinib and quercetin causes the reduction in the proinflammatory
expressing cells obtained by skin biopsy. Likewise Jonsson Comprehensive
Cancer Center evaluated that quercetin enhanced the anticancer effects of
green tea relating to their preclinical studies in phase 1 trial, prostate cancer
patients were taken as subjects [22]. Although quercitin is considered as the
group 3 carcinogen to human health, intravenous administration of doses
greater than 945 mg/sq. m has been associated with nephrotoxicity and with
nausea, vomiting, diaphoresis, flushing, and dyspnea. It is also suggested as
causing genotoxicity by a significant increase in the frequency of sister chro-
matid exchange in a dose-dependent fashion and the maximum frequency
was raised 1.7- to 3.3-fold greater than that of the control values. The fre-
quency of chromosome aberrations was elevated 1.7- to 7.8-fold compared
with controls.
2.2 Capsaicin
Capsaicin comes from plants of the genus Capsicum, which belong to the
Solanaceae family. Capsaicin is a naturally occurring bioactive phytochem-
ical abundant in red and chili peppers that is responsible for its hot pungent
taste. It is an odorless fat-soluble compound which is readily absorbed through
the skin. It causes a burning sensation when in contact with mucous mem-
branes due to its interaction with pain- and heat-sensing neurons. Though
capsaicin is the main pungent chemical, the others being dihydrocapsaicin,
nordihydrocapsaicin, homodihydrocapsaicin, and homocapsaicin [23]. It is
widely used in some brands of pepper sprays. Recently, several studies
focussed upon its analgesic [24], antioxidant [25], antiinflammatory [26],
and antiobesity [27] properties besides its medicinal value. Epidemiological
and basic research studies report controversial role of Capsaicin in carcinogen-
esis [28]. Some authors reported it to possess chemopreventive effects, while
others showed that it may act as carcinogen or cocarcinogen [29]. The pro-
posed anticancer mechanisms of capsaicin include inhibition of CDK2,
CDK4, and CDK6 inducing cell-cycle arrest, modulation of p53
ubiquitination and acetylation causing apoptosis, and inhibition of MMPs
and EMT, but the exact cellular mechanisms are still not completely
understood [30].

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is a fat-, alcohol-, and
oil-soluble crystalline, odorless homovanillic acid derivative alkaloid.
The molecular formula of capsaicin is C18H27NO3 and its molecular weight
is 305.40 g/mol. In 1919 Nelson and Dawson resolved its molecular
structure. Earlier it was first crystallized and named in 1876 by Thresh
[31] (Fig. 3.2).
CH3 O
O CH3
N
H CH3
HO
Capsaicin
Fig. 3.2 Structure of capsaicin.
2.2.2 Sources
As mentioned earlier, Capsaicin comes from pepper plants of the genus
Capsicum, which belong to the Solanaceae family. The hotness of these chil-
lies due to the presence of capsaicin is measured on Scoville heat scale. It is
the amount of sugar water required to dilute it before the “heat” could no
longer be detected by volunteers. For example, if, for 1 mL of pepper extract,
it took 100 mL of sugar water to dilute it until its hotness was no longer
detectable, then it would rank at 100 Scoville heat units. Capsaicin is abun-
dant in red and chili pepper varieties like Moruga Scorpion, Scotch Bonnet,
Red savina habanero, Jamaica pepper, cayenne pepper having the highest
amount at 250,000–2 million Scoville units [32]. Varieties of sweet pepper
(Capsicum annum) that include bell pepper, cherry, cone, or paprika pepper
contain lesser amount of capsaicin, nevertheless they are a good source when
consumed regularly. It is also present in trace amounts in ginger roots.

No direct epidemiological data are available correlating capsaicin with the
incidence of colorectal cancer. However, contradictory to in vitro and in
vivo studies, several epidemiological studies indicate that hot pepper
consumers, containing varied amount of capsaicin, possess higher risk of
developing gallbladder or gastric cancer [33]. Nevertheless, hot chili pepper
not only contains capsaicin but other bioactive compounds too, e.g., lutein,
B-carotene, ascorbic acid, and vitamin E [34] which may play part in the
observed effect. Furthermore, statistical imprecision and biased classification
of subjects limits the conclusions drawn in the epidemiological studies.
Capsaicin decreases the growth of human colon cancer cells in vitro
because of its potential to mediate cell cycle arrest and ability to induce cell
apoptosis. However, exhaustive research on elucidating the molecular mech-
anism of capsaicin-induced growth arrest and apoptosis in colorectal cells is
still lacking. Suggested mechanisms that are involved in capsaicin-induced
apoptosis in colon cells include the upregulation of several proapoptotic pro-
teins [30], activation of peroxisome proliferator-activated receptor-γ
(PPARγ) signaling pathway [35], activation of AMPK signaling pathway
and the c-Jun NH2-terminal kinases [36], dysfunction of ubiquitin–
proteasome systems [37], disruption of mitochondrial transmembrane poten-
tial [38], as well as activation of intrinsic pathway to drive caspase activation
[39]. Lee et al. explained that human colorectal cancer cell growth was
suppressed by β-catenin/TCF-dependent pathways via multiple mecha-
nisms, including suppression of β-catenin transcription, activation of
proteosomal degradation of β-catenin, and disruption of β-catenin/TCF-4

interactions [40]. In addition, Yang et al. demonstrated that therapy with a
high concentration of capsaicin (200 μM for SW480 and CT-26 cell lines;
25 μM for HCT116 cell line) inhibited colorectal cancer cell prolifer-
ation in a dose-dependent manner [41]. Clark et al. have reviewed the syn-
ergistic anticancerous properties of capsaicin with other compounds against
different types of human cancers [42]. The combinational compounds used
for colorectal cancer include resveratrol [43] and 3,30 -diindolylmethane
(DIM) which is a major in vivo metabolite of indole-3 carbinol, abundant
in cruciferous vegetables [42]. It synergistically induces apoptosis by eleva-
tion of NO via a p53-dependent manner when combined with resveratrol;
whereas when combined with DIM, it modulated transcriptional activity of
NF-κB, p53, and target genes associated with apoptosis [42,43]. Capsaicin
also possesses the ability to attenuate xenograft growth of Colo 205 and
HT29 which has been elucidated in two different studies [44].
An in vivo study by Yoshitani et al. in 2001, that used azoxymethane as a
chemical inducer of colon cancer in male F344 rats showed that rats gavaged
with 500 ppm of capsaicin for 4 weeks significantly inhibited ACF forma-
tion, elevated phase II enzymes, glutathione S-transferase (GST), and qui-
none reductase (QR) levels confirming the role of this alkaloid in preventing
the development of early colon neoplasia [45]. It was also found that dietary
exposure of capsaicin during the initiation phase significantly reduces the
incidence of colonic adenocarcinoma. Another in vivo study in 2010 using
immune-deficient nude mice bearing Colo 205 tumor xenografts showed
that capsaicin effectively inhibited tumor growth [46]. To further test anti-
cancer effects of capsaicin on a more advanced staged tumor, Lee et al. in
2016 employed a mouse model which typically develops small adenomas
or polyps in intestine due to deletion in the APC gene which make it resem-
ble human familial adenomatous polyposis (FAP) syndrome [47]. Treatment
with capsaicin (20 mg/kg body weight) tended to prevent the formation or
enlargement of polyps in mice, implying a potential anticancer activity of
capsaicin in the early stages (adenoma) of colon cancer. In an attempt to
identify low cost substitutes for capsaicin, another study in 2017 was
designed to determine and compare the permeability of capsaicin with a syn-
thetic analog, nonivamide through different intestinal regions in rats. The
results demonstrated that capsaicin and nonivamide exhibit varying perme-
ability across the intestine [48]. The potent in vivo antitumor activities of
capsaicin suggest that capsaicin might be developed for the treatment of
human colon cancer.

In phase I/II clinical trials, Capsaicin was found to produce positive out-
comes in the treatment of inflammatory diseases such as Interstitial Cystitis
and vulvar vestibulitis [49]. It is also expected to contribute toward treatment
of prostate cancer and hence a phase II study is underway checking the
potential of Capsaicin as a chemopreventive agent [50]. Furthermore, its role
in curing diabetic peripheral neuropathy has also been demonstrated [51].
However, clinical trials evaluating its use in treatment of colorectal cancer
are not available so far.
2.3 Epigallocatechin-3-gallate
Green tea is one of the widely consumed beverages around the world. Green
tea is rich in antioxidants and has been associated with positive effects on
human health. Polyphenols are the major constituents of all antioxidants
present in tea. Epigallocatechin-3-gallate (EGCG) is the most abundant
polyphenol present [52]. Others include gallic acid, catechin, epicatechin,
gallocatechin, catechin gallate, gallocatechin gallate, epicatechin gallate,
and epigallocatechin. EGCG is a type of catechin and mixture of
epigallocatechin and gallic acid. EGCG is used in many dietary supplements.
EGCG is correlated with the anticancer effect of green tea as it is the most
effectual of 10 of the polyphenols found in tea [52]. However, human bio-
availability studies suggest that EGCG has poor absorption. Most of the
ingested EGCG is cleared from blood with a half-life of approximately
3 h and excreted via bile to the colon [53]. EGCG has shown numerous
health promoting effects acting through different pathways, as antioxidant,
antiinflammatory, and antiatherogenic agent, showing gene expression
activity, functioning through growth factor-mediated pathways, the
mitogen-activated protein kinase-dependent pathway, the ubiquitin/
proteasome degradation pathway, etc. [54]. Due to its unpredictable bio-
availability, there are contradictory epidemiological inferences and inconsis-
tencies between in vitro and in vivo studies. Aspects concerning these facts,
but also relating to dose levels, administration frequency, and potential side
effects, remain to be addressed in future clinical trials.

