1. 1
Phytochemicals and Cancer
An essay Submitted to
Department of Zoology,
Faculty of Science,
Alexandria University
In partial Fulfillments of the Requirements
For
The Award of the Degree of B.Sc
In Molecular Biology
By
Amr El-shayeb Nada Saad Samira Hamed
Maha Saad Tasneem Mohamed Saly Ali
Supervised by
Dr. Mahmoud I.M. Khalil
Lecturer of Molecular Biology,
Zoology Department,
Faculty of Science,
Alexandria University
2016
4. 4
6.1.10 Ellagitannin ............................................................................................................49
7. Breast cancer......................................................................................................................51
7.1 Breast cancer Chemoprevention by Using Phytochemicals ..................................51
7.1.1 Epigallocatechin gallate (EGCG) ...........................................................................51
7.1.2 Curcumin...................................................................................................................53
7.1.3 Genistein....................................................................................................................54
7.1.4 Blueberry.................................................................................................................55
7.1.5 Green tea ...................................................................................................................55
7.1.6 Resveratrol ...............................................................................................................55
7.1.7 Mangostin..................................................................................................................55
7.1.8 Fig ...............................................................................................................................56
7.1.9 Gingerol .....................................................................................................................56
7.1.10 Kaempferol.............................................................................................................56
7.1.11 Lycopene .................................................................................................................56
7.1.12 PEITC........................................................................................................................56
7.1.13 Rosmarinic acid.....................................................................................................56
7.1.14 Triterpenoids.........................................................................................................56
7.1.15 Vitamin D ................................................................................................................57
7.1.16 Sulforaphane..........................................................................................................57
7.1.17 Piperine...................................................................................................................57
7.1.18 Rottlerin..................................................................................................................57
7.1.19 SPARSTOLONIN B ..................................................................................................57
8. Esophageal cancer.............................................................................................................58
8.1 ESOPHAGEAL CANCER Chemoprevention by Using Phytochemicals........................58
8.1.1 Isothiocyanates........................................................................................................58
8.1.2 EGCG ...........................................................................................................................58
8.1.3 Curcumin...................................................................................................................59
8.1.4 Resveratrol ...............................................................................................................59
8.1.5 Luteolin......................................................................................................................60
8.1.6 Dried strawberry.....................................................................................................60
8.1.7 Black raspberry .......................................................................................................60
9. Oral cancer..........................................................................................................................60
9.1 oral carcinogenesis Chemoprevention by Using Phytochemicals............................60
5. 5
9.1.1 Garlic C.......................................................................................................................61
9.1.2 Flavonoids.................................................................................................................61
9.1.3 Luteolin......................................................................................................................61
9.1.4 Astaxanthin...............................................................................................................61
9.1.5 Limonoids..................................................................................................................61
9.1.6 Spirulina fusiformis ................................................................................................62
9.1.7 Neem and turmeric .................................................................................................62
9.1.8 Azadirachta indica leaf...........................................................................................62
9.1.9 Green tea phenols....................................................................................................62
9.1.10 Ferulic acid .............................................................................................................62
9.1.11 Black raspberries..................................................................................................62
9.1.12 Red wines................................................................................................................62
9.1.13 Procatechuic acid and costunolid......................................................................62
9.1.14 ocimum sanctum ...................................................................................................62
9.1.15 Protocatechiuc acid of mangostin......................................................................63
9.1.16 Ferrulic acid of mangostin...................................................................................63
9.1.17 Freeze-dried strawberry .....................................................................................63
10. Stomach cancer................................................................................................................65
10.1 Stomach cancer Chemoprevention by Using Phytochemicals................................65
10.1.1 Prunes......................................................................................................................65
10.1.2 Mangostin ...............................................................................................................65
10.1.3 capsaicin .................................................................................................................66
11.Intestinal cancer...............................................................................................................66
11.1 Intestinal cancer Chemoprevention by Using Phytochemicals..............................66
11.1.1 Dried bilberry ........................................................................................................66
11.1.2 Apricot.....................................................................................................................66
11.1.3 Resveratrol.............................................................................................................66
11.1.4 Lycopene .................................................................................................................66
12. Colorectal Cancer.............................................................................................................67
12.1 Colorectal cancer chemoprevention by using phytochemicals..............................67
12.1.1 Prunes......................................................................................................................67
12.1.2 Longan seed extract..............................................................................................67
12.1.3 EGCG.........................................................................................................................67
6. 6
12.1.4 Luteolin ...................................................................................................................68
12.1.5 Phenolic compounds of virgin olive oil.............................................................68
12.1.6 Sasa quelpaertensis extract (SQE).....................................................................68
12.1.7 Curcumin.................................................................................................................68
12.1.8 Apple polysaccharides .........................................................................................70
12.1.7 Mushroom glucans................................................................................................72
12.1.8 aris saponins ..........................................................................................................72
12.1.9 insenosides.............................................................................................................73
12.1.10 resveratrol (trans-3,5,40-trihydroxystilbene).............................................74
12.1.11 quercetin (3,3’,4’,5,7-pentahydroxyflavone) ................................................75
13. Gastric Cancer ..................................................................................................................76
13.1 Gastric cancer chemoprevention by using phytochemicals ...................................77
13.1.1 curcumin.................................................................................................................77
13.1.2 Resveratrol.............................................................................................................78
13.1.3 sulforaphane ..........................................................................................................79
13.1.4 Plumbagin (PLB) ...................................................................................................79
14. Tongue cancer..................................................................................................................82
14.1 Tongue cancer chemoprevention by using phytochemicals...................................82
14.1.1 Ferrulic acid ...........................................................................................................82
14.1.2 protocatechuic acid of mangostin......................................................................82
14.1.3 Plumbagin (PLB) ...................................................................................................82
15. Gallbladder cancer ..........................................................................................................83
15.1 Gallbladder cancer chemoprevention by using phytochemicals...........................83
15.1.1 Capsaicin.................................................................................................................83
16. Leukemia...........................................................................................................................83
16.1 Leukemia cancer chemoprevention by using phytochemicals...............................84
16.1.1 curcumin.................................................................................................................84
16.1.2 Allyl isothiocyanate ..............................................................................................84
16.1.3 phenylhexyl isothiocyanate................................................................................84
16.1.4 Quercetin ................................................................................................................84
17. Lymphocytic leukemia ....................................................................................................84
17.1 Lymphocytic leukemia chemoprevention by using phytochemicals.....................84
17.1.1 Genistein: ................................................................................................................84
7. 7
17.1.2 Rosmarinic acid:....................................................................................................85
18. Myelogenous leukemia....................................................................................................85
18.1 Myelogenous leukemia chemoprevention by using phytochemicals ....................85
18.1.1 Camptothecin (CPT)..............................................................................................85
18.1.2 resveratrol..............................................................................................................85
18.1.3 Sulforaphane (SFN)...............................................................................................85
18.1.4 APOPTOSIS..............................................................................................................85
19. Cervical cancer.................................................................................................................86
19.1.1 Curcumin.................................................................................................................86
19.1.2 Genistein .................................................................................................................86
20. Lung cancer.......................................................................................................................87
20.1 Lung cancer Chemoprevention by Using Phytochemicals ......................................87
20.1.1 EGCG.........................................................................................................................87
20.1.2 Curcumin.................................................................................................................87
20.1.3 Crocetin ...................................................................................................................87
20.1.4 Fisetin ......................................................................................................................87
20.1.5 Kaempferol.............................................................................................................88
20.1.6 PEITC........................................................................................................................88
20.1.7 Lycopene .................................................................................................................88
20.1.8 Luteolin ...................................................................................................................88
20.2 Mechanisms involved in cancer chemoprevention and treatment: ......................88
Hedgehog signaling pathway: .............................................................................................88
21. human malignant neuroblastoma................................................................................90
21.1 Human malignant neuroblastoma Chemoprevention by UsingPhytochemicals 91
21.1.1 B82((1E,4E)-1,5-bis(5-bromo-2-ethoxyphenyl)penta-1,4-dien-3-
one):curcumin derivative................................................................................................91
21.1.2 Pomegranate..........................................................................................................91
21.1.3 Plumbagin (PLB) ...................................................................................................91
22. ovarian cancer .................................................................................................................91
22.1 Ovarian cancer Chemoprevention by Using Phytochemicals.................................92
22.1.1 Genistein .................................................................................................................92
22.1.2 Piceatannol.............................................................................................................92
22.1.3 Hirsutenone............................................................................................................93
8. 8
22.1.4 Citrus flavonoid tangeritin..................................................................................93
23. Endometrial cancer .........................................................................................................93
23.1 Endometrial cancer chemoprevention by using phytochemicals..........................94
23.1.1 Genistein .................................................................................................................94
24. Neuroplasma cancer .......................................................................................................94
24.1 Neuroplasma Cancer Chemoprevention by Using Phytochemicals.......................95
24.1.1 β-Carotene ..............................................................................................................95
Oxidative stress and cancer..................................................................................................99
25. References.......................................................................................................................100
9. 9
Figures blueprint:
pageNameNumber
13Skin carcinogenesis.1
25the mechanism of action of phytochemicals on the
migration and invasion potential of melanoma cells.
2
37Epigenetic pathways affected by plant phytochemicals in colon
cancer cells.
3
41Epigenetic pathways affected by plant phytochemicals in
prostate cancer cells.
4
41Hedgehog signaling pathway5
50Mi MicroRNA regulation by dietary agents6
54Modulatory effects of EGCG, curcumin, and genistein.7
78H. pylori8
89Hedgehog signaling pathway9
92A hypothetical model of chemoresistance in human ovarian
cancer cells.
10
96The Kelch-like ECH-associated protein 1 (Keap1)-
nuclear factor E2-related factor 2 (Nrf2)-
antioxidant response elements (ARE) signaling pathway.
