Cancer Prevention With Natural Compounds

Norleena P. Gullett,a A.R.M. Ruhul Amin,b Soley Bayraktar,c John M. Pezzuto,d Dong M. Shin,b
Fadlo R. Khuri,b Bharat B. Aggarwal,e Young-Joon Surh,f and Omer Kucukb

Botanical and nutritional compounds have been used for the treatment of cancer throughout
history. These compounds also may be useful in the prevention of cancer. Population studies
suggest that a reduced risk of cancer is associated with high consumption of vegetables and fruits.
Thus, the cancer chemopreventive potential of naturally occurring phytochemicals is of great
interest. There are numerous reports of cancer chemopreventive activity of dietary botanicals,
including cruciferous vegetables such as cabbage and broccoli, Allium vegetables such as garlic and
onion, green tea, Citrus fruits, soybeans, tomatoes, berries, and ginger, as well as medicinal plants.
Several lead compounds, such as genistein (from soybeans), lycopene (from tomatoes), brassinin
(from cruciferous vegetables), sulforaphane (from asparagus), indole-3-carbinol (from broccoli),
and resveratrol (from grapes and peanuts) are in preclinical or clinical trials for cancer chemopre-
vention. Phytochemicals have great potential in cancer prevention because of their safety, low cost,
and oral bioavailability. In this review, we discuss potential natural cancer preventive compounds
and their mechanisms of action.
Semin Oncol 37:258-281. © 2010 Published by Elsevier Inc.

T here is growing interest in medicinal botanicals

as part of complementary medicine in the
United States. Approximately 40% of Americans
use alternative remedies, including herbal medicine,
hand, these preparations may sometimes have thera-
peutic benefit due to their active chemical constitu-
ents.
Botanicals have been used by human beings
for disease prevention and therapy.1 The high cost, side throughout history. Medical literature documents the
effects, and therapeutic limitations of conventional widespread use of herbal remedies in many countries
medications are key factors that are driving the revival throughout the world, and the presence of certain
of herbal remedies. People can easily obtain herbal phytochemical constituents supports the pharmacolog-
medicines or botanical supplements on an over-the- ical and physiological efficacy of some botanical treat-
counter basis, and feel comfortable consuming these ments. Considerable epidemiological and experimental
products, even though safety and efficacy are generally evidence has accumulated indicating risk reduction for
not established on a rigorous scientific basis. Some- numerous cancers. The cancer-inhibitory potential of
times this may be a serious problem due to drug– drug nutrient as well as of non-nutrient constituents (phyto-
interactions and harmful consequences.2,3 On the other chemicals) from plants has been confirmed in animal
models.4
aDepartment
Cancer chemoprevention has developed as a major
of Radiation Oncology, Winship Cancer Institute, Emory
University, Atlanta, GA.
field of scientific investigation. Cancer chemopreven-
bDepartment of Hematology and Medical Oncology, Winship Cancer tion is defined as pharmacological intervention with
Institute, Emory University, Atlanta, GA. synthetic or naturally occurring compounds that may
cDepartment of Medicine, Division of Hematology/Oncology, University
prevent, inhibit, or reverse carcinogenesis, or prevent
of Miami, Sylvester Comprehensive Cancer Center, Miami, FL. the development of invasive cancer. Dietary consump-
dCollege of Pharmacy, University of Hawaii at Hilo, Hilo, HI.

eDepartment of Experimental Therapeutics, The University of Texas

tion of foods and herbal medicines is a convenient
M.D. Anderson Cancer Center, Houston, TX.
method of administering potentially chemopreventive
fCollege of Pharmacy, Seoul National University, Seoul, South