EGCG [(2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-
2H-chromen-3-yl] 3,4,5-trihydroxybenzoate is a phenolic antioxidant
with a molecular weight of 458.375 g/mol. It has a melting point of
140–142°C and its molecular formula is C22H18O11 (Fig. 3.3).
OH
OH
O
OH OH
OH
HO O
OH
EGCG
OH
Fig. 3.3 Structure of EGCG.
2.3.2 Sources
Green tea is the major source of EGCG 7380 mg/100 g. It is also found in
white tea and black tea, however, black contains a very small quantity of
EGCG. According to a study by USDA, apples, blackberries, and carob flour
also contain 6.26 mg/100 g, 7.44 mg/100 and 109 g, 46 mg/100 g, respec-
tively. Some foods like peaches, plums, avocados, nuts, etc. also contain
EGCG in trace amounts [55].

A number of studies have shown the chemopreventive and anticancerous
activity of EGCG in colorectal cancer in different experimental scenarios.
EGCG is reportedly known to alter Wnt/β-catenin signaling pathway in
suppressing colorectal carcinogenesis [56]. As demonstrated by Chen
et al., EGCG prevented the spheroid formation, inhibited the cell prolifer-
ation, and induced apoptosis in colorectal cancer cells through repressing the
Wnt/β-catenin signaling [57]. EGCG also inhibits sphere formation in
HCT-116 cells [58]. EGCG also exerts its effect by altering Akt,
ERK1/2, and p38MAPK activity and induced cell death in HT-29 cells
[59]. Combining EGCG with cisplatin or oxaliplatin enhanced the thera-
peutic effect in human colorectal cancer cells [60]. Liver is the primary
location for metastasis of colorectal cancer. It has been documented that
EGCG is capable of preventing the liver metastasis of colorectal cancer cells
[61]. Epigenetic modifications like DNA hypermethylation and histone
deacetylation are one of the important mechanisms involved in gene silenc-

ing, and EGCG has shown its capability in reducing the expression of
DNMT3A and HDAC3 in methylation-sensitive HCT-116 colon cancer
cells [62]. Indoleamine 2,3-dioxygenase (IDO) is an immune suppressor
and is associated with cancer-related immunosuppression [63]. Colorectal
cells are able to avert the specific immune response, and IDO helps cancer
cells to avoid the immune response. EGCG helps in inhibiting the IDO in
colorectal cancer cells, thus showing antitumor properties [64]. There are
several reports available documenting the involvement of dysregulation of
notch pathway in colorectal cancer [65]. EGCG also exerts its antip-
roliferative and apoptotic effect in colorectal cancer cells via inhibiting notch
signaling [66]. Cyclin D1 and p21 were also identified as targets of EGCG in
colon cancer cells [67]. EGCG exposure to SW260 colon cancer cells
inhibited the activity of transcription factor NF-κB and ERK1/2 [68].
EGCG degrades the Trop-2 mRNA in SW-260 cells posttranscriptionally
and in HCT-116 cells it altered its expression at protein level [69]. Trop2 is
the cell surface glycoprotein and is the calcium signal transducer [70] and
recently its association has been found with cancer, thus presenting a suitable
target for cancer therapy.
EGCG treatment reduces the number of ACFs in the AOM/DSS-
induced colitis mouse model. It also maintains the stability of gut microbiota
[71]. In Kyoto Apc Delta rat, a novel adenomatous polyposis coli mutant
rat strain, EGCG reduced the development of colon tumors by 71% and
level of inflammatory mediators in serum was also affected [72]. Acetylated
EGCG downregulates the PI3K/Akt/NF-κB phosphorylation and inhibits
histone 3 lysine 9 acetylation. It also activates ERK1/2 signaling and acet-
ylation of Nrf2 in dextran sulfate sodium-induced colitis in mice [73]. In the
xenograft mouse model, EGCG delayed the tumor incidence and inhibits
the HSP60 and HSP70 expression [74]. EGCG induced the Nrf2 expression
which is associated with increased UGT1A expression and it also modulate
these signaling pathways in colon cancer cells suggesting this as one of the
modes of its effect in chemoprevention of colorectal cancer cells [75].
C57BL/KsJ-db/db (db/db) mice, which are obese and develop diabetes
mellitus, were injected subcutaneously with azoxymethane. EGCG treat-
ment causes a decrease in premalignant lesions in mouse colon and reduction
in IGF-IR, phosphorylated form of IGF-IR (p-IGF-IR), p-GSK-3beta,
beta-catenin, cyclooxygenase-2, and cyclin D1 protein expression [76].
However, it has been also reported that EGCG when used in high concen-
tration in mice having colon inflammation may enhance colon bleeding and
promote colon carcinogenesis [77].

More than 60 trials on various EGCG extracts and formulations have been
conducted or are ongoing, the majority on various types of cancer. In a study
with volunteers of more than 50 years of age, it has been found that green tea
extracts reduced the mRNA of DNA methyltransferase and NF-κB. Green
tea extracts specifically target the genes associated with inflammation, meth-
ylation, and WNT signaling [78]. Green tea extracts reduced the relapse of
adenoma in patients with colorectal adenoma after polypectomy [79].
2.4 Resveratrol
Resveratrol (RSV) is a dietary phytochemical (phytoalexin) and efficiently
binds to organic molecular complexes; because of its chemical and physical
features it can either cross to cell membranes or interact with membrane
receptors. RSV may also interact with fatty acids. Recent in vitro studies
showed that more than 90% of free trans-resveratrol binds to human plasma
lipoproteins. This binding is also found in vivo, as shown by the presence
of dietary RSV compounds detected in isolated low-density lipoprotein
in blood samples of healthy humans [80]. Pleiotropic properties of RSV
have been observed in various types of cancers including breast, prostate,
lung, skin, and colon. In rodents and humans, when resveratrol is con-
sumed orally, 70%–80% is quickly absorbed via passive diffusion in the
intestines [81].

RSV is formed by a condensation processes between three molecules of
malonylcoA and one molecule of 4-coumaroyl in the presence of resvera-
trol synthase. RSV (3,5,40 -trihydroxystilbene) is a low molecular weight
(228.25 g/mol) natural polyphenol. The basic structure of resveratrol con-
sists of two phenolic rings which are bonded together by a double styrene
bond, which forms the 3,5,40 -trihydroxystilbene. This double bond is res-
ponsible for the isomeric cis- and trans-forms of resveratrol (as shown in
Fig. 3.4). It has been observed that the trans-isomer is the most stable from
the steric point of view. cis- and trans-isomers of resveratrol stick together in
plants and in wine. However, the cis-form of resveratrol has never been
found in grape extract whereas the trans-isomer appears to be the more dras-
tically and stable natural form. However, when trans-resveratrol is exposed
to sun light, artificial light, or ultraviolet radiation (254 or 366 nm), it
converts into cis-resveratrol [80] and also, it is less soluble in water but highly
soluble in ethanol and organic solvents.
OH
HO
OH
Resveratrol
OH
HO HO
HO HO
OH
trans-Resveratrol cis-Resveratrol
Fig. 3.4 Structure of resveratrol.
2.4.2 Source
RSV is produced by more than 70 plant species such as grapes, jackfruit, soy,
peanuts, blueberry, cranberry, and mulberry [80,82]. RSV is not only found
in plant species, but is also found in processed products such as red wine but
in lesser amounts. Red wine is richer in resveratrol than white wine, because
during the production of red wine, parts of the grape where resveratrol is
concentrated are soaked whereas this does not happen in case of white wine
[80]. The concentration of resveratrol in plants depends on various factors.
For example, in wines, the two most important factors are the weather and
presence of fungus. RSV concentrations significantly vary in different plant
species such in blueberries (32 ng/g), peanuts (1920 ng/g), and grapes
(3540 ng/g) [83].

RSV has been found as potent anticancer agent against in vitro and in vivo
models. RSV can modulate the all three stages of cancer including initiation,
promotion, and progression. This anticancer effect is induced by TGF-β
through multiple approaches such as suppressing the TGF-β-induced
epithelial–mesenchymal transition (EMT), decreasing the rate of lung
metastases, hepatic metastases, and preventing TGF-β1, that are involved
in invasion and metastasis of colorectal cancer by decreasing the
E-cadherin and increasing the vimentin expression through the TGF-β1/
Smads signaling pathway [84].
Resveratrol has the potential to stimulate cell cycle arrest leading to apo-
ptosis of tumor cells, inhibits tumor-derived nitric oxide synthase expression
to block tumor growth and migration, as well as acts as an antioxidant to
prevent DNA damage that can lead to tumor formation. In addition, resver-
atrol inhibits cyclooxygenase (COX) activity, which is known to play a role
in tumorigenesis by converting arachidonic acid to prostaglandins, inflam-
matory compounds that promote tumor cell proliferation [85]. However,
resveratrol suppresses the expression of several transcription factors
(STAT3, AP-1, NF-κB), inflammatory enzymes (COX2, MMP-9, PPAR),
inflammatory cytokines (IL-6, IL-8, and TNF-α), and chemokines (CCL3,
CCL4, CCL5) at molecular level [84]. Although in a study it was found that
a modulatory role on mitomycin C (MMC)-mediated effects of colorectal
cancer via inhibiting cell growth, modulating genes, upregulating p21
(WAF1/CIP1) that suppresses the cell cycle at G0/G1 and G2/M
phases [86].
Resveratrol suppresses the invasive and migratory ability of LoVo cells,
by upregulating the E-cadherin expression while downregulating vimen-
tin expression along with inhibition of the TGF-β1/Smads signaling
pathway [87].
It is also reported that RSV suppressed proliferation and induced apopto-
sis via p53 activation in HT-29 and SW-480 human colon cancer cell lines,
however, it was effective only at high concentrations (75–100 μM) [88].
A study also showed the antiproliferation effect of RSV at a concentration
of 10 μM on Caco-2 colon cancer cells. Interestingly, RSV inhibited cell
cycle progression by enhancing the levels of cyclin E and cyclin A along with
a decrease in cyclin D1 which suggests that resveratrol, at doses 50 μM,
which mainly suggests that RSV exerts cytostatic but not cytotoxic effects
on colon cancer cells [89]. Furthermore, some other studies demonstrated
that the pretreatment of HT-29 colon epithelial cells along with 25 mM
of resveratrol and 500 mM of 5-aminosalicylic acid, and followed by expo-
sure of the cells to a combination of cytokines (IL-1α, TNF-α, IFN-c) for a
certain period of time and found that resveratrol, at a concentration 20 times
lower than 5-aminosalicylic acid, could significantly decrease the produc-
tion of prostaglandin E2 (PGE2) and NO (nitric oxide), iNOS and
COX-2 expression by JAK–STAT pathway [90]. Resveratrol inhibited
the proliferation and promoted the apoptosis of human colon cancer cell line
(HCT-116) by regulating the PTEN/PI3K/Akt and Wnt/β-catenin signal-
ing and suppressed the xenografts tumor growth of colon cancer as well.
Basically, resveratrol upregulated the expression of phosphatase and tensin
homolog (PTEN) and decreased the phosphorylation of Akt1/2. The exog-