11
10. 10
LIST OF TABLES
Number Table page
1 Flavonoids 26
2 Reported onco preventive agents in Oral carcinogenesis 63
3 Reported onco preventive agents in Gastric carcinogenesis 81
4 Summary of studies using Nrf2 inhibitor 98
11. 11
1. Introduction
single phytochemicals and enriched natural extracts able to interfere with self-renewal and
drug resistance pathways in CSCs have been identified. This is a milestone in the
improvement of cancer treatment because the synthetic anticancer drugs that are currently
used are often highly toxic for healthy organs and weakens the patient’s immune system.
These phytochemical compounds or extracts, which show low levels of toxicity for normal
cells can be used against cancers. For example: Curcumin, isolated from the rhizomes of
the plant Curcuma longa, is the most important yellow pigment present in turmeric, a
popular spice. Curcumin has been shown to interrupt the carcinogenetic process by
inhibiting the initiation step or suppressing the promotion and progression stages in animal
models. It increases the efficacy of many anticancer drugs including 5-fluorouracil, vinca
alkaloid, vinorelbine, cisplatin and gemcitabine.
2. Skin cancer
Skin cancer is still a major cause of morbidity and mortality worldwide. These days cancer
chemoprevention is recognized as the most hopeful and novel approach to prevent, inhibit,
or reverse the processes of carcinogenesis by intervention with natural products.
Phytochemicals have antioxidant, anti-mutagenic, anti-carcinogenic, and carcinogen
detoxification capabilities thereby considered as efficient chemopreventive agents.
Considerable efforts have been done to identify the phytochemicals which may possibly act
on one or several molecular targets that modulate cellular processes such as inflammation,
immunity, cell cycle progression, and apoptosis. Till date several phytochemicals in the light
of chemoprevention have been studied by using suitable skin carcinogenic in vitro and in vivo
models and proven as beneficial for prevention of skin cancer.
Primary chemoprevention refers to the use of an agent that prevents carcinogenesis in a
healthy patient who would have otherwise gone onto develop a cancer.
12. 12
Secondary chemoprevention refers to preventing the full transition to malignancy in a patient
that already has developed a pre-malignant lesion.
Tertiary chemoprevention refers to the use of an agent that prevents a second primary cancer
or metastasis in a patient who has had a first malignancy that had been treated.
2.1 Skin Cancer Chemoprevention by Using Phytochemicals
Cancer chemoprevention by using phytochemicals to prevent or suppress the process of
carcinogenesis is still an area of active investigation. Epidemiological studies have provided
persuasive evidence that phytochemicals can prevent this process. Laboratory researches
have further established the effectiveness of a number of bioactive natural components that
have the capacity to check cancer andother chronic diseases. Skin carcinogenesis, a
multistep process, allows for the possible curative intervention; thus, cancer chemoprevention
is a very promising approach to successfully achieve this goal. Lots of compounds belonging
to diverse chemical classes have been identified and proved as potential skin cancer
chemopreventive agents. Fruits, vegetables, seeds, flowers, leaves, and bark represent huge
reservoirs of phytochemicals such as polyphenols, flavonoids, isoflavonoids, proantho-
cyanidins, phytoalexins, anthocyanidins, and carotenoids. Many of them have already been
studied extensively for their potential anticancer or chemopreventive efficacy and some of
them are at clinics now
13. 13
Fig .1. Skin cancer develops in series of events in multiple steps; however in most of studies, is
progressed in three key steps, that is, initiation, promotion, and progression, and many phytochemicals
could prevent the abrupt changes in each of the steps to reverse the process of developing skin cancer.
2.1.1 Grapes
Are one of the most widely consumed fruits in the world and its seeds are the rich source of
proanthocyanidins which are well known to exert anti-inflammatory, antioxidant, antiarthritic,
and antiallergic activities, prevent skin aging, and inhibit UV radiation-induced peroxidation
activity and DNA repair mechanisms .
Grape seed proanthocyanidins (GSPs) are promising bioactive phytomolecules that
have shown anti-skin carcinogenic effects and reveal no apparent toxicity in vivo.
Intake of GSPs resulted in prevention against UVB-induced complete initiation and
promotion stages of photocarcinogenesis in terms of tumor incidence, multiplicity,
and size.
14. 14
Treatment of GSP significantly inhibited UVB or Fe3+ induced lipid peroxidation,
thus suggesting the strong antioxidant mechanism of photoprotection offered by
GSPs.
GSPs have the ability to protect the skin from the adverse effects of UVB radiation
via modulation of the MAPK and NF-𝜅B pathways.
GSPs inhibited UVB induced infiltration of pro-inflammatory leukocytes and the
levels of myeloperoxidase (MPO), Cox-2, PGE2, CyclinD1, and PCNA in the skin
and skin tumors compared to non-GSPs-treated UVB irradiated counterpart .
GSPs reduced the UVB-induced increase in immunosuppressive cytokine
interleukin (IL-) 10 in skin and draining lymph nodes.
In contrast, GSPs enhanced the production of immune stimulatory cytokine IL-12 in
the draining lymph nodes.
Results suggest that GSPs prevent UVB-induced immunosuppression through DNA
repair dependent functional activation of dendritic cells and re-expression of tumor
suppressor genes RASSF1A, p16INK4a, andCip1/p21.
Skin painted with GSPs before UV radiation showed fewer sunburn cells and mutant
p53-positive epidermal cells and more Langerhans cells compared with skin treated
with UV radiation only.
Researchers observed that in vitro treatment of NHEK with GSPs resulted in the
prevention of UVB-induced depletion of antioxidant defense enzymes (GPx,
catalase, SOD, and GSH) and H2O2 production. Further, GSPs inhibit H2O2-
induced phosphorylation of ERK1/2, JNK, and p38 proteins.
GSPs inhibited skin cancer cell proliferation which was mediated through the
inhibition of cyclin-dependent kinases (Cdk) Cdk2, Cdk4, and Cdk6 and cyclin D1,
D2, and E, increase in cyclin dependent kinase inhibitors (Cdki), Cip1/p21 and
Kip1/p27, and enhance binding of Cdki-Cdk.
GSPs have the ability to inhibit highly metastasis-specific human melanoma cells
invasion/migration by targeting the endogenous Cox-2 expression and PGE2
production and reversingthe process of epithelial-to-mesenchymal transition.
15. 15
Treatment of skin cancer cells with GSPs decreased the levels of global DNA
methylation, 5-methylcytosine, DNA methyltransferase (DNMT) activity, and mRNA
and protein levels of DNMT1, DNMT3a, and DNMT3b in treated cells.
Treatment of melanoma cells with GSPs resulted in the suppression of
mesenchymal biomarkers, such as vimentin, fibronectin and N-cadherin, while
restoring the levels of epithelial biomarkers such as, E-cadherin, desmoglein 2,
keratin-8 and -18 in melanoma cells .
2.1.2 Tea Polyphenols
Tea has been consumed as a popular beverage worldwide and skin photoprotection
by green tea polyphenols (GTPs) has been widely investigated.
Oral feeding of a GTP or water extract of green tea affords protection against UVB
radiation induced inflammatory responses and carcinogenesis in animals.
Further elevated levels of nucleotide excision repair (NER) genes show a novel
mechanism by which drinking GTPs prevents UV-induced immunosuppression.
Prevention of photocarcinogenesis by GTPs is mediated through IL-12-dependent
DNA repair and a subsequent reduction in skin inflammation.
Thearubigins or polymeric black tea polyphenols (PBPs) have been shown to
possess antitumor-promoting effects in two-stage skin carcinogenesis.
PBPs pretreatment decreased TPA induced translocation of PKC isozymes (𝛼, 𝛽, 𝜂,
𝛾, and𝜀) from cytosol to membrane and PKC phosphorylation.
These anti-promoting effects of PBPs are due to modulation of TPA-induced PI3K-
mediated signal transduction .PBPs decreased TPA-induced cell proliferation by
decreasing the activation of signaling kinases (c-Jun, ERK, p38, and Akt),
transcription factors (AP-1 and NF-𝜅B), and inflammatory protein (Cox2).
Recent findings suggest that GTP reduce skin cancer cells survival by influencing
polycomb group proteins (PcG-) mediated epigenetic regulatory mechanism.
A population-based, case-control study conducted on 450 individuals showed that
tea concentration specifically black tea, brewing time, and beverage temperature
has major influences on the potential protective effects of tea in relation to skin
squamous cell carcinoma.
16. 16
Studies indicate that tea extracts are effective in reducing UVB- and PUVA-
mediated DNA damage and expression of early response genes and early
inflammatory changes in human skin.
Epigallocatechin-3-gallate (EGCG) is considered to be the major and most effective
component of tea catechins.
EGCG has been found to inhibit TPA-induced migration of melanoma cells.
TPA promotes COX-2 expression and subsequently enhances cell migration.
the inhibitory effect of EGCG on melanoma cell migration was mediated through an
inhibitory effect on the PGE2 receptors.
Thus, EGCG acts by decreasing the expression of both COX-2 and the PGE2
receptors,thereby affecting the levels of both the ligand (PGE2) and receptor (EP).
treatment of melanoma cells with EGCG resulted in suppression of mesenchymal
biomarkers while restoring the levels of epithelial biomarkers. These observations
suggest that EGCG has the ability to reverse EMT and that this may be one of the
possible mechanisms through which EGCG reduces the invasiveness of melanoma
cells and inhibits migration of melanoma cells.
EGCG inhibited invasion and metastasis of melanoma cells by increasing the
expression of E-cadherin .
2.1.3 Pomegranate fruit
Pomegranate fruit extract (PFE) possesses antitumor promoting effects in a mouse
model of skin carcinogenesis induced by chemicals as well as UV radiations.
Application of PFE prior to TPA on CD-1 mouse skin afforded significant inhibition in
TPA-induced increase skin edema and hyperplasia, epidermal ODC activity, and
protein expression of ODC and Cox-2.