enous expression of PTEN inhibited the PI3K/Akt signal and promoted the
growth inhibitory effects of resveratrol in HCT116 cells [91].
It is found that oral administration of resveratrol in mice prevented the
development of colon cancer and reduced the formation of intestinal tumors
by 70% in comparison with the control group and further found that resver-
atrol downregulated the genes (cyclin D1 and D2) that are involved in cell
cycle progression and proliferation and it upregulated the genes that are
involved in recruitment and activation of immune response [92]. It has been
documented that resveratrol significantly reduces the number and multiplic-
ity of ACF in the colorectal mucosa on azoxymethane-induced carcinogen-
esis and also found that resveratrol regulates the expression of BAX and p21
in mucosa with ACF and non-ACF peripheral mucosa.

To study the effectiveness, best regimen, and side effects of resveratrol in
colorectal cancer patients, the US National Cancer Institute has sponsored
a phase I clinical trial. In addition to this, various other phase I/II clinical
trials utilizing oral resveratrol are under way. These clinical studies are
focused upon studying the effect of grape-derived low-dose resveratrol
on biomarkers related to the Wnt pathway, a key signaling pathway acti-
vated in >85% of colon cancers for colon cancer prevention. A phase
I/II clinical trial would not only examine the effects of resveratrol directly
on colon cancer but also on surrounding normal colonic mucosa [93].
2.5 Sulforaphane
Sulforaphane (SFN) (1-isothiocyanato-4-methylsulfinylbutane) is a com-
pound within the isothiocyanate group of organosulfur compounds and
mainly found in cruciferous vegetables [94]. It is produced when the enzyme
myrosinase transforms glucoraphanin, a prodrug or storage form of SFN,
into SFN upon damage to the plant (such as from chewing), which allows
the two compounds to mix and react [95]. Glucoraphanin is one of a few
molecules known as isothiocyanates, existing alongside Sinigrin (metabo-
lized into allylisothiocyanate). SFN promotes detoxification, prevents and
combats cancer, lowers cholesterol, improves diabetes, can boost the
immune system, is antiviral, antibacterial, and antifungal, combats inflamma-
tion, protect skin, eyes, kidneys, and brain, and restores its cognitive func-
tion [96]. Deep insight in several studies has reported that dietary intake of
cruciferous vegetables has a direct association in the decline in the incidence
of various tumors such as prostate, cervical, ovarian, and lung cancer. It

improves the liver function, attenuates pain, improves hair growth, pro-
motes bone formation, and prevents muscle damage. SFN treatment reduces
DNA damage and mutation rate when cancer-causing chemicals bind DNA.
Although an ideal dosage is not known, the dietary addition of 0.1–0.5 mg/
kg SFN to rats has been noted to be bioactive. This is an estimated human
dose of 7–34 mg for a 150 lb person; 9–45 mg for a 200 lb person; 11–57 mg
for a 250 lb person.

SFN [Sulforaphane; DL-Sulforaphane] in liquid form is slightly yellow in
color, with a molecular weight about 177.28 g/mol. SFN has an average
melting point of 74.6°C, although it may range between 58.6°C and
91.2°C and its molecular formula is C6H11NOS2. It is soluble in DMSO,
methanol, or water-like solvents (Fig. 3.5).
2.5.2 Sources
SFN exists in food in its food-bound form known as Glucoraphanin. It is
present in a wide range of vegetables such as cabbage, cauliflower, bok choy,
kale, chinese broccoli, mustard, turnip, radish, and watercress [97].

Among the individuals who consumed at least one portion of cruciferous
vegetables per week as their dietary intake had a significantly reduced risk
of oral cavity, pharynx, esophageal, colorectal, breast, and kidney cancers
with very little effect on healthy cells [98]. Apart from being effective in
its own right, SFN also enhances the efficacy of various anticancer drugs
including cisplatin, gemcitabine, doxorubicin, and 5-fluorouracil, toward
pancreatic, prostate, and colorectal cancer cells, while limiting their toxicity
to normal cells. Mechanisms followed by SFN in preventing cancer are:
• SFN induces Phase II enzymes NQO1, GSTA1, and HO-1 that are
responsible for eliminating chemicals that damage DNA.
S N
C
O S
Sulforaphane
Fig. 3.5 Structure of sulforaphane.
• SFN changes gene activation/deactivation. It causes demethylation,

thereby restoring the activity of important tumor-suppressing and
cell-cycle controlling genes.
• SFN induces cancer cell death by activating caspase-3, caspase-7,
caspase-8, and caspase-9, decreasing antiapoptotic Bcl-2 and Bcl-XL,
increasing proapoptotic Bax, inducing p21 (CDKN1A) and p53, inac-
tivates polyadenosine ribose polymerase (PARP), decreases HIF1A
and β-catenin (CTNNB1).
• SFN inhibits the NF-κB pathway and cyclooxygenase 2 (COX-2), thus
reducing inflammation.
• SFN induces cell cycle arrest and thereby inhibits cancer cell prolifera-
tion [99,100].

In a clinical trial, consumption of broccoli sprouts by human volunteers cau-
sed a 10-fold increase in LTR activation in white blood cells. But these
effects are transient, and it remains to be determined whether they are bio-
logically meaningful [101]. During some other clinical studies, in human
volunteers, no records of abnormal events related to broccoli sprout con-
sumption were reported. During the pharmacokinetic study of SFN, it
has been reported that the plasma concentration of SFN and its metabolite
increase quite rapidly after 1–3 h of administration. However, a clinical trial
involving SFN as a dietary supplement has been done on lung cancer in for-
mer smokers to assess the chemopreventive effect with it for 1 year.
2.6 [6]-gingerol
Ginger is a popular spice used in the world especially in most of the Asian
countries. Ginger contains various active phenolic compounds such as [6]-
gingerol, [8]-gingerol, [10]-gingerol, and [6]-shogaol [102]. Among them
[6]-gingerol is an important pungent component of ginger and was found
to possess various pharmacological effects, such as cardiotonic, antiemetic,
antioxidant, antitumor, antiplatelet, and antiinflammatory [103]. Apart from
these phenolic compounds, it also contains more than 400 different com-
pounds including carbohydrates, lipids, terpenes (zingiberene, -bisabolene,
α-farnesene, β-sesquiphellandrene, α-curcumene), amino acids, raw fiber,
ash, protein, phytosterols, vitamins (nicotinic acid and vitamin A), and
minerals [6]. In addition to its extensive use as a spice, the rhizome of ginger
is also used as a herbal medicine for common cold, digestive disorders,
rheumatism, neurologia, colic, and motion-sickness. Ginger is also used
for the treatment of many unrelated diseases that include arthritis, rheuma-
tism, sprains, muscular aches, pains, sore throats, cramps, constipation, indi-
gestion, vomiting, hypertension, dementia, fever, infectious diseases, and
helminthiasis. Moreover, it is used in many gastrointestinal problems includ-
ing morning sickness, colic, upset stomach, gas, bloating, heartburn, flatu-
lence, diarrhea, loss of appetite, and dyspepsia. It is a well-known remedy for
nausea during pregnancy and is recommended to enhance the digestion of
food by Indian Ayurvedic medicinal system [104]. Besides these, ginger has
been reported as for treatment of upper respiratory tract infections, cough,
bronchitis, and also used to warm the body for boosting the circulation and
lowering high blood pressure [6].
A pharmacokinetics study showed that after orally administered ginger
extracts in human beings, [6]-gingerol was detected a significant levels,
either in free or conjugated form (glucuronide and sulfate conjugates) in
plasma and colon tissue and [6]-gingerol detected at concentration of
4.3 mg/mL in rats plasma after 10 min administration [105]. All these facts
support a study on anticancer effects of [6]-gingerol on colon cancer.

[6]-Gingerol (1-40-hydroxy-30-methoxyphenyl-5-hydroxy-3-decanone)
is a pungent phenolic substance with a molecular weight of 294.39. Gingerol
can remain in two form either [6]-gingerol or [10]-gingerol which depends
upon the position of methoxy group (Fig. 3.6).
2.6.2 Source
The main source of [6]-gingerol is ginger (Zingiber officinale), which belongs
to the Zingiberaceae family. Beside [6]-gingerol, ginger also contains [8]-
gingerol, [10]-gingerol, and [6]-shogaol [103].
O OH
HO [6]-Gingerol
OCH3
Fig. 3.6 Structure of [6]-gingerol.