Further, PFE resulted in inhibition of TPA-induced activation of ERK1/2, p38,
JNK1/2, NF-B, and IKKproteins.
Feeding of PFE for 14 days inhibited UVB induced skin edema, hyperplasia,
infiltration of leukocytes, lipid peroxidation, H2O2, ODC activity, and expression of
ODC, Cox-2, PCNA iNOS, cyclin D1 and MMP-2, MMP3 and MMP-9proteins in
SKH-1 mice.
17. 17
PFE supplemented diet also enhanced the repair of UVB-mediated formation of
both CPDs and 8-oxodG and these events were associated with PFE induced
inhibition of MAPK and NF-𝜅B path- ways.
Treatment of NHEK cells with PFE prior to UVA exposure resulted in a dose-
dependent inhibition of UVA-mediated phosphorylation of STAT3 at Tyr705, AKT at
Ser473, ERK1/2 and mTOR at Thr2448, and p70S6K at Thr421/Ser424. Further,
PFE pretreatment of NHEK was found to increase the G1 phase cell-cycle arrest
and the expression of Bax and Bad with down regulation of Bcl-xL .
PFE was effective in protecting UV induced cell death and likely related to a
reduced activation of NF-𝜅B, a down regulation of caspase3, and an increased
G0/G1phase.
The effects of pomegranate-derived products, POMx juice, POMx extract, and
pomegranate oil (POMo), against UVB-mediated damage using reconstituted
human skin were determined.
Pretreatment of epiderm resulted in inhibition of UVB-induced CPD, 8-OHdG,
protein oxidation, and expression of collagenase (MMP-1), gelatinase (MMP-2,
MMP-9), stromelysin (MMP-3), marilysin (MMP-7), elastase (MMP12), tropoelastin,
c-Fos, c-Jun, and PCNA. Collectively, these results suggest that all three
pomegranate-derived products may be useful against UVB-induced damage to
human skin.
2.1.4 Resveratrol
Diet containing resveratrol shown to inhibit DMBA/croton oil-induced skin papillomas
correlated with prolonging tumor latency period and inhibiting croton oil-induced
epidermal ODC activities.
Topical doses of resveratrol either pre- or post- UVB irradiation has been tested for
its efficacy against the development of skin cancer.
Topical doses of resveratrol to SKH-1 hairless mice significantly inhibited single or
multiple doses of UVB mediated phototoxicity as evidenced by reversal of bi-fold
skin thickness, skin edema, and hyperplasia.
18. 18
Similarly, in mouse skin DMBA-TPA model, treatment with resveratrol doses
showed up to a 98% reduction in skin tumors and 60% reduction in papillomas.
Resveratrol doses in SKH-1 mice skin decreased the expression of cyclins D1 and
D2, Cdk 2, 4, and 6, and PCNA and increased expression of p21WAF1/CIP.
Further, activation of p53 and Bax along with reduced expression of anti-apoptotic
proteins (survivin and Bcl-2) and markers of tumor promotion (Cox-2andODC) was
observed .
Findings suggest that resveratrol targets IKK in blocking TPA-induced NF-B
activation and Cox-2 expression in mouse skin.
Chemopreventive properties of resveratrol in DMBA induced mouse skin tumors
were also reflected by delay in onset of tumorigenesis, reduced cumulative number
of tumors, and reduction in tumor volume.
DMBA suppressed (p53, Bax, and Apaf-1) and increased (Bcl-2 and survivin)
expression of proteins were modulated by resveratrol treatment.
Resveratrol supplementation resulted in regulation of PI3K/AKT pathway .
Toll-like receptors (TLR4) are an important mediator of resveratrol induced
chemoprevention in DMBA skin tumorigenesis.
Resveratrol combinations with ellagic acid, grape seed extract, and other
phytochemicals are very potent inhibitors of DMBA induced skin tumorgenesis .
In the normal skin keratinocytes, resveratrol doses blocked UVB-mediated activation
of NF-B, phosphorylation and degradation of IB, and activation of IKK .
In vitro data demonstrate that resveratrol inducesG1-phase cell-cycle arrest
accompanied by p21WAF1/CIP1 induction and inhibition of MEK1, ERK1/and AP-1
signaling in A431 cells.
Resveratrol doses arbitrated TGF-2 down regulation; this event appears to occur
through the inhibition of both TGF-2/Smad dependent and independent pathways
and thus suppressed the invasiveness of A431 cells Through the establishment of
A431 cells xenografts in nude mice, noted that the anticancer mechanism of
resveratrol was through inducing apoptosis as it altered p53 and survivin
expression.
19. 19
2.1.5 Silymarin
Silymarin and its major constituent silibinin, isolated from the medicinal plant
Silybum marianum.
Recently, these orally active flavonoids have also been interrogated for their
significant anticancer effects in a variety of in vitro and in vivo systems of
carcinomas including skin.
Topical treatment of silymarin inhibited DMBA-initiated and several tumor promoters
like TPA, mezerein, benzoyal peroxide, and okadaic acid induced mouse skin
carcinogenesis .
Mechanism of such effects involves inhibition of promoter-induced edema,
hyperplasia, cell proliferation, and oxidative stress.
Application of silymarin prior to TPA resulted in a great protection against tumor
promotion in DMBA initiated mouse skin and was apparent in terms of reduction in
tumor incidence, multiplicity, and volume .
Silymarin feeding significantly inhibited tumor growth, decreased proliferation index,
increased apoptotic index, and decreased phospho-ERK1/2.
Results from another short term experiments suggested that silymarin application
resulted in inhibition of UVB-caused sunburn and apoptotic cell formation, skin
edema, depletion of catalase activity, and induction of Cox and ODC activities and
ODC mRNA expression .
Preventive efficacy of silibinin against UVB induced photocarcinogenesis involves
the inhibition of DNA synthesis, cell proliferation, and cell cycle progression and an
induction of apoptosis.
Dietary feeding of silibinin to mice before UVB irradiation affords strong protection
against UV-induced damage in epidermis via decrease in thymine dimer positive
cells and increase in p53-p21/Cip1 proteins expression.
Silibinin also showed a strong phosphorylation of ERK1/2, JNK1/2, and p38 MAPK
but inhibited Akt .
The inhibitory effect of silymarin, in spite of whether it is given before or after UV
irradiation, was of similar degree.
20. 20
Treatment of skin cancer A431 cells by silibinin resulted in cell growth inhibition and
death, which was found to be coupled with a decrease in MAPK/ERK1/2 levels and
an up regulation of SAPK/JNK1/2 and p38 MAPK activation .
Studies suggest that both silymarin and silibinin are equally beneficial in the removal
of UVB and UVA damaged skin cells.
Following the doses of silibinin the expression of Fas-associating protein with death
domain was totally abolished and was associated with inhibition of cleavage of
procaspase-8, decreased release of cytochrome c, and reduced expression of
inhibitor of caspase-activated DNase and PARP.
Silymarin application extensively reduced formation of DNA single strand breaks,
ROS production, lipid peroxidation, GSH depletion, and caspase-3 activity in
irradiated cells.
silymarin inhibits the invasion or cell migration of melanoma cells, and that this is
associated with the inactivation of β-catenin signaling pathway. It has been shown
that phosphorylation of β-catenin at critical target residues such as at Ser45,
Ser33/37 and Thr41 by GSK-3β and CK1α within the cytosolic destruction complex
leads to degradation of β- catenin and thus reduces its nuclear accumulation.
In this study, the treatment of melanoma cells with silymarin enhances the
expression of GSK-3β and CK1α, and β- catenin is phosphorylated at critical target
residues. This then lead to degradation of β- catenin within the degradation complex
resulting in its reduced nuclear accumulation.
A major regulator of β-catenin stability and activity is β-TrCP.
2.1.6 Lupeol
A phytosterol and triterpene, is widely found in edible fruits and vegetables.
Effects of lupeol on TPA- induced markers of skin tumor promotion were evaluated.
Topical application of lupeol prior to TPA onto the skin of CD-1 mice afforded
significant inhibition against TPA-mediated increase in skin edema and hyperplasia,
epidermal ODC activity, and protein expression of ODC, Cox-2, and nitric oxide
synthase (NOSs).
21. 21
The animals pretreated with lupeol showed significantly reduced tumor incidence,
tumor burden, and delay in the latency period for tumor appearance.
Lupeol doses resulted in the inhibition of TPA-induced activation of PI3K,
phosphorylation of Akt, activation of NF-B and, IKK and degradation and
phosphorylation of IB.
Both pre- and post-treatment of lupeol showed significant preventive effects in
DMBA induced DNA strand breaks in dose and time dependent manner.
Cell-cycle analysis showed that lupeol-induced G2/M-phase arrest mediated
through inhibition of the cyclin-B-regulated signaling pathway involving p53,
p21/WAF1, cdc25C, cdc2, and cyclin-B gene .
Lupeol induced apoptosis was associated with upregulation of bax and caspase-3
genes and downregulation of bcl-2 and survivin genes.
In vitro apoptosis inducing effects of lupeol were studied in A431 skin carcinoma
cells.
Lupeol-induced apoptosis was associated with caspase dependent mitochondrial
cell death pathway through activation of Bax, caspases, and Apaf1, decrease in Bcl-
2, and subsequent cleavage of PARP.
lupeol inhibits the migration of melanoma cells in vitro by targeting the actin
cytoskeleton of the cells.
2.1.7 Curcurmin
Anti-carcinogenic and chemo-preventive effects of curcurmin are attributed to its
effect on several apoptotic molecules, transcription factors, and cellular signaling
pathways.
The inhibitory effects of curcurmin were credited to its capacity to scavenge UVA
induced ROS by several researchers.
In vitro doses of curcumin have been reported to prevent UV induced apoptotic
changes in human skin cancer (A431) cells, accompanied with release of
cytochrome c and activation caspase-3.
UV induced ROS generation was also abolished by curcurmin.