2.6.3 Molecular target

[6]-Gingerol targeted several genes that are involved in colorectal cancer. It
has been shown that [6]-gingerol is a potential inhibitor of leukotriene A4
hydrolase (LTA4H) which is highly expressed in colorectal cancer [106].
A study has also shown that [6]-gingerol inhibited the growth of numerous
types of tumors of renal, melanoma, and colon by enhancing the penetra-
tions of tumor-infiltrating lymphocytes CD4 and CD8 of T-cells and
B220+ B-cells [107]. Ginger-derived [6]-gingerol regularly inhibits cell
proliferation in various human colorectal cancer cell lines. It has been shown
that the exposure to 150–200 μM of [6]-gingerol of a colorectal cell line
(HCT-116) reduce by 22% and 28% cell growth rate, respectively, after
the 72 h incubation. And, it is also observed in other human colorectal
cancer cell lines including SW480, HT-29, LoVo, and Caco-2 cells treated
with 200 μM of [6]-gingerol for 72 h and observed a reduction in the
growth rate of 17%, 28%, 13%, and 8%, respectively. In addition, apoptosis
analysis showed that apoptotic cells were also significantly increased in
SW480 and LoVo cells, but not in case of HT-29 and Caco-2 cell lines
[102,107]. Furthermore, a study has been shown indicating [6]-
gingerol-stimulated ROS production and p53 activation as well as inhibits
the degradation of p27Kip1 and p21Cip1 in LoVo cells, which induces the
cell cycle arrest at S and G2/M phases [108]. However, some other studies
revealed that at lower concentration of [6]-gingerol (100 μM) induce early
apoptosis by the activation of caspases 8, 9, 7, 3 in SW-480 cells and also
confirms mitochondrial pathways were involved in [6]-gingerol-mediated
apoptosis. It further hinders the expression of ERK1/2 and JNK MAP
kinases in phorbol-12-myristate-13-acetate-induced proliferation in colon
cancer cells [109]. [6]-Gingerol has the ability to reduce expression of
cyclin D1, a protein that plays an important role in cell-cycle transitions
specially G1 to S transitions and hypophosphorylation of p-Rb in
HCT-116 cells. There are multiple mechanisms by which [6]-gingerol
downregulates cyclin D1 expression. One of these, [6]-gingerol decreased
localization of β-catenin, which is followed by the inhibition of cyclin
D1 expression at the transcriptional level. Another mechanism to
suppress cyclin D1 expression is the activation of proteasome degradation.
The suppression of cyclin D1 and induction of NAG-1 [nonsteroidal
antiinflammatory drug (NSAID)-activated gene-1 (NAG-1)] by [6]-
gingerol were observed at 150 and 200 mM concentrations. It is believed
that a higher concentration of [6]-gingerol is required for inducing apoptosis
in CRC [109].

To assess the safety and efficacy of [6]-gingerol supplementation for
preventing colorectal cancer clinical trials are ongoing. Some study showed
that 20 colorectal cancer patients were given 2.0 g/day ginger for 28 days and
found that ginger did not decrease levels of prostaglandin (PGE)-2, leuko-
triene B4 (LTB4), 13-hydroxy-octadecadienoic acids, and 5-, 12-, and
15-hydroxyeicosatetraenoic acids (HETE) but it was both tolerable and safe
[6]. However, earlier in a phase II study it showed no significant difference in
eicosanoids levels in 30 people with colorectal cancer but they found a sig-
nificant decrease the level of PGE2 and HETE [110]. Furthermore, another
study on 66 colorectal cancer patients observed that ginger significantly
reduce COX-1 protein expression [6].
2.7 Lycopene
Lycopene is a natural fat-soluble red carotenoid pigment synthesized in some
microorganisms, found largely in tomatoes and other red fruits, like water-
melon, papaya, pink grapefruit, and pink guava [111]. It obtained its name
from the tomato’s species classification, Solanumly copersicum. It is an essential
nutrient in animal diets and may possess antioxidant properties protecting
organisms from toxic effects of light and oxygen, may retard aging and
many degenerative diseases. Apart from its antioxidant properties, it also
plays a role in regulating hormone action, cell cycle progression, cell death
and survival mechanisms, gap junction communication, and epigenetics
which complement together to generate its anticancerous effect [112].
Nonetheless, there are contradictory studies available regarding inverse cor-
relation between lycopene intake and cancer risk [113]. This aspect could,
however, be explained, in part, by interindividual variations with regard to
genetic background. Lycopene can be considered as a promising carotenoid
with effects related to cancer prevention and therapy.

Lycopene is a water-insoluble, bright red, most common dietary carotenoid
synthesized by photosynthetic organisms (plants, algae, and some types of
fungus) and chemically characterized by a large unsaturated hydrocarbon
chain (tetraterpene) containing 35–40 carbon atoms with chemical formula
C40H56 and a melting point of 172°C [111]. Its color is due to its many
conjugated carbon double bonds and owing to its intense color it is a
permitted food-coloring agent approved for use in the United States and
European Union.
2.7.2 Sources
As mentioned earlier, it is largely found in varying concentration in tomatoes
and other red fruits, like watermelon, papaya, pink grapefruit, and pink
guava [111,114]. However, processed tomato products contain higher
amounts of lycopene as processing steps often involve water loss [115].
Our body organs store varying amount of lycopene. For example, it is found
in higher concentration in adipose tissues, adrenal glands, testes, and liver
while in lower concentration in kidney, prostate, lungs, and ovary [111].

An epidemiological study in elderly Americans indicated that high tomato
intake was associated with a 50% reduction in mortality from cancers at all
sites, and a case–control study in Italy showed potential protection from high
consumption of lycopene from tomatoes against cancers of the digestive tract
[116]. Epidemiological studies support the possibility that lycopene can
reduce cancer risk. In a meta-analysis of 72 studies, 57 reported an inverse
association between lycopene ingestion and the risk of diverse cancer types
(including prostate, breast, lung, and colon), and 35 studies reported statis-
tically significant associations. None of these studies reported any adverse
effects of increased tomato intake or increased circulating lycopene levels
[106]. Lycopene treatment induces an alteration of serum concentrations
of components of the IGF system in both prostate and colorectal cancer
patients [117,118].
It is reported that lycopene can alter the functionality of different inflam-
matory pathways in vitro. Various in vitro studies have demonstrated that it
possesses antiinflammatory, antiangiogenic, antiinvasive, and antimetastatic
properties which assure its promising role in the prevention of colon cancer.
It suppresses the nuclear translocation of NF-κBp65 subunit and inhibits the
phosphorylation of IKKα and IKBα resulting in overall inactivation of
NF-κB. Lycopene-induced NF-κB inactivation further inhibits the expres-
sion of downstream IL-8, a proinflammatory cytokine, both at gene as well
as protein level [119]. Lycopene also inhibits TNFα, cyclooxygenase
(COX)-2, inducible nitric oxide synthase (iNOS), and interleukin (IL)-6
secretion [105]. In addition, lycopene treatment was shown to reduce
expression of MAP kinases including ERK1/2, JNK, and p38MAPK
phosphorylation and increased expression of PPARγ, resulting in enhanced
PTEN activity and the inactivation of AKT [120]. Palozza et al. [121]
demonstrated that tomato products that contain lycopene can inhibit
the growth of colon adenocarcinoma cells by decreasing the expression of
cyclin D and the antiapoptotic proteins Bcl-2 and Bcl-XL. Lycopene effi-
ciently suppresses cell growth by attenuating the activity of PI3K/Akt/
mTOR pathway and upregulating the expression of apoptotic proteins such
as Bax and fas ligand in human HT-29 human colon cancer cells [122].
A number of recent in vivo studies have shown that lycopene inhibits the
progression of colon cancer through pleiotropic modulation of multiple
molecular targets that includes transcription factors, growth factors, cyto-
kines, enzymes, and genes involved in cell proliferation. Lycopene inhibits
the progression of colon cancer in vivo by decreasing proliferating cell
nuclear antigen (PCNA), increasing p21 and the activation of caspase-3,
increasing the E-cadherin adhesion molecule, and decreasing nuclear levels
of β-catenin [112]. Moreover, the effects of lycopene are associated with the
suppression of COX-2, PGE2, and ERK1/2 phosphorylation, which is
inversely correlated with plasma levels of MMP-9 in tumor-bearing mice
[123]. Tang et al. [124] reported that lycopene and fish oil combined at
physiological concentration induced a synergistic inhibitory effect on tumor
growth in a mouse xenograft model of colon cancer due to enhanced
expression of cell-cycle inhibitors such as p21CIP1/WAF1 and p27Kip1
and suppression of PCNA, β-catenin, cyclin D1, and c-Myc proteins.
Furthermore, this chemopreventive combination inhibited tumor progres-
sion and inflammation through suppression of MMP-7, MMP-9, COX-2,
and PGE2.

As in vivo and in vitro findings suggest the ability of lycopene to interfere
with proliferation-related pathways, it is expected to produce positive
outcomes regarding its use in treatment of metastatic colorectal cancer
[125]. Hence, a double blind phase I/II pilot study assessing the effectiveness
of lycopene with panitumumab-treated colorectal patients is underway
[126]. However, there is a need for conducting more phase II clinical trials
to address the safety of lycopene supplementation as well as to establish its
efficacy as a chemopreventive agent.
2.8 Inositol hexaphosphate

Inositol hexaphosphate also known as phytic acid is a polyphosphorylated
carbohydrate. It belongs to the family of inositols. Inositols are versatile
molecules with important roles in controlling diverse cellular activities
[127]. Studies have demonstrated that sufficient intake of dietary fibers with
IP6 content can reduce the risk of colorectal cancer [128]. IP6 may serve as a
natural antioxidant and possibly as a neurotransmitter [127]. IP6 is available

in markets as a dietary supplement. Anticancer effects of IP6 are demon-
strated in different experimental models. Studies suggest that IP6 increases
the differentiation of malignant cells which results in reversion of normal
phenotype [127]. IP6, an important dietary component, as a colorectal can-
cer chemopreventive agent provides a good opportunity to understand the
correlation between colorectal cancer and its prevention with dietary mod-
ifications. However, there are some concerns regarding mineral deficiency
due to high intake of IP6, but this can be overcome by combination of diet
that is high in oligoelements.