22. 22
In HaCaT cells curcurmin and UVR synergistically induced apoptotic cell death
through activation of caspases 8, 3, and 9 and release of cytochrome c.
Treatment with curcumin strongly inhibited COX-2 mRNA and protein expression in
UVB irradiated HaCaT cell.
Curcurmin inhibited UVB-induced AP-1 transcriptional activation and p38/JNK
signaling pathway .
curcumin inhibited the invasive potential of melanoma cells by inhibiting the
expression levels of MMPs. Curcumin also has been shown to inhibit osteopontin-
induced cell migration and NF-κB-mediated MMP-2 activation.
2.1.8 Ginger
Inhibit several cancers including skin cancer.
A study suggested that [6]-gingerol (oleoresin from the root of ginger) could be an
effective therapeutic agent providing protection against UVB-induced skin disorders.
Topical doses of gingerol prior to UVB irradiation in SKH-1 mice inhibited the
induction of COX-2 mRNA and protein, as well as NF-B translocation.
In JB6 cells [6]-gingerol block EGF-induced cell transformation and inhibited EGF-
induced AP-1 DNA binding activity.
In vitro, pretreatment with gingerol reduced UVB-induced intracellular ROS levels,
activation of caspases (3, 8, -9), and Fas expression.
It also reduced UVR-induced expression and transactivation of COX-2.
Translocation of NF-B from cytosol to nucleus in HaCaT cells was inhibited by
[6]-gingerol via suppression of IB phosphorylation.
2.1.9 Soybean
Genistein, the most abundant isoflavone of the soy derived phytoestrogen
compounds, is a potent antioxidant and inhibitor of tyrosine kinase activity.
Soybean containing diet is associated with cancer chemoprevention.
Genistein exerts its anti-initiational and promotional effects on skin carcinogenesis
probably through blockage of DNA adduct formation and inhibition of oxidative
(H2O2) and inflammatory (ODC activity) events in mouse skin.
23. 23
Pretreatment of animals with genistein 1 h prior to UVB exposure significantly
inhibited UVB-induced H2O2 and MDA in skin and 8-OHdG in epidermis as well as
internal organs.
The inhibitory effect of soy isoflavones on TPA-induced cutaneous inflammation
includes inhibition of pro-inflammatory cytokines, attenuation of oxidative stress, and
activation of NF-B and expression of Cox-2.
Genistein 1h prior to UVB radiation inhibited UV-induced DNA damage and dose
dependently preserved cutaneous proliferation and repair mechanics in skin
samples.
Genistein inhibits invasive and metastatic potential of B16-BL6 melanoma cells by
targeting protein tyrosine kinase.
Genistein might repair extracellular matrix signaling and subsequently results in
prevention of cancer cell invasion.
2.1.10 Norathyriol
Topical application of norathyriol mangiferin (0.5 or 1 mg) significantly suppressed
UVB-induced formation of skin papillomas by blocking the activation of NF-kB and
activator protein-1 (AP-1) in SKH-1 hairless mice.
2.1.11 Black raspberry
Topical application of standardized black raspberry extract (500 μg) significantly
reduced ultraviolet B (UVB) radiation-induced skin carcinogenesis in female SKH-1
hairless mice.
2.1.12 Prunes
Topical application of chlorogenic acid of prunes (10 μmol) suppressed TPA-
induced papilloma formation in CD-1 mouse skin.
2.1.13 Figs
The latex of figs is used as treatment of skin tumor.
24. 24
2.1.14 Limonoids
were found to inhibit both initiation and promotion phases of carcinogenesis in skin
of mice.
2.1.15 Berberine
Treatment of the melanoma cells with berberine inhibited the migration of cells in a
dose-dependent manner and this was found to be associated with inhibition of
COX-2 expression and PGE2 production.
Treatment of melanoma cells with an EP4 agonist enhanced cell migration and EP4
agonist-induced cell migration was inhibited by the treatment of cells with berberine
further suggesting that berberine inhibits melanoma cancer cell migration by
targeting PGE2 receptor.
Berberine also reduced the activity of NF-κB and the levels of other proteins of NF-
κB family in melanoma cells.
25. 25
Figure.2. Schematic diagram summarizes the mechanism of action of phytochemicals on the migration and
invasion potential of melanoma cells. Phytochemicals may target the endogenous expression of COX-2 and
production of PGE2 which leads to degradation of β- catenin. Degradation of β-catenin leads to inhibition of
migration of melanoma cells, (MMP) matrix metalloproteinases.
28. 28
3. Pancreatic cancer
Pancreatic cancer is the fifth leading cause of cancer death in Europe for men and
women combined. Cases are almost always diagnosed at an advanced stage, and with
few treatment options available, the resulting 5-year survival rates are among the lowest
(<5%) of any cancer. The best option for treatment is still surgery, but this is available
only for <20% of cases with smaller lesions at diagnosis and those that have not spread
beyond the pancreas. A history of tobacco smoking, excess central adiposity, and long-
standing diabetes are common preventable causes of pancreatic cancer, but these
factors are not present in the majority of cases. An important aim of the EPIC Pancreatic
Cancer Working Group is therefore to evaluate environmental and genetic risk factors
for pancreatic cancer, and to identify pre-diagnostic biomarkers for early detection of this
aggressive cancer.
3.1 pancreatic Cancer Chemoprevention by Using Phytochemicals
3.1.1 Vitamin A
The most biologically active form of Vitamin A, retinoic acid (RA), acts as a tumor
suppressor in pancreatic cancer.
3.1.2 Curcumin
A bioactive ingredient in turmeric, possesses anti-inflammatory, antioxidant, and
anti-carcinogenic properties.
An initial study evaluated miRNA profiles in curcumin-treated pancreatic cancer
cells, with evidence for upregulation of 11 miRNAs and down regulation of 18
miRNAs. MiR-22 was upregulated upon curcumin treatment, and the predicted
targets were ERα and transcription factor Sp1.
MiR-196 was significantly downregulated after curcumin treatment.
Curcumin and its CDF (diflourinated-curcumin) analog, alone or in combination,
29. 29
attenuated expression of miR-200 and miR-21 leading to induction of tumor
suppressor PTEN.
The CDF analog inhibited sphere forming ability (pancreatospheres) by
attenuating cancer stem cell markers and other signaling molecules, via changes
in miR-21 and miR-200.
Many studies have addressed NFkB as a prime target of curcumin in various
cancer models. demonstrated that NFkB and IKK are constitutively active in
pancreatic cancer cell lines and inhibition of these molecules by curcumin was
associated with growth suppressive activity. Interestingly, NFkB downstream
effectors such as COX-2, PGE2 and IL-8 were also down-regulated by curcumin
treatment.
These effector molecules are known to be closely associated with growth and
invasiveness of pancreatic cancer.
Curcumin treatment enhanced the IL-8 receptors CXCR1 and CXCR2 on the cell
surface; however, exogenous addition of IL-8 had no effect on IL-8 receptors.
These observations suggest that curcumin inhibits the growth of the pancreatic
cancer cells by inhibiting NFkB and IL-8 receptor internalization.
Single treatment of BxPC-3 cells with 2.5 μM curcumin for 24 h caused significant
G2/M cell cycle arrest and apoptosis.The G2/M cell cycle arrest by curcumin was
associated with DNA damage and the activation (phosphorylation) of ATM and
Chk1.
Scientists demonstrated that curcumin down-regulates the expression of p50 and
p65 along with the down-regulation of Specificity Proteins (Sp1, Sp3 and Sp4),
which are known to be constitutively active in pancreatic cancer.
3.1.3 Isoflavones
Soy isoflavones, including genistein have been implicated in anti-carcinogenic
mechanisms.
Isoflavone treatment increased both miR-200 and let-7 family miRNAs by
modulating EMT transcription factors, such as vimentin, slug, and ZEB1.
30. 30
Genistein also upregulated miR-146a in pancreatic cancer cells, inhibiting their
invasive potential by downregulating EGFR, NFκB, IRAK-1, and MTA-2.
Genistein is found to have potent antitumor effects and is found to augment the
efficacy of cisplatin in pancreatic cancer by down-regulating Akt expression.
3.1.4 Indoles
The major compound found in vivo in human plasma is 3, 3′-diindolylmethane
(DIM) which has been examined for chemoprotective mechanisms in pancreatic
cancer.
Along with soy isoflavones, DIM influenced EMT via differentially expressed
miRNAs in pancreatic cancer cells.
DIM also induced the expression of miR-146a, which resulted in reduced
pancreatic cancer cell invasion.
3.1.5 Benzyl isothiocyanate (BITC)
Is quite effective in suppressing pancreatic tumor growth by inhibiting various key
signaling pathways, such as AKT, STAT3, HDAC, NFKB.
BITC induces apoptosis in pancreatic cancer cells in a dose- and time-
dependent manner. BITC reduced NFKB expression in BxPC-3 cells but not in
Capan-2 cells, indicating that BITC acts differentially in different cell lines.
BITC also significantly induced ROS generation in pancreatic cancer cells.
Eventually, ROS generation led to DNA damage as demonstrated by increased
phosphorylation of H2A.X and G2/M cell cycle arrest through ChK2
phosphorylation.
Tumor growth in BITC-fed mice was substantially reduced as compared to
control mice. Tumors appeared to grow more slowly in BITC-fed mice as
compared with control mice. For example, six weeks after treatment with 12
μmol BITC, the average tumor volume in control mice was about 1.92 fold
higher than that in BITC-treated mice, indicating potential anticancer activity.
31. 31
3.1.6 capsaicin
Studies from laboratory support the theory that capsaicin can suppress caerulin-
induced carcinogenesis in transgenic mice and suppresses pancreatic tumor
growth both in vitro and in vivo.
Four-week old LSL-KrasG12D/Pdx1-Cre mice developed chromic pancreatitis
and PanIN lesions after a single dose of caerulin. However, mice fed a daily diet
including 10 or 20 p.p.m of capsaicin for eight weeks significantly reduced the
severity of chronic pancreatitis and PanIN lesions. Results from our laboratory
further show that capsaicin dose-dependently induces mitochondrial-dependent
apoptosis in ASPC-1 and BxPC-3 pancreatic cancer cells.
Capsaicin failed to cause any ROS generation or induce apoptosis in normal
pancreatic epithelial (HPDE-6) cells, indicating the selectivity of capsaicin towards
cancer cells.
3.1.7 Green tea
catechins are known to inhibit the growth of various cancers by targeting multiple
signaling pathway,however few of these targets such as HSP90, FAK and STAT3
were evaluated in pancreatic cancer.
GTE altered 32 protein expressions in HPAF-II cells, which were involved in drug
resistance, motility and metabolism.
Particularly, GTE altered the expression of heat-shock proteins such as Hsp-90,
Hsp-75 and Hsp-27.
In addition, GTE inhibited the phosphorylation of AKT and p53, leading to
apoptosis and suppression of pancreatic tumor growth.
Green tea polyphenols were quite effective in suppressing angiogenesis and
metastasis of pancreatic cancer.
32. 32
3.1.8 Resveratrol
Is shown to target various signaling pathways in pancreatic cancer such as
hedgehog, FOXO, leukotriene A4 hydrolase, macrophage inhibitory cytokine-1,
Src and STAT3.
Resveratrol induces apoptosis in pancreatic cancer cells through mitochondrial-
dependent pathway,resveratrol exhibited lower toxicity to normal pancreatic cells.
Resveratrol treated PanC-1 and ASPC-1 pancreatic cancer cells showed growth
inhibition and cell cycle arrest in G0/G1 phase.
Resveratrol has an anticancer effect due to inhibition of oncogenic miR-21.
3.1.9 Quercetin
when used with catechins, was shown to enhance the expression of let-7 in
pancreatic cancer cells followed by K-ras inhibition and reduction of the
advancement of pancreatic cancer.
3.1.10 Crocetin
affects the growth of cancer cells by inhibiting nucleic acid synthesis, enhancing
anti-oxidative system, inducing apoptosis and hindering growth factor signaling
pathways.
3.1.11 Gingerol
has been studied for its anti-cancerous effects for the tumor.
3.1.12 Triterpenoids
exert their chemopreventive and anti-cancer activities via enhancing apoptosis,
NO, stimulating DR4, DR5, caspase-3/7, caspase 8, Bax, JNK, MAPK, p38,
decreasing phosphor-STAT3, PARP cleavage, suppressing COX-2, IL-1β, NF-κB,
33. 33
IKKα/β, cyclin D1, cyclin A, cyclin B1, ERα protein and mRNA, HER2
phosphorylation, caveolin-1, Akt, JAK1, STAT 3, Bcl2, c-Jun, cFos, JNK, mTOR,
blocking cell cycle at G1, G1-S, G2-M, etc.
3.1.13 Vitamin E
inhibits AKT and ERK activation and suppress pancreatic cancer cell proliferation by
suppressing the ErbB2 pathway.
3.1.14 Luteolin
Is a flavonoid abundant in several green vegetables, such as cabbage, spinach and
peppers.
Indeed, Luteolin has been found to increase the efficacy of gemcitabine against
pancreatic cancer.
3.1.15 ulforaphane
A recent study showed the effectiveness of sulforaphane extracted from
broccoli in inducing apoptosis in pancreatic CSCs by interfering with NF-κB
anti- apoptotic signaling.
4.Colon cancer
Colon cancer represents 57% of colorectal cancers for men and 63% for
women.Much research has been conducted within the EPIC CRC Working Group to
explore associations with dietary and lifestyle factors using the detailed dietary and
lifestyle data of EPIC along with biological samples for biomarker and genetic
analyses. These studies suggest a multifactorial etiology with compelling evidence
for a strong promotive or predisposing role of obesity , metabolic syndrome and its
associated factors, namely hyperinsulinaemia, hyperglycaemia , dyslipidaemia ,
inflammation , and oxidative stress. These factors appear to be, in large part,
34. 34
metabolic consequences of dietary habits characterized by high intakes of
red/processed meats and low intakes of dietary fibre , fish, nuts, seeds , and fruits
and vegetables . The Working Group has also identified smoking, heavy alcohol
consumption, and low body vitamin D levels as important CRC risk factors.
4.1 Colon Cancer Chemoprevention by Using Phytochemicals
4.1.1 Fatty Acids
Protective roles of Polyunsaturated fatty acids (PUFAs) have been documented in
colon cancer.
A recent study evaluated the chemopreventive effects of PUFAs on azoxymethane-
induced colon cancer in rats.
Carcinogen treatment resulted in significant downregulation of five known tumor
suppressor miRNAs.
Based on transfection experiments in vitro, tumor suppressor PTEN was found to be
targeted by oncogenic miR-21 in human colon cancer cells.
Similarly, beta site amyloid precursor protein-cleaving enzyme (BACE-1) was
reported as a functional target of tumor suppressor miR-107 and was downregulated
in carcinogen-induced tumor tissues versus normal colonic mucosa.
4.1.2 Resveratrol
Several ―signature‖ miRNAs for colon cancer such as miR-21, miR-196a, miR-25,
miR-17, and miR-92a-2 were significantly downregulated by resveratrol.
Simultaneously, miR-663- mediated regulation of Dicer, PDCD4, PTEN, and TGFβ
signaling through the SMAD promoter was observed.
A resveratrol-induced, miR-663-dependent effect was observed in monocytic cells
used to evaluate adaptive and innate immune responses.
35. 35
MiR-663 was reported to target Activator Protein-1 (AP-1) through the Jun signaling
pathway.
Resveratrol also impaired the upregulation of oncogenic miR-155 in a miR-663-
dependent manner.
4.1.3 Catechins
Chemopreventive effects of epigallocatechin-3-gallate (EGCG) and other tea
catechins have been described in preclinical models for all major sites of cancer
development, including colon cancer.
4.1.4 Indoles
Di-indolyl methane (DIM) which has been examined for chemoprotective
mechanisms in colon cancer.
4.1.5 Black raspberry
Administration of freeze-dried black raspberry extract (5 or 10%) in diet for 7-14 days
reduced dextran sulphate sodium (DSS)-induced colitis, a condition that often leads
to the development of colon cancer, in C57BL/6 mice.
4.1.6 Mangiferin
Dietary administration of mangiferin (0.1%) for 4 weeks reduced the incidence and
the multiplicity of colon tumor formation in AOM-treated male F344 rats.
4.1.7 Raisins
suppressed cell proliferation with significant reduction in p65, COX-2, and interleukin
(IL)-8 levels in human colon cancer HT29 cells.
4.1.8 Grapefruit
Limonin and obacunone isolated from grapefruit have been shown to decrease the
incidence of colonic adenocarcinomas induced by AOM in male F344 rats.
36. 36
Oral administration of grapefruit juice (0.8, 4.1, and 8.2 μl/g) for seven weeks dose-
dependently suppressed the number of CF-1 lon A female mouse coCF induced by
AOM.
4.1.9 Curcumin
A dose-dependent decrease in miR-21 promoter activity and expression following
curcumin treatment was inferred due to reduced binding of AP-1 to the promoter and
induction of the tumor suppressor gene,programmed cell death protein 4 (Pdcd4),
which is a miR-21 target and is overexpressed in RKO and HCT116 human colon
cancer cells, promoting invasion and metastasis.
4.1.10 Sulforaphane (SFN )
In human colon cancer CaCo-2 cells, Sulforaphane (SFN ) treatment resulted in the
down-regulation of DNMT1 activity.
37. 37
Fig. 3. Epigenetic pathways affected by plant phytochemicals. Numerous pathways
are deregulated in colon cancer cells. Major epigenetic mechanisms that regulate
gene expression are DNA methylation, alterations in the chromatin structure by post
translational modification of histones, and miRNAs which can either degrade mRNAs
38. 38
or modulate their translation process.
● Curcumin inhibited the transcriptional regulation of oncogenic miR-21 causing
inhibition of growth, invasion, and metastasis.
Treatment with a curcumin analogue, difluorinated curcumin, restored the
expression of miR-34a and miR-34c which has a role in Proliferation, anchorage-
independent growth, drug resistance and Apoptosis.
Modified citrus pectin and quercetin chalcone (flavonoids) resulted in decreased
tumor size.
Resveratrol treatment upregulated miR-141 and resulted in a significant reduction of
invasiveness.
Resveratrol also inhibited the cell growth and induced apoptosis through
upregulating miR-34a expression.
Apigenin from parsley induces apoptosis in human colon cancer cells
Crocetin affects the growth of cancer cells by inhibiting nucleic acid synthesis,
enhancing anti-oxidative system, inducing apoptosis and hindering growth factor
signaling pathways.
Cyanidins from grapes inhibits cell proliferation, and iNOS and COX-2 gene
expression.
EGCG nterfered with EGFR signaling, and inhibited hepatocyte growth factor-
induced cell proliferation.
Fisetin has anti-carcinogenesis effects in HCT-116 human colon cancer cells
Genistein is thought to contribute to reduced colonic inflammation in 2,4,6-
trinitrobenzenesulfonic acid (TNBS)-induced colitis
39. 39
Gingerol: has been studied for its anticancerous effects for the tumor
Lycopene from tomato possesses inhibitory effects on colon cancer
Resveratrol: inhibits metastasis via reducing hypoxia inducible factor-1α and MMP-9
expression
rosmarinic acid:inhibits migration, adhesion, and invasion dose dependently
sulforaphane: induced cytotoxicity and lysosome- and mitochondria-dependent cell
death in colon cancer cells with deleted p53.