Myo-inositol is the parent compound of IP6. The phosphate grouping in
positions 1, 2, and 3 (axial-equatorial-axial) is unique for IP6, providing a
specific interaction with iron to completely inhibit its ability to catalyze
hydroxyl radical formation, making IP6 a strong antioxidant (Fig. 3.7).
2.8.2 Sources
Inositol hexaphosphate is abundantly present in certain dietary fibers, partic-
ularly in most cereal grains, legumes, and seeds high in oil. In addition, it can
also be found in almost all mammalian cells acting as a secondary messenger.

Numerous in vitro studies have established the potential of IP6 as an anti-
cancer agent in colorectal cancers. IP6 altered the expression of genes COX
and LOX and reduced the inflammation in human colon cancer cell line
Caco-2, and thus may prevent colon carcinoma via regulating arachidonic
acid-dependent pathways [129]. Liu et al. showed that IP6 inhibits cell
OPO3H2
H2O3PO OPO3H2
H2O3PO OPO3H2
OPO3H2
Inositol-6-phosphate
Fig. 3.7 Structure of inositol hexaphosphate.
proliferation and cell survival and induced apoptosis in human colorectal

adenocarcinoma (HT-29) cells by reducing the expression of PI3K and
Akt [130]. Another study performed on HT-29 cells established the
proapoptotic role of IP6 via regulating Bax and Bcl-xl [131]. IP6 causes
reduction of cell proliferation in HT-29 cells via reducing the expression
of p53 and PCNA. In colon cancer epithelial cells (Caco-2), IP6 causes
the decrease in expression of MMPs TIMP resulting in inhibition of cell
migration and invasion [132]. Kapral et al. also showed that IP6 is able to
alter the expression of MMP-1, TIMP1, and TIMP-2 in Caco-2 cells [133].
The chemopreventive action of IP6 has also been described in various
animal models. IP6 is known to cause a decrease in tumor incidence in
dimethylhydrazine induced the rat colorectal cancer model. This study
suggested the possibility of crosstalk between PI3K/Akt and Wnt pathways
in mediating the tumor-inhibiting and antiproliferative action of IP6 [134].
IP6 in combination with inositol deregulates the expression of extracellular
matrix proteins collagen IV, fibronectin, and laminin; the adhesion factor
receptor integrin-β1; the proteolytic enzyme matrix metalloproteinase 9;
and the angiogenic factors vascular endothelial growth factor, basic fibroblast
growth factor, and transforming growth factor beta and inhibit the metastasis
of colorectal cancer to the liver in balb/c mice [135]. In the azoxymethane-
induced colorectal cancer rat model exposure to IP6 through drinking water
for 16 weeks causes the alteration in Wnt/β-catenin and COX-2-signaling
pathways, thereby exhibiting anticancer effects [136,137]. In another study
using azoxymethane-induced Sprague–Dawley rat model, IP6 decreased the
tumor number and their multiplicity suggesting its capability of reducing
colorectal cancer [138]. IP6 causes substantial difference in the expression
of TGF-β in AOM-induced rat model [139]. Inositol given to female
C57BL/6 mice, exposed to dextran sodium sulfate, through drinking
water reduced the chances of ulcerative colitis-associated colorectal cancer.
Alteration of macrophage-mediated inflammation, nitro-oxidative stress,
and cell proliferation is correlated with downregulation of tumor incidence
via inositol compounds [140]. IP6 enhances the natural killer cell activity
that was reduced in rats exposed to dimethylhydrazine and prevents the
tumor growth [141].

Although IP6 emerges as a potential candidate for its chemopreventive and
anticancer effects in colorectal cancer; however, the compound still needs
clinical trials to assess its effect.
2.9 Curcumin
Curcumin is a commonly used spice in India and Southeast Asia. It is a
polyphenolic compound derived from the rhizomes of turmeric plant
(Curcuma longa), which belongs to the Zingiberaceae family. There are three
types of curcuminoids including curcumin, demethoxycurcumin, and
bisdemethoxycurcumin, which are obtained from the natural extract of tur-
meric, of which curcumin is the major constituent [142]. Curcumin is used
as a coloring and flavoring agent for preparation of curries and spicy dishes in
India, Pakistan, Bangladesh, and other countries of Asia [143]. Besides its
traditional use as a food coloring and flavoring agent, it also has a well-
documented history in medicine in India and Southeast Asia. Curcumin
has been proved as an antiseptic, analgesic, antiinflammatory, antimalarial,
antioxidant, and chemopreventive agent that is used for the treatment of
various diseases such as inflammation, respiratory conditions, liver disorders,
diabetic wounds, cough [144,145]. Furthermore, curcumin has shown
beneficial effects in various types of cancer, including breast, oral epithelial,
cervical, gastric, hepatic, leukemia, ovarian, head and neck, melanoma,
brain, ovarian pancreatic, prostate, and colorectal cancers [146]. Conven-
tional treatment for colorectal cancer, which includes surgery, chemother-
apy, and radiation, is still not completely effective in curing the disease due to
the development of secondary cancers or tumors. It has been described that
curcumin has potential to suppress inflammation and inhibit the growth of
neoplastic cells at all three different stages of colon carcinogenesis including
initiation, promotion, and progression and there are no toxicities or side
effects associated with curcumin either in experimental animals or humans
even at very high doses [147]. Apart from the numerous uses of curcumin, it
is also confirmed that it enhances the effectiveness of some cancer therapeu-
tics, such as 5-fluorouracil (5-FU). This is especially beneficial because
patients can develop a resistance to 5-FU. Cells, treated with 5-FU and cur-
cumin concomitantly in culture, showed cell cycle growth arrest, increased
apoptosis, and a decrease in cell surface markers associated with cancer [148].

Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione
or diferuloylmethane] is a crystalline molecule with a molecular weight of
368.37 and is hydrophobic in nature. Curcumin has a melting point of
183°C and its molecular formula is C21H20O6. Curcumin is the most abun-
dant and most bioactive analog of curcuminoids, comprising of about 77% of
the total. Each curcuminoid shares a common aromatic ring, but differs in
the methoxy substitutions of aryl moieties [145]. Curcumins are photopho-
bic compounds. In alkaline conditions, curcumin is unstable and exists in an
enol form and appears reddish in color whereas in neutral or acidic condi-
tions at high temperature, it is insoluble and exists in a keto form [149,150].
Also it is found to be soluble in organic solvents like ethanol, acetone, meth-
anol, DMSO, isopropanol and is moderately soluble in hexane, dioxane,
cyclohexane, and tetrahydrofuran [151] (Fig. 3.8).
2.9.2 Source
The main source of curcumin is the turmeric plant (C. longa).

Multiple drugs are currently available for treatment of colon cancer but have
limited potential because they are very toxic, highly expensive, and ineffi-
cient in treating colon cancer. Recently, researchers use curcumin as a
chemopreventive agent for treatment of colon cancer because it is less
expensive, easily available, and has less toxic effects compared to other che-
motherapeutic drugs. Various studies have shown that curcumin is potent in
modulating multiple cellular signaling pathways (e.g., TGF-β signaling
pathway and Wnt/β-catenin pathways) and interacts with many molecular
targets including transcription factors, growth factors, and their receptors,
cytokines, enzymes, and genes regulating cell proliferation. Interestingly,
curcumin is also involved in apoptosis and has potent anticancer activities
including inhibition of cell proliferation, induction of apoptosis, suppression
of angiogenesis, and metastasis. Even though it was found that curcumin
O O
HO OH
Curcumin
O O O OH
HO OH OH
Keto form HO
Enol form
Fig. 3.8 Structure of curcumin.
blocks proliferation of cancer cells by arresting them in various phases of

the cell cycle by directly or indirectly binding to multiple molecular
targets: downregulation of various transcription factors (NF-κB, STAT 3,
β-catenin, and AP-1), growth factors (TGF-β EGF, PDGF, p21, and
VEGF), enzymes (COX-2, iNOS, and MMPs), oncoproteins (c-Myc,
Ras, and Fas), kinases (AMPK, GSK-3β, cyclin D1, CDKs, Akt, and
PKC), inflammatory cytokines (TNF, MCP [Monocyte Chemoattractant
Protein], IL-1, and IL-6), and upregulation of proapoptotic (Bax, Bad,
and Bak, caspase-3, -8, -9), and tumor suppressor genes (Rb, p53, PTEN),
which induces apoptosis and blocks invasion of colon cancer in vitro and
in vivo [152]. In certain studies it is shown that curcumin also has potential
to inhibit the expression of COX-2 (cyclooxygenase-2) that plays an im-
portant role in colon carcinogenesis. Additionally, it downregulates cyclin
D1, cyclin E, and MDM2, whereas it upregulates to p21, p27, and p53 that
induce apoptosis [144]. Thus, curcumin is a promising compound for cancer
therapeutics that can inhibit cell growth cycle and survival mechanisms.
Various recent in vitro studies have shown that curcumin inhibits the
growth of a variety of cell lines by inducing cell cycle arrest and apoptosis,
through pleiotropic modulation on several different cancer targets including
nuclear factor kappa B (NF-κB), STAT-3, cyclooxygenase-2 (COX-2),
tumor necrosis factor alpha (TNF-α), and cyclin D1 [8]. It has been shown
that curcumin has the potential to inhibit the proliferation of numerous
colon cancer cell lines by arresting the cell cycle in G1/M phase. Cyclin
D1 is necessary for cells to progress through the G1 phase of the cell
cycle and cyclin D1 gene expression is downregulated by curcumin via
decreased activation of NF-κB [153]. Curcumin hampered several differ-
ent molecular pathways that are responsible for colon cancer progression
like Wnt/β-catenin pathways and TGF-β signaling pathway. Previous stud-
ies showed that in HT-29 and HCT-116 colon cancer cell lines, curcumin
causes DNA fragmentation, chromatin condensation, and cell shrinkage
through regulating growth arrest by elevation of the DNA damage inducible
gene (DDIT3) at the protein and mRNA levels. In addition, curcumin
inhibits the proliferation and induces apoptosis via caspase-3-mediated
β-catenin cleavage and also blocks cell cycle progression through down-
regulation of c-myc, cyclin D, and cyclin B expression and increased the
activity of cell division control 2 (CDC2) in colon cancer cell lines [154].
Furthermore, curcumin induces activation of PPARγ in colon cancer
cells, inhibits cell growth, and mediates suppression of cyclin D1 and the
epidermal growth factor receptor (EGFR) and it is shown that in Caco-2
and HT-29 colon cancer cells, curcumin inhibits the expression of EGFR
through reducing the activity of EGR1. Interestingly, curcumin likewise
decreases the expression of PGE2 in colon cancer and induces apoptosis
and cancer cell growth arrest. In addition, the treatment of curcumin to
HCT-116 and SW480 colon cell lines decreases tumor growth by suppres-
sion of proliferation and induction of apoptosis through the inhibition
of proteasomes and increases the expression of caspase-3 and caspase-7
[152]. Some other in vitro studies have shown that curcumin induces
apoptosis in various transformed cells such as immortalized NIH 3T3 fibro-
blasts and colon cancer cells [155]. Interestingly, it has been shown to induce
apoptosis of cancer cells without any significant cytotoxic effects on healthy
cells [156]. During proapoptotic processes, it generates reactive oxygen
species, induces p53 as well as proapoptotic proteins such as BAX while
downregulating antiapoptotic genes Bcl-2 and BclXL. In addition, cur-
cumin stimulates the release of cytochrome c from mitochondria leading
to caspase-3 activation, which results in cleavage of PARP and inhibitor
of caspase-activated deoxyribonuclease [155]. Thus, curcumin-induced
apoptosis can be mediated by both mitochondria-dependent and -
independent mechanisms. Also it has been reported that curcumin inhibits
CRC cell proliferation by alternating the glycolytic pathway, in which cur-
cumin promotes dissociation of hexokinase-II from the mitochondria
through AKT-mediated phosphorylation and induces mitochondrial-
mediated apoptosis in CRC [156]. Some research group found that cur-
cumin in combination with celecoxib inhibit synergistically to human colon
cancer cells including HT29, IEC-18-Kras, Caco-2, and SW-480 [157].
Curcumin inhibits activity of NF-κB activity through blocking NF-κB from
binding to DNA that leads to downregulation of NF-κB-facilitated gene
expression of several intracellular adhesion molecules including, adhesion
molecules intracellular adhesion molecule-1, vascular cell adhesion
molecule-1, and endothelial leukocyte adhesion molecule-1 (ELAM-1).
In addition, matrix metalloprotein-9 (MMP-9) is also downregulated by
curcumin again via downregulation of NF-κB. Matrix metalloproteinase
are proteases that contribute to metastasis, and thus MMP-9 downregulation
contributes to curcumin-mediated inhibition of metastasis [149]. Some
in vitro studies demonstrated that curcumin in combination with FOLFOX
results in significantly greater apoptosis and growth inhibition than either
curcumin, 5-FU (5-Fluorouracil), oxaliplatin (FOLFOX), or curcumin with
5-FU. In addition to curcumin in combination with EGFR-related protein
(ERRP), a pan-ERB inhibitor, causes a greater inhibition of growth of
colon cancer cells than either agent alone [158]. Curcumin also shows
antimetastatic activity against colorectal cancer cells using mouse animal
model by upregulating E-cadherin expression, and thus inhibiting EMT
[159]. Furthermore, another study have shown antitumor activity of
curcumin in colon cancer using a xenograft mouse model. In this study
authors revealed that curcumin exerts its antitumor activity by inhibiting
proliferation rather than promoting apoptosis of the colon cancer cells by
inhibiting Wnt/β-catenin pathways via miR-130a [160].
2.9.4 Clinical trial

Phase I clinical trials on curcumin have been completed. Phase II and phase
III clinical trials are ongoing at different research centers throughout the
world. Several studies over the past decades suggested that curcumin is safe
and well tolerated even at a very high dose level (such as 12 g/day/adult) in
humans [152]. It is shown in a study that oral administration of curcumin
(3.6 g/day) by six human subjects shows decrease in PGE-2 levels in blood
[161]. In another study involving 15 patients with CRC, curcumin was
given in doses ranging from 36 to 180 mg/day for 4 months. Of the
15 patients, 5 had radiologically stable disease for 3 months or longer. At
36 mg of curcumin/day, the levels of leukocyte GST declined; but no such
decline was observed at higher doses [162].
2.10 Folic acid

Folic acid is water-soluble micronutrient, sometimes also termed as
pteroylglutamic acid or vitamin B9, it is the form of folate which naturally
presents in high concentrations in leafy vegetables such as spinach, lettuce,
broccoli, okra, asparagus, fruits (such as bananas, melons, and lemons),
beans, yeast, mushrooms, and meat [163]. Medically, folic acid is used for
several kinds of diseases which usually occur due to the deficiency of folate
such as low blood pressure or anemia (tired blood). It is the essential vitamin
required for cellular growth and regeneration that still remains most under-
appreciated. Various essential functions that folic acid performs in our body
include nucleotide biosynthesis in cells, provides one-carbon groups in
methylation of DNA, contributes to DNA synthesis, repair, and replication,
red blood cell creation, epigenetic regulation of gene expression, and
prevention of anemia. It also encourages normal fetal development and its
deficiency may lead to negative effects on fetal brain development. In fact,
folic acids along with calcium and iron have been considered as the holy
trinity of prenatal wellness. A deficiency of this vitamin in pregnant women
can have significant negative effects on unborn children’s brain develop-

ment. Commonly people confuse folic acid with folate, although both
the terms are commercially employed but biologically, folate is the bioavail-
able, natural form of vitamin B9 found in a variety of plant and animal foods
while folic acid is the synthetic form of the vitamin, primarily found in
supplements and fortified foods.

Folic acid [(2S)-2-[[4-[(2-amino-4-oxo-1H-pteridine-6-yl) methylamino]
benzoyl]amino] pentanedioic acid] is an odorless orange-yellow in color,
with a molecular weight about 441.404 g/mol. Folic acid has a melting point
of 482°F and its molecular formula is C19H19N7O6. It is hydrophilic and
slightly soluble in methanol, ethanol, and butanol-like organic solvent
(Fig. 3.9).
2.10.2 Sources
Dark leafy green vegetables like spinach, collard greens, turnip greens, mus-
tard greens, and romaine lettuce are among the most prevalent sources of
folic acid that are reported to have maximum folate amount [164]. Asparagus
had been reported to contain up to 262 μg of folic acid additionally it
fulfills the need of vitamin K, vitamin C, vitamin A, and manganese. Like-
wise, avocado/butter pea was reported to contain up to 110 μg of folate per
cup. Similarly, Brussels sprouts, besides being rich in vitamin C, vitamin K,
vitamin A, manganese, and potassium covering 25% of the daily requirement
of folic acid in one cup. Also, beans, peas, and lentils including pinto beans,
lima beans, green peas, black-eyed peas, and kidney beans are excellent
sources of folic acids [165].
O OH
O
OH
O N
N H O
NH N
H
NH2 N N Folic acid
Fig. 3.9 Structure of folic acid.

Folic acid, if chronically insufficient in humans (below the recommended
level of 400 μg per day) may come under critical increased risks of colo-
rectal, breast, ovarian, pancreas, brain, lung, cervical, and prostate cancers
[166–168]. Such patients are administered the drug methotrexate to inhibit
the production of the active form of tetrahydrofolate from the inactive
dihydrofolate and to alleviate its side effects like inflammation, folinic acid
is taken as a drug named leucovorin as a supplement to give cells dividing
less rapidly enough folate to maintain normal cell functions [169]. Folate
depletion has been shown to induce the upregulation of p16INK4A,
p21WAF1, and p53 tumor suppressor genes, which are involved in DNA
damage signaling, inhibition of cell-cycle progression through checkpoints,
and apoptosis [170–172]. Folic acid supplementation is reported to inhibit
the risk of colorectal cancer [173]. In a cohort study overall, the risk of
an adenomatous lesion was not increased (odds ratio 1.09, 95% confidence
interval 0.93–1.28) among patients who received folate supplementation
for up to 3 years; however, for those who received folate for over 3 years,
the risk of an adenomatous lesion was increased (odds ratio 1.35, 95%
confidence interval 1.06–1.70). The risk associated with treatment was
the highest for the occurrence of an advanced lesion (odds ratio 1.50,
95% confidence interval 1.06–2.10). There was no significant statistical
heterogeneity in the analyses [174]. However, some studies have reported
that there is no significant effect on the risk of colorectal cancer due to
the intake of folic acid or folate which may occur due to the differences
in bioavailability and metabolism of synthetic folic acid and natural dietary
folate as well as variation in the baseline characteristics of individuals
[175,176]. Additionally, various methods of folate status assessment might
be the main reasons for such deviations. Findings of such studies highlight
the importance of individualized folic acid supplement intake given the
fact that the beneficial effects of long-term folic acid supplementation are
not confirmed [177].