5.prostate cancer
Worldwide, prostate cancer is the fourth most common cancer in both sexes combined
and the second most common cancer in men. The only well-established risk factor for
prostate cancer is male sex, increasing age, positive family history, and a number of
genetic markers. In EPIC, a wide range of potential risk factors has been examined,
including lifestyle, dietary and hormonal, and genetic factors. The most important finding
so far is that the risk of prostate cancer is positively associated with serum
concenttrations of insulin-like growth factor-I (IGF-I). The group has also shown that
serum levels of IGF-I are positively associated with the protein content of the diet, and
has shown a modest positive association of dairy protein consumption with prostate
cancer risk. Studies of other candidate risk factors have produced largely null results, for
example for selenium, vitamin D, carotenoids, and tocopherols. Current research
projects have been designed to improve our understanding of the relationship of diet,
particularly dietary protein, with metabolomic profile in blood samples and prostate
cancer risk.
40. 40
5.1 Prostate cancer chemoprevention by using phytochemicals
5.1.1 Vitamin A
The most biologically active form of Vitamin A, retinoic acid (RA), acts as a tumor
suppressor in prostate cancer.
5.1.2 Catechins
Chemopreventive effects of epigallocatechin-3-gallate (EGCG) and other tea
catechins have been described in preclinical models for all major sites of cancer
development, including prostate cancer.
5.1.3 Isoflavones
Soy isoflavones, including genistein have been implicated in anti-carcinogenic
mechanisms.
5.1.4 Genistein
Is currently undergoing clinical trials for chemopreventive and therapeutic
effects in prostate cancer.
Study examined mini chromosome maintenance (MCM) genes involved in DNA
replication, which are commonly dysregulated in cancer cells.
In prostate cancer cells treated with genistein, MCM2 was downregulated by miR-
1296.
Genistein induced the expression of miR-1296 by up to five-fold, along with cell
cycle arrest in S-phase.
5.1.5 Indoles
The major compound found in vivo in human plasma is 3, 3′-diindolylmethane
(DIM) which has been examined for chemoprotective mechanisms in prostate
cancer.
Treatment with ursolic acid of persimmon (i.p. 200 mg/kg body weight) for 6
weeks suppressed the growth of human prostate cancer cells.
41. 41
Administration of α-mangostin (100 mg/kg body weight) by oral gavage
significantly inhibited the growth of 22Rv1 prostate cancer cells.
Oral pomegranate juice supplementation significantly suppressed prostate tumor
growth by inhibition of Akt/ mTOR pathways in TRAMP model.
Nrf2, a master regulator of cellular antioxidant defense systems, has been shown
to be epigenetically silenced during the progression of prostate tumorigenesis in
TRAMP mice.
Curcumin treatment of TRAMP C1 cells led to demethylation of the first 5CpGs
within the promoter region of the Nrf2 gene and re-expression of both Nrf2mRNA
and protein, and enhanced expression of a major downstream target gene
NQO1,responsible for the chemopreventive effect of curcumin
In human prostate cancer PC-3, DU-145, and LNCaP cell lines, in which
promoters of GSTP1 and EPHB2 are strongly methylated, treatment with soy
isoflavones genistein and daidzein caused demethylation of these promoters
and increased protein expression.
Genistein treatment significantly decreased promoter methylation, reactivated
BTG3 expression, increased levels of acetylated histone H3 and H4, H3K4me2,
H3K4me3, and RNA polymerase II, decreased DNA methyltransferase and
methyl-binding domain protein 2 activity, and increased HAT activity in prostate
cancer cells.
Genistein also possesses histone modifying activity and was shown to induce the
expression of p21/waf1/cip1 and p16INK4a tumor suppressor genes in human
prostate cancer cells by epigenetic mechanisms involving active chromatin
modification, including up regulation of the expression of HATs.
In vivo studies using animal cancer models have shown that lycopene can inhibit
prostate cancer.
42. 42
Fig. 4. Epigenetic pathways affected by plant phytochemicals. Numerous pathways are deregulated in
prostate cancer cells. Major epigenetic mechanisms that regulate gene expression are DNA
methylation, alterations in the chromatin structure by post translational modification of histones, and
miRNAs which can either degrade mRNAs or modulate their translation process.
43. 43
Curcumin treatment also restored expression of Neurog1, another cancer-related
gene silenced by promoter hypermethylation, in prostate cancer LNCaP cells, by
demethylating the first 14 CpG sites within its promoter; curcumin also
significantly decreased MeCP2 binding to the promoter of Neurog1.
Treatment with curcumin increased HDAC1, 4, 5, and 8 levels, but decreased
HDAC3. HDAC activity H3K27me3 levels, binding at the Neurog1 promoter
region was decreased after treatment, suggesting ability of curcumin to re-
express yet another gene silenced by epigenetic modification in cancer.
Isoflavone efficiently demethylated the promoter region of miR-29a and miR-1256
and subsequently upregulated their expression.
Genistein inhibited the migration and invasion of PC3 and DU145 cells through
down regulating oncogenic miR-151.
(DIM) / (I3C) from Brassica vegetables demonstrated exceptional anti-cancer
effects against hormone responsive cancers like prostate.
Lycopene from tomato was found to inhibit human cancer cell proliferation, and to
suppress insulin-like growth factor-Istimulated growth.
PEITC from cruciferous vegetable induced apoptosis mediated by the activation
of caspase-8, -9, and -3-dependent pathways.
Sulforaphane has significant inhibitory effects on prostate tumorigenesis.
.Low diet vitamin D or VDR (vitamin D receptor) deletion provided a prostate
environment that is permissive to early pro-carcinogenic events that enhance
prostate cancer risk.
EGCG is the most abundant polyphenol in green tea. It is able to induce the
caspase 8 dependent apoptosis in tumor cell cultures and animal
models.EGCG’s has an ability to synergistically increase the efficacy of
conventional drugs against prostate carcinoma.
Lycopene is a natural antioxidant that gives tomatoes, watermelon, and pink
grapefruit their red color. Epidemiological studies have shown that high intake of
lycopene-containing vegetables is inversely associated with the incidence of
certain types of cancer, including cancer of the prostate. A combination of vitamin
45. 45
finger protein GLI1; GSK3beta, glycogen synthase kinase 3 beta; LEF1/TCF1, lymphoid enhancer-
binding factor 1/T-cell specific factor 1; MYCN, N-myc proto-oncogene protein; PTCH1, Patched 1; SHH,
Sonic hedgehog; SMO, Smoothened; SUFU, Suppressor of Fused; WNT, Wingless.
The hedgehog signaling pathway provides instructions to the cells to be
developed properly into different parts based on the different concentrations of
hedgehog signaling proteins at a specific time.
Activation of the hedgehog pathway has been implicated in the cancers in
various organs, including brain, lung, prostate, and skin
It is shown that abnormal activation of the pathway may give rise to cancer
through transformation of adult stem cells into cancer stem cells and researcher
are studying specific inhibitors of hedgehog signaling in an effort to devise an
efficient therapy for a wide range of cancer.
In vertebrate cells, sonic hedgehog (SHH) contains a ~20 kDa N-terminal
signaling domain ( SHH-N) and a ~25 kDa C-terminal domain with unknown
signaling role. When SHH binds to the Patched-1 (PTCH1) receptor, the
downstream protein Smoothened (SMO) inhibited by PTCH1 is activated and
leads to the activation of the GLI transcription factors.
The activated GLI accumulates in the nucleus and controls the transcription of
hedgehog target genes. Activation of the hedgehog pathway leads to the
increases of angiogenic factors, cyclins, anti-apoptotic genes and the decreases
of apoptotic genes, such as Fas.
Sarkar, Marini, and Gupta recently reviewed Hedgehog signaling as a target
pathway for cancer treatment. Thus far, modulating SMO, PTCH and Gli3 are the
approaches to regulate the hedgehog pathway in the search of hedgehog
antagonist for solid tumor, and Gli1 siRNA has been used to inhibit cell growth
and promote apoptosis in prostate cancer.
46. 46
5.1.6 Geraniol
is an effective plant-based mosquito repellant present in a number of essential
oils including citronella.
This acyclic monoterpene has been shown to independently induce apoptosis
and autophagy via the inhibition of Akt and the activation of AMPK. It has also
been demonstrated that the combined effect of Akt inhibition and AMPK signaling
is more potent at suppressing prostate cancer cell growth than either action alone
5.1.7 Rottlerin
a natural plant polyphenol compound derived from the kamala tree (Mallotus
philippinensis). Rottlerin possesses a cytotoxic effect against a wide spectrum of
tumors and cancer cells including those which are apoptotic competent and
apoptotic resistant. Despite its well documented anti-cancer properties, yet the
exact mechanisms of rottlerin's anti-cancer effects are not known.
Targeting survival pathway
a)Suppressing the two targets of both Wnt/β-catenin and mTORC1 signaling,
which are cyclin D1 and and survivin.
b)Inhibiting Wnt/β-catenin and mTORC1 signaling promoted LRP6 degradation
and the low density lipoprotein receptor-related protein-6.
5.1.8 EF24 (diphenyl difluoroketone): curcumin derivative
potently inhibits tumorigenesis in a mouse model of prostate cancer by
downregulating NF-𝜅B and miRNA-21 expression.
5.1.9 curcumin
A polyphenol natural compound extracted from the plant Curcuma longa L
Rapidly inhibits the phosphorylation of mTOR and its downstream effector
molecules such as p70S6K and 4E-BP1, indicating that curcumin may
executeits anticancer activity primarily by blocking mTOR-mediated signalling
pathways
47. 47
suppresses murine double minute 2 (MDM2) oncogene expression through the
erythroblastosis virus transcription factor 2 (EST2) by modulating
PI3K/mTOR/ETS2 signalling pathway
5.1.10 Reservatrol
a polyphenolic compound present in grapes and red wine with potential anti-
inflammatory and anticancer properties
inhibits PI3K/Akt signalling pathway and induces apoptosis
5.1.11 Genistein
the predominant isoflavone found in soybean found to have potent anti-tumor
effects.
6. Liver cancer
Primary liver cancer, and in particular the most common form of it, hepatocellular
carcinoma, is one of the most lethal cancers and the third most common cause of
cancer-related deaths worldwide. It shares one major common characteristic with lung
cancer: it is difficult to treat, but it is largely preventable. Most relevant cohort studies
have been undertaken in Asia, where this malignancy is relatively common. Few such
studies, however, have been conducted in Europe or North America,where the risk
profile of the disease is likely to be different from the one prevailing in Asia or Africa. An
important aim of the EPIC Liver Cancer Working Group is therefore to identify the
dominant risk factors in a European population and quantify their contribution to the
burden of the disease in Europe.
48. 48
6.1 hepatocellular carcinoma Chemoprevention by Using Phytochemicals
6.1.1 Mangiferin
It induced the activities of several antioxidant and detoxification enzymes in liver of
tumor bearing mice.
mangosteen fruit, attenuated the liver metastasis of implanted B16/F10 melanoma
cells by blocking the activity of MMP-2 and NF-kB in C57/BL6 mice.
6.1.2 Apricot
Dietary administration of sun-dried apricot powder (15 or 30%) protected ethanol-
induced liver damage in rats by activating the cytoprotective enzymes such as
superoxide dismutase, quinone reductase, GST and gluthathione peroxidase,
indicating its potential to prevent liver carcinogenesis.
6.1.3 Isothiocyanate
Treatment of hepatocellular carcinoma SMMC-7721 cells with phenylhexyl
isothiocyanate inhibited cell growth and induced apoptosis, which correlated with
increased acetylation of Histone H3 and H4, increased methylation of H3K4, and
decreased methylation of H3K9.
6.1.4 Curcumin
has pro-apoptotic, anti-inflammatory and antiangiogenic actions both in vitro and in
vivo, and has been shown to have a protective effect in mouse models of aflatoxin-
induced hepatocarcinogenesis.
Although no clinical trials have been performed with curcumin in patients with HCC.
6.1.5 Resveratrol
Might also inhibit carcinogenesis by suppressing hepatic carcinogen activating
enzymes such as cytochrome P450, and inducing oxidoreductases and glutathione
S-transferase.
49. 49
Resveratrol exerts its proapoptotic effect via p53 upregulation and has been shown
to suppress proliferation in hepatoma cell lines.
In vivo studies have also demonstrated protective effects of resveratrol in
diethylnitrosamine-initiated HCC.
6.1.6 Epigallocatechin-3-gallate (EGCG)
induces apoptosis through enhanced expression of miR-16
6.1.7 Saffron
It is listed as a potential agent for a novel anti-cancer drug against hepatocellular
carcinoma.
6.1.8 Vitamin A
The most biologically active form of Vitamin A, retinoic acid (RA), acts as a tumor
suppressor in liver cancer.
6.1.9 Catechins
Chemopreventive effects of epigallocatechin-3-gallate (EGCG) and other tea
catechins have been described in preclinical models for all major sites of cancer
development, including liver cancer.
Recently, miRNAs were included among the molecular targets of EGCG.
In human hepatocellular carcinoma cells, one of the 13 miRNAs that was
upregulated on EGCG treatment was miR-16, a tumor suppressor miRNA that
mediated apoptosis via downregulation of Bcl-2.
6.1.10 Ellagitannin
Ellagitannin was examined for anti-proliferative effects in human liver cancer cells,
along with profiling of miRNAs.
50. 50
Fig .6. MicroRNA regulation by dietary agents . Dietary agents such as curcumin, resveratrl, DIM,
I3C, EGCG, and ellagitannin modulate miRNAs that regulate cancer signaling pathways.
● Administration of mangiferin (100 mg/kg body weight) in diet for 18 weeks
inhibited B(a)P-induced lung carcinogenesis in Swiss albino mice.
● Mangiferin induced the activities of several antioxidant and detoxification
enzymes in lung of tumor bearing mice.
● pomegranate extract (0.2%) in drinking water for 1 week and exposed to B(a)P
and N-nitroso-tris-chloroethylurea (NTCU) had statistically significant lower lung
tumor multiplicities than mice treated with carcinogens alone.
51. 51
● Curcumin treatment significantly downregulated expression of miR- 186* in
A549/DDP multidrug-resistant human lung adenocarcinoma cells and induced
apoptosis.
● In vivo studies using animal cancer models have shown that
● lycopene can inhibit lung cancer.
● Luteolin is a flavonoid abundant in several green vegetables, such as cabbage,
spinach and peppers. It exhibits anticancer effects by inducing cell cycle arrest,
senescence or apoptosis in cells of human hepatoma
7. Breast cancer
Among the different types of cancer, breast cancer causes the highest number of deaths
among women worldwide. Breast cancer is a highly heterogeneous tumor that is sub-
classified into several subtypes based on their molecular characteristics. Among the
several existing sub-classifications of breast cancer, a subtype that generates great
concern among caregivers is the one whose cells do not present estrogen receptors
(ERs) on their surface, namely, ER-negative tumors. These tumors behave in an
aggressive manner, and are resistant/ unsusceptible to the effect of hormone therapies,
particularly ER modulators.
7.1 Breast cancer Chemoprevention by Using Phytochemicals
7.1.1 Epigallocatechin gallate (EGCG)
● Polyphenol present in several natural sources, but mainly in green tea It has
chemopreventive effects in several types of cancers.
● One of the ways that EGCG manifests its protective/preventive effect gainst cancer
has been proven in vitro in both cervical and breast cancer cells.
● It does so by detaining the cell cycle in the G1 phase and by influencing the
synthesis of several proteins, such as CDK1 and cyclins D and E.
● In addition, this particular polyphenol can induce processes such as apoptosis,
positively regulating the function of proteins such as pRb, p53,P27,etc, especially in
breast cancer cells in vitro.
52. 52
● Dietary polyphenols, including EGCG, administered in low doses appear to promote
survival genes and protective mechanisms by activating the mitogen-activated
protein kinase (MAPK) signaling pathway; however, in higher doses they can induce
anti-tumorigenic processes such as apoptosis.
● EGCG can influence programmed cell death by triggering and activating pro-
apoptotic proteins, such as caspases 3, 8, and 9, and by downregulating the natural
inhibitors of these cellular process, such as Bcl2, Bid, XIAP, or IAP2.
● This effect is enhanced alongside by dietary polyphenols upregulating p53, p21, and
Bax.
● The role of EGCG as an activator of apoptosis through studies, some of which
showed a synergistic effect on combining the treatment of HeLa cells with EGCG
and siRNA-p53, which reversed the oncogenic role of the mutated p53 gene present
in cancer cells.
● This therapeutic effect was achieved by modulating various genes that belong to
families such as caspases, TNF receptor associated factor, Caspase recruitment
domain, death domain, or Bcl2.
● Thus, this suggests that EGCG has a role as gene expression coactivator, and
therefore could be used as an anticancer therapy.
● Hyper-activation of MAPK signaling pathway may constitute one of the mechanisms
that lead to the loss of ERα expression in breast cancer, promoting an ER-negative
phenotype.
● Nuclear factor-κB (NF-κB) is another signaling pathway that is usually deregulated in
cancer.
● In ER-negative breast cancer cell models, NF-κB is constitutively active.
● EGCG was observed to decrease the production of NF-κB.
● Thus, it may be stated that this phytochemical not only appears to promote the
reactivation of the ER expression, but it may be working as a preventive mechanism
to lessen the activity of genes that could lead to regaining an ER-positive phenotype.
● EGCG may be predicted to be achieving this by modulating the levels of significant
molecules in key signaling pathways.
53. 53
● Alternatively, it is possible that polyphenols, such as EGCG, do not actually revert
the hormonal phenotype from ER negative back to ER positive, but just detain a
sequence of events responsible for the loss of ER expression.
● The inhibitory effect that EGCG has on the NF-κB molecule, and consequently on
the signaling pathways it takes part in, appears to achieve a desired effect in breast
cancer cells.
7.1.2 Curcumin
● The inhibitory effect that curcumin has on NF-κB resembles the effect the EGCG has
on it.
● In this manner, it may also interfere with processes that lead to diminished ER
expression.
● The influential effect of curcumin on NF-κB also extends to other molecules that are
part of its signaling pathway, such as COX2, MMP9, BlcxL, and Bcl2.
● Curcumin may also have inhibitory effects on other oncogenic signaling pathways,
such as Akt.
● As a result, it can initiate apoptotic processes and inhibit tumor cell Proliferations.
● Curcumin could potentiate the effect of anti-hormonal therapy in cancer by positively
influencing processes that can reinstate ER expression.
● Furthermore, it has overall beneficial effects for cancer patients by promote
apoptosis in tumor cells.
● In human breast cancers, overexpression of enhancer of zeste homolog 2 (EZH2)
gene indicates poor prognosis; curcumin treatment of MDA-MB-435 breast cancer
cells led to the down regulation of EZH2 expression in a dose- and time-dependent
manner, which also correlated with decreased cell proliferation.
● Curcumin induces downregulation of EZH2 through activation of MAPK, c-Jun NH2-
terminal kinase, ERK, and p38 leading to anti-proliferative Effects.
● polyphenol natural compound extracted from the plant Curcuma longa L rapidly
inhibits the phosphorylation of mTOR and its downstream effector molecules such as
p70S6K and 4E-BP1, indicating that curcumin may execute its anticancer activity
primarily by blocking mTOR-mediate signalling pathways.
54. 54
7.1.3 Genistein
It is an isoflavone found in large quantities in soybeans.
Genistein functions as a phytoestrogen, binding to the ERs, causing its effects in
adose-dependent manner.
At low doses, genistein acts as an estrogen agonist, promoting cell Proliferation.
When administered in concentrations higher than 5 μM, it displays an antagonistic
activity by inhibiting the growth of ER-dependent tumor cells.
Genistein is a down-regulator of several molecules and signaling pathways known
for their involvement in tumorigenesis, cancer development, and Progression.
In breast and cancers, genistein inhibits tumor cell growth and proliferation in vitro.
In MCF-7 breast cancer cells, genistein decreases protein expression of total Akt
and phosphorylated Akt, suggesting that genistein could offer protection against
breast cancer through downregulation of the PI3K/Akt signalling pathway.
Fig .7.Modulatory effects of EGCG, curcumin, and genistein.
55. 55
7.1.4 Blueberry
Administration of whole blueberry powder in diet (10%) for 8 week significantly
reduced the tumor volume in female nude mice implanted with human breast cancer
MDA-MB231 cells and blocked the liver metastasis of these cells.
7.1.5 Green tea
● Treatment of breast cancer MCF-7 cells with Polyphenon-60 of green tea
significantly altered the expression of 23 miRNAs, includ down-regulation of miR-21
and miR-27, which were initial overexpression in these cancer cells.
7.1.6 Resveratrol
● a polyphenolic compound present in grapes and red wine with potential anti-
inflammatory and anticancer properties decreases mTOR and p70S6K
phosphorylation, and in combination with rapamycin, suppresses the
phosphorylation of Akt.
● An additive effect of resveratrol and rapamycin combination suggests some
therapeutic value in breast cancer .
● Resveratrol in combination with Vitamin D3 was highly effective in reducing
methylation of PTEN promoter and inducing expression of PTEN, down-regulating
DNMT, and regulating p21 in ER-positive MCF-7 breast cancer cells, but had no
notable effects in triple-negative MDA-MB-231 breast cancer cells.
● In both estrogen receptor (ER)-positive and ER-negative breast cancer cells,
resveratrol activates AMP-activated kinase (AMPK) and subsequently
downregulates mTOR, 4E-BP1 and mRNA translation.
7.1.7 Mangostin
● Oral administration of ferrulic acid of mangostin (40 mg/kg body weight) by
gavage significantly attenuated DMBA-induced rat mammary tumor formation.
56. 56
7.1.8 Fig
● Fig latex and its derivatives have been shown to suppress the growth of
spontaneous mammary tumors in mice.
7.1.9 Gingerol
● Gingerol has anti-cancerous effects for the tumor.
7.1.10 Kaempferol
● Is a breast cancer resistance protein (Bcrp, Abcg2) inhibitor and may also be a Bcrp
substrate, which may represent one possible mechanism for the low bioavailability
of kaempferol
7.1.11 Lycopene
It possesses inhibitory effects on breast cancer cells.
7.1.12 PEITC
● PEITC from cruciferous vegetable has been intensively studied for chemoprevention
against breast cancer cells.
7.1.13 Rosmarinic acid
It may inhibit bone metastasis from breast carcinoma mainly via the pathway of the
NF-κB and by simultaneous suppression of interleukin-8 (IL-8).
7.1.14 Triterpenoids
● Triterpenoids exert their chemopreventive and anti-cancer activities via enhancing
apoptosis, NO, stimulating DR4, DR5, caspase-3/7, caspase 8, Bax, JNK, MAPK,
p38, decreasing phosphor-STAT3, PARP cleavage, suppressing COX-2, IL-1β, NF-
κB, IKKα/β, cyclin D1, cyclin A, cyclin B1, ERα protein and mRNA, HER2
phosphorylation, caveolin-1, Akt, JAK1, STAT 3, Bcl2, c-Jun, cFos, JNK, mTOR,
blocking cell cycle at G1, G1-S, G2-M, etc.
57. 57
7.1.15 Vitamin D
● Vitamin D from mushroom has been involved in breast cancerFor example, women
with mutations in the VDR (vitamin D receptor) gene had an increased risk of breast
cancer and VDR may be a mediator of breast cancer risk which could represent a
target for cancer prevention efforts .
7.1.16 Sulforaphane
● It able to downregulate the Wnt/β-catenin self-renewal pathway in breast cancer
cells by inducing β-catenin phosphorylation, leading to its degradation by the
proteasome, through the activation of GSK-3β .
7.1.17 Piperine
Is also able to inhibit breast CSCs self-renewal by targeting Wnt signalling.
7.1.18 Rottlerin
● It is a natural plant polyphenol compound derived from the kamala tree (Mallotus
philippinensis).
● Rottlerin possesses a cytotoxic effect against a wide spectrum of tumors and
cancer cells including those which are apoptotic competent and apoptotic
resistant[8-9]. Despite its well documented anti-cancer properties, yet the exact
mechanisms of rottlerin's anti-cancer effects are not known.
● By autophagy targeting : Inhibition of mTORC1 activity through a novel AMPK
and mTORC1 phosphorylation-independent mechanism.
7.1.19 SPARSTOLONIN B
● SsnBis a novel bioactive compound isolated from Sparganium stoloniferum.
SsnB inhibits the growth and arrests the cell cycle progression and induces
apoptosis by inhibition of Akt and NF-kappaB signaling with their upstream target
c-Met and downstream targets Bcl-2/Bax, osteopontin, VEGF, MMP-9, and
MMP-2.
58. 58
8. Esophageal cancer
Esophageal cancer is a disease in which malignant (cancer) cells form in the tissues of
the esophagus. The esophagus is a muscular tube that moves food and liquids from the
throat to the stomach.The most common types of esophageal cancer are squamous cell
carcinoma and adenocarcinoma. Squamous cell carcinoma begins in flat cells lining the
esophagus. Adenocarcinoma begins in cells that make and release mucus and other
fluids.Smoking and heavy alcohol use increase the risk of esophageal squamous cell
carcinoma. Gastroesophageal reflux disease and Barrett esophagus may increase the
risk of esophageal adenocarcinoma. Esophageal cancer is often diagnosed at an
advanced stage because there are no early signs or symptoms.
8.1 ESOPHAGEAL CANCER Chemoprevention by Using Phytochemicals
8.1.1 Isothiocyanates
● isothiocyanates are released from their precursor via hydrolysis catalyzed by
myrosinase. Of its metabolites, phenethyl isothiocyanate (PEITC) PEITC (> 1.0
μmol/g diet) protects against esophageal cancer by inhibiting tumor incidence and
multiplicity in rats treated with N nitrosobenzylmethylanime (NMBA) .
● Several studies of the molecular mechanism where by PEITC inhibits NMBA-
induced esophageal tumorigenesis have revealed that PEITC suppresses the
activity of cytochrome P450 enzymes in rats with NMBA induced esophageal
cancer, and also inhibits DNA methylation by inhibiting the formation of the pro-
mutagenic adduct O6-methylguanine in rat esophageal DNA .
8.1.2 EGCG
● EGCG is the most abundant and active constituent among tea polyphenols.
● In general, the anticarcinogenic activities of EGCG are mediated via multiple
mechanisms, including the inhibition of mitogen activation protein kinases (MAPK),
activator protein-1 and cell transformation, inhibition of epidermal growth factor
receptor (EGFR) phosphorylation, induction of cell cycle arrest (G0/G1) and
apoptosis, and inhibition of DNA methyltransferase (DNMT) activity.
59. 59
● EGCG also regulates multiple targets and mechanisms in protecting against
esophageal cancer. EGCG (40 μmol/L) inhibits phosphorylation of ERK1/2, c-Jun,
and cyclooxygenase-2 (COX-2), which are increased in the human esophageal
cancer cell lines .
● EGCG (4 mg/kg i.p.) attenuates cyclin D1 and COX-2 gene expression,
thereby reducing the production of prostaglandin E2 (PGE2) in rats treated with NMBA
.
●Lastly, EGCG also inhibits DNA methylation, thereby suppressing the onset of
esophageal cancer.
8.1.3 Curcumin
The antioxidant capacity of curcumin contributes to the prevention of esophageal
cancer by increasing the activity and/or expression levels of antioxidant enzymes,
including SOD, and reducing pro-oxidant enzymes, such as COX-2.
Several studies have demonstrated that curcumin inhibits NF-κB activity in
esophageal adenocarcinoma.
Nuclear factor κB (NF-κB) is a well-known proinflammatory transcription factor
involved in the initiation, promotion and progression of cancers . It is also known that
increased NF-κB activity is associated with greater cell proliferation, invasion,
angiogenesis, metastasis, suppression of apoptosis, and chemoresistance in
various types of cancer .
Recently, it was demonstrated that curcumin induces cell death (apoptosis) and cell
cycle arrest by blocking Notch signaling pathways.
8.1.4 Resveratrol
It is a phytoalexin, an important constituent of red wine, abundant in the grape skin.
Prophylactic use of resveratrol has been shown to reduce the number and size of
esophageal tumors.
60. 60
8.1.5 Luteolin
● It is a flavonoid abundant in several green vegetables, such as cabbage, spinach
and peppers. It exhibits anticancer effects by inducing cell cycle arrest, senescence
or apoptosis in cells of human esophageal adenocarcinoma.
8.1.6 Dried strawberry
● Dietary administration of freeze-dried strawberry (5 or 10%) induced esophageal
carcinogenesis by suppressing NMBA-DNA adduct formation through the inhibition
of cytochrome p450 (CYP) enzymes, which are responsible for metabolic activation.
8.1.7 Black raspberry
● Freeze-dried black raspberry its role is reduction of the multiplicity of NMBA-induced
esophageal tumors.
9. Oral cancer
Oral carcinomas are one of the most prevalent carcinomas representing 10 most common
causes of death. It is said to be a major health problem in most of the developing countries
attributing to the present life style.There are wide etiological factors of oral cancer which
can be internal or external with external factors being tobacco, chemicals, radiation and
infectious organisms and the internal factors include inherited mutations, hormones and
immune status causing cancers.Phytochemicals have been attracting scientists due to their
property in altering cell cycle control, apoptosis evasion, angiogenesis and metastasis.
They have proved their efficacy in mono treatments or in association with other
chemopreventive agents.
9.1 oral carcinogenesis Chemoprevention by Using Phytochemicals