To evaluate the safety and effectiveness of folic acid addition for preventing
colorectal adenomas, clinical trials were done which included a double-
blind, placebo-controlled, 2-factor, phase 3 trial. The randomized clinical
trial was conducted at nine clinical centers between July 6, 1994, and
October 1, 2004. The study included 1021 subjects both men and women
with a recent history of colorectal adenomas and no previous invasive
large intestine carcinoma. During the first 3 years, 987 participants (96.7%)
underwent colonoscopic follow-up, and the incidence of at least 1 colorec-
tal adenoma was 44.1% for folic acid (n ¼ 221) and 42.4% for placebo
(n ¼ 206) (unadjusted risk ratio, 1.04; 95% confidence interval [CI],
0.90–1.20; P ¼ 0.58). Incidence of at least one advanced lesion was 11.4%
for folic acid (n ¼ 57) and 8.6% for placebo (n ¼ 42) (unadjusted, 1.32;
95% CI, 0.90–1.92; P ¼ 0.15). A total of 607 participants (59.5%) underwent
a second follow-up, and the incidence of at least one colorectal adenoma
was 41.9% for folic acid (n ¼ 127) and 37.2% for placebo (n ¼ 113)
(unadjusted, 1.13; 95% CI, 0.93–1.37; P ¼ 0.23); and incidence of at least
one advanced lesion was 11.6% for folic acid (n ¼ 35) and 6.9% for placebo
(n ¼ 21) (unadjusted, 1.67; 95% CI, 1.00–2.80; P ¼ 0.05). Folic acid was
associated with higher risks of having three or more adenomas and of
noncolorectal cancers. Sex, age, smoking, alcohol use, body mass index,
baseline plasma folate, or aspirin allocation played no crucial role in the
modification of results. They concluded that folic acid at 1 mg/day does
not reduce colorectal adenoma risk. Further research is needed to check
out the probability that folic acid addition might lessen the risk of colorectal
neoplasia.
2.11 Organosulfur compounds of garlic

Garlic, a plant of Allium genus, is known for its medicinal value for a long
period of time. Garlic is constituted of water, fiber, carbohydrates, proteins,
fat, and 33 sulfur-containing compounds [178]. Cutting or crushing of garlic
clove causes allinase-mediated conversion of S-allylcysteine sulfoxide to alli-
cin [178]. Decomposition of allicin yields diallyl sulfide (DAS), diallyl disul-
fide (DADS), and diallyl trisulfide (DATS). Garlic contains about 5–20 mg of
allicin per clove [178]. Garlic intake is associated with reduced risk of colo-
rectal cancer, myeloma, gastric cancer, lung cancer, and prostate cancer
[179]. Organosulfur compounds are the main ingredients of garlic respon-
sible for its beneficiary effects. DAS, DADS, and DATS are the organosulfur
compounds of garlic. DAS is reported to inhibit the cancers of mammary
gland, stomach, colon, and lung. Similarly, DADS is also found to be effec-
tive against colon, renal, skin, mammary glands, and esophagus cancers
[178]. Organosulfur compounds of garlic are reported to regulate several
pathways viz. cell cycle arrest, apoptosis, angiogenesis, invasion, and migra-
tion [179,180]. These properties make them suitable candidates for chemo-
prevention and therapeutic intervention. A few of the clinical trials have
been performed for these compounds in other cancers; however, clinical

studies are required for the documentation of their role in colorectal cancer.

DAS, DADS, and DATS are organosulfur compounds derived from garlic
and other Allium plants. They are nonpolar compounds, hence practically
insoluble in water, although miscible with alcohol, chloroform, ether,
and carbon tetrachloride (Fig. 3.10).
2.11.2 Sources
Plants of Allium genus are the major source of DAS, DADS, and DATS.
Crushing of garlic cloves releases these organosulfur compounds providing
therapeutic ability to garlic.

Organosulfur compounds of garlic mainly exhibit their effect through cell
cycle arrest and inducing apoptosis. DAS as one of the organosulfur com-
pounds of garlic that is known to have anticancer potential against colorectal
cancer. DAS is reported to decrease the colonic polyps and its multiplicity
in male C57BL/6J-ApcMin/+ mice. C57BL/6J-ApcMin/+ is an animal
model for FAP and sporadic colorectal cancer [181]. In azoxymethane-
induced preneoplasia in male Sprague–Dawley rats, DAS treatment reduces
the number of aberrant crypt foci by 43.65%. This study also demonstrate
the reduction in the expression of cyclooxygenase-2 and inducible nitric
oxide synthase and suggested the association between reduction of these
enzymes with the decreased number of aberrant crypt foci [182]. However,
a study also reported the increase in azoxymethane-induced aberrant crypt
H2C CH2
S
Diallyl sulfide
S CH2
H2C S
Diallyl disulfide
S S
H2C S CH2
Diallyl trisulfide
Fig. 3.10 Structure of DAS, DADS, and DATS.
foci in Fischer-344 rat colon when DAS was given in large doses through
gavage [183]. DAS is known to induce apoptosis and promotion of cell cycle
arrest considerably at G2/M phase in human colon cancer cells. It also causes
increased ROS and decreased cell proliferation in colon cancer cells [184].
DADS prevents the colitis-induced colorectal cancer in the mouse model
via inhibiting the GSK-3β. DADS also prevents the nuclear translocation
of NF-κB and reduces the expression of COX-2 in both in vitro and in vivo
scenarios. NF-κB and COX-2 contribute to tumorigenesis and the reduction
in the expression of NF-κB and COX-2 is found to be GSK-3β dependent
[185]. DADS also suppressed the growth of xenograft from a well-known
colon cancer cell line in nude mice [186]. DADS is also reported to cause
G2/M phase cell cycle arrest like DAS in human colon cancer cell lines
[187]. This cell cycle arrest was associated with decreases in PCNA, p53,
and cyclin B1 [188,189]. DATS has the capability to disturb the microtubule
assembly and thus causes G2/M cell cycle arrest in colon cancer cells. It has
also been shown that alkenyl groups in trisulfides are responsible for the
disassembly of microtubules as they interact with the sulfyhydryl groups in
cysteine residues of microtubule proteins [190]. In human colon cancer cell
lines HCT-15 and DLD-1, DATS treatment causes the G2/M phase arrest
and activation of caspase-3, leading to apoptotic cell death [191]. Further-
more, DATS induces apoptosis in human primary colorectal cancer cells
via upregulating the levels of cytochrome c, Apaf-1, AIF, and caspase-3 and
caspase-9 [192]. Intraperitoneal injection of DATS reduces the tumor volume
and weight in balb/c mice injected with CT26 cancer cells [193]. DAS,
DADS, and DATS, all three compounds are recognized to migration and
invasion of human colon cancer cell line colo 205. The mechanism involved
in inhibition is the downregulation of PI3K, Ras, MEKK3, MKK7, ERK1/2,
JNK1/2, and p38 which ultimately causes the inhibition of MMP2, 7, and 9.
Among these three organosulfur compounds, DATS is the most potent in
inhibiting migration and invasion in colon cancer cells [194]. Further, several
epidemiological studies have associated the chemopreventive effect of garlic
with reduced risk of colorectal cancer.

A study conducted on adults aged from 35 to 64 in Linqu County, Shandong
Province, China with baseline endoscopies was given placebo of aged garlic
extract and steamed garlic oil for 7.3 years documented that long-term usage
of garlic extract causes no significant effect on prevalence of precancerous
gastric lesions [195]. Furthermore, a follow-up study for 14.7 years on
mortality of gastric cancer after garlic treatment of 7.3 years states that garlic
supplement showed no statistically significant effect of mortality [196]. Aged
garlic extracts caused enhanced NK cell activity in patients with nonoperable
colorectal cancer but no other significant effect was observed [197]. In
another study conducted on 37 patients (19 in supplement group and
18 in control group) with colorectal adenoma showed that aged garlic
extracts reduced the size and number of colon adenomas after 12 months
of treatment [198]. Synthetic allitridium (100 mg) given along with selenium
(100 μg) orally every alternate day prevented the gastric in men in 288 nat-
ural villages of seven communities in Qixia County, Shandong Province,
China [199].
2.12 Genistein
Genistein (GEN) [5,7-dihydroxy-3-(4-hydroxyphenyl)chromen-4-one] is
one of the most abundant isoflavones that is found in a wide variety of
plant-derived foods especially in soybeans and soy-based foods. GEN derives
its chemical name from dyer’s greenweed (Genista tinctoria) from which it
was first isolated in the late 19th century. It possess structural similarity with
human estrogen so it is also called a phytoestrogen. It is the hydrolysis prod-
uct of glycoside genistin. A number of studies have used in vitro models and
revealed the anticancer effects of the molecule [200]. There are several
reports that claim that due to the presence of GEN, consumption of soybean
reduces the risk of development of breast, prostate, and colon cancer [201].
GEN mainly targets the estrogen receptors (ERs), protein tyrosine kinases
(PTKs), and mammalian DNA topoisomerase II [202,203]. Early reports
have identified GEN as a potent inhibitor of PTK which acts on the EGFR.
Erlotinib which is one of the first personalized chemotherapeutic drugs also
inhibits EGFR and hence the possible interaction of GEN with this drug was
studied. In this study, GEN was found to antagonize the cytostatic effect of
the drug on epithelial A431 cells by modulating erlotinib-mediated EGFR
inhibition [204]. Its combined effect with other chemotherapeutic agents
(5-fluorouracil and platinum compounds) was also studied and it has been
found to synergistically augment growth inhibition in chemoresistant cancer
cells [205]. Furthermore, GEN possess low bioavailability in plasma hence it
is necessary to study the potential chemopreventive effects of GEN at
low doses.

It is the aglycone of the heteroside genistin representing a major active com-
pound of Glycine max (Fabaceae) having structural similarity with estradiol
OH O
OH O
OH
Genestein
Fig. 3.11 Structure of genistein.
leading to its binding ability to ERs [202]. It is a water-insoluble, pale

yellow-colored dendritic needle-like powder with chemical formula
C5H10O5 and melting point being 297–298°C (Fig. 3.11).
2.12.2 Sources
The main source of GEN is the glucoside genistin. In stomach and intestine
by the action of acid hydrolysis and bacterial enzymes it is released from
genistin. The best known sources of GEN are soy-based foods such as
soycheese and beverages such as soy milk. Other legumes, such as chickpeas,
contain small amounts of GEN. In mature soybeans, GEN has been shown
to range from 5.6 to 276 mg/100 g [206]. In addition to GEN, soy foods
contain another major isoflavone, daidzein, which differs from GEN by
the lack of the hydroxyl group and glycitein, an O-methylated isoflavone.
The average dietary isoflavone intake in Asian countries ranges between
25 and 50 mg/day, whereas in Western countries the estimated intake is
as low as 2 mg/day [206]. This is largely because a number of traditional
Asian food recipes use soybean as major ingredient. Moreover, legumes
are considered the second most significant source of GEN, at
0.2–0.6 mg/100 g, present together with daidzein [207]. The seeds of some
legumes belonging to genus Lupinus are widely cultivated because of their
high nutritional value similar to soya bean. Other principal legumes that
contain significant amounts of GEN, though less than soybeans are chick
peas and broad beans. The concentration of GEN in fruit, vegetables, and
nuts can vary considerably upto a range from 0.03 to 0.2 mg/100 g [208].
However, it has been reported upto a concentration of 4.4 mg/100 g in some
native cherries of Hungarian origin [206]. Fermentation of soybean products
result in an increase of GEN and related aglycones content [209]. Through
genetic manipulation, it is also possible to obtain GEN from nonlegume
plant sources, such as rice. In a study, it was shown that cloning of the gene
of isoflavone synthase enzyme from Sinpaldalkong II, a GEN-rich Korean
soybean cultivar, had resulted in a 30-fold increase in GEN content of rice

[210]. With the recognition of medicinal value of GEN, soy-based products
have recently gained popularity in Europe and the United States.

Many reports claim that consumption of soy has been found to reduce colon
cancer risk in human and animal studies [211]. Among 10 epidemiological
studies on association between total isoflavone intake and colorectal
cancer risk among healthy subjects, seven studies [212–218] reported that
people with higher intake of soya bean-based diet had a significant decreased
risk of developing colorectal cancer, while three studies [219–221] showed
no significant association. However, consumption of fermented soy paste
which possesses high salt content was found to be associated with
high risk of colorectal cancer in men, though limited evidence suggests
the role of high salt intake in colorectal carcinogenesis. Moreover, it was
observed that, with respect to phytoestrogen intake, enzymes [cytochrome
P450 (CYP), catechol O-methyl transferase (COMT), GSTs, UDP-
glucuronosyltransferase (UGT)] that encode polymorphic genes involved
in the metabolism of phytoestrogens were not subjected to modifications
[215]. These findings that suggest the reduction of colorectal cancer risk
on increasing phytoestrogen intake are important because dietary habits
are modifiable.
Numerous in vitro studies have shown anticancer properties of GEN
against colorectal cancer, and the mechanisms whereby it exerts anticancer
effects have been widely investigated which include its apoptotic, anti-
angiogenic, antimetastatic, antiproliferative, and antiinvasive mode of
action. Kim et al. showed that in HT-29 cells GEN efficiently suppresses
cell growth by attenuating the activity of the PI3K/Akt pathway [222],
which has a critical role in the regulation of colon cancer progression. In
addition, GEN also affects the expression of estrogen receptor-beta (ERs)
and tumor suppressor genes [223,224]. Furthermore, it can also inhibit
uncontrolled cell growth by attenuating Wingless and integration 1
(Wnt)/β catenin signaling cascade which is another critical pathway in colon
cancer development in human colorectal adenocarcinoma cell line, DLD-1
[225] by interfering with promoter methylation of WNT5a gene. It also
activate sFRP2, another WNT antagonist by demethylating CpG islands
within the gene [226]. In particular, GEN-enhanced transcriptional activity
of the Wnt-signaling pathway antagonist, Dickkopf-related protein 1
(DKK1), through the induction of histone acetylation at the promoter
region in an SW480 human colon cancer cell line at an early stage of colon
cancer development [226]. Zhang et al. elucidated the anticarcinogenic
mechanism of GEN on HCT-116 and SW-480 human colon cancer cells
[227]. These findings revealed that GEN (2.5–100 μM for 48 h) showed
growth inhibitory activity and promoted apoptosis in a dose-dependent
manner. GEN causes p53-dependent G2/M phase cell cycle arrest in colon
cancer cells. Moreover, GEN activates ATM/p53, p21, and GADD45a and
downregulates the expression of CDK1 and cdc25A, which are mainly
involved in the regulation of cell cycle and apoptosis [227]. GEN treatment
in human colonic cancer HT-29 cells has revealed that GEN promoted
FOXO3 activity and inhibited EGF-induced proliferation in HT-29 cells.
Moreover, the increased FOXO3 activity facilitates the expression of p27,
which leads to cell cycle arrest [224].
Epigenetic studies suggested that in growth and progression of colon
cancer, loss of normal cell cycle regulation and increase in cell proliferation
are most important prerequisite factors [228]. Some recent studies emphasize
on the pivotal role of regulatory factors such as ERKs, tumor suppressor
gene p53, and cell cycle regulators in the progression of colon cancer
[229]. The preventive role of GEN on development of early colon neoplasia
was confirmed by Zhang et al. in an in vivo study on male Sprague–Dawley
rats that used azoxymethane as colon cancer inducer which showed that rats
fed with GEN from gestation to 13 weeks of age resulted in downregulated
expression of Wnt5a, Sfrp1, Sfrp2, Sfrp5, as well as WNT target genes viz.
Cyclin D1 and c-myc and caused a reduction in total aberrant crypts. [230].

Due to in vivo and in vitro findings, GEN is expected to produce positive
outcomes regarding its use in treatment of metastatic colorectal cancer.
Hence, a phase I/II pilot study checking the hypothesis that combination
of GEN with regimens of FOLFOX or FOLFOX-Avastin regimens will
reduce chemotherapy resistance is currently enrolling participants [231].
3. CONCLUSION AND FUTURE PERSPECTIVES

The growing interest toward the use of natural products as chemopre-
ventive agents brings out the importance of dietary phytochemicals as
effective therapy in various cancers. This chapter documented the chemo-
preventive potential of various dietary phytochemicals in colorectal cancer.
The medicinal values of these phytochemicals have been known for many
years. In addition, a number of in vitro, in vivo, and epidemiological

studies proved their ability to be effective against colorectal cancer. Consid-
ering the literature data, these dietary phytochemicals affect multiple signal-
ing pathways in order to achieve the desired results. Although several studies
have identified the chemopreventive and anticancerous role of dietary
phytochemicals in colorectal cancer, nonetheless, their practical applications
require the translation of these studies in clinical trials. Only a limited num-
ber of clinical trials have been performed on these dietary phytochemicals
against colorectal cancer, despite of their chemopreventive potential. This
chapter points out the need of establishing the association between human
colorectal cancer patients and dietary phytochemicals, thus validating
the efficacy of dietary phytochemicals against colorectal cancer. This will
provide a safe and cost-effective alternative in the prevention and therapy
of colorectal cancer.
CONFLICT OF INTEREST
Authors declare no conflict of interest.
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Chemopreventive Role of Dietary Phytochemicals in Colorectal Cancer

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Chemopreventive Role of Dietary Phytochemicals in Colorectal Cancer

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CHAPTER THREE

Advances in Molecular Toxicology, Volume 12 Copyright # 2018 Elsevier B.V. 69

Bioflavonoid Extract, Citrus Flavones, and Citrus Flavonoids. Quercetin is

2.1.1 Chemical composition and molecular structure

a melting point of 601–603°F with molecular formula as C15H10O7. Quer-

concentrations of quercetin cause nerve cell damage with equal chances of

2.1.3 Molecular targets

2.1.4 Clinical trials

2.2.1 Chemical composition and molecular structure

2.2.3 Molecular targets

proteosomal degradation of β-catenin, and disruption of β-catenin/TCF-4

2.2.4 Clinical trials

2.3.1 Chemical composition and molecular structure

2.3.3 Molecular targets

deacetylation are one of the important mechanisms involved in gene silenc-

2.3.4 Clinical trials

2.4.1 Chemical composition and molecular structure

Fig. 3.4 Structure of resveratrol.

2.4.3 Molecular targets

homolog (PTEN) and decreased the phosphorylation of Akt1/2. The exog-

2.4.4 Clinical trials

of various tumors such as prostate, cervical, ovarian, and lung cancer. It

2.5.1 Chemical composition and molecular structure

2.5.3 Molecular targets

• SFN changes gene activation/deactivation. It causes demethylation,

2.5.4 Clinical trials

2.6.1 Chemical composition and molecular structure

Fig. 3.6 Structure of [6]-gingerol.

2.6.3 Molecular target

2.6.4 Clinical trials

2.7.1 Chemical composition and molecular structure

2.7.3 Molecular targets

2.7.4 Clinical trials

2.8 Inositol hexaphosphate

natural antioxidant and possibly as a neurotransmitter [127]. IP6 is available

2.8.1 Chemical composition and molecular structure

2.8.3 Molecular targets

proliferation and cell survival and induced apoptosis in human colorectal

2.8.4 Clinical trials

2.9.1 Chemical composition and molecular structure

2.9.3 Molecular targets

blocks proliferation of cancer cells by arresting them in various phases of

2.9.4 Clinical trial

2.10 Folic acid

can have significant negative effects on unborn children’s brain develop-

2.10.1 Chemical composition and molecular structure

2.10.3 Molecular targets

2.10.4 Clinical trials

2.11 Organosulfur compounds of garlic

been performed for these compounds in other cancers; however, clinical

2.11.1 Chemical composition and molecular structure

2.11.3 Molecular targets

2.11.4 Clinical trials

2.12.1 Chemical composition and molecular structure

leading to its binding ability to ERs [202]. It is a water-insoluble, pale

soybean cultivar, had resulted in a 30-fold increase in GEN content of rice

2.12.3 Molecular targets

2.12.4 Clinical trials

3. CONCLUSION AND FUTURE PERSPECTIVES

years. In addition, a number of in vitro, in vivo, and epidemiological

[51] J. Kiani, F. Sajedi, S.A. Nasrollahi, F. Esna-Ashari, A randomized clinical trial of

supplementation elevates circulating insulin-like growth factor-binding protein-1

[151] K.I. Priyadarsini, Photophysics, photochemistry and photobiology of curcumin:

[203] T. Akiyama, J. Ishida, S. Nakagawa, H. Ogawara, S. Watanabe, N. Itoh, M. Shibuya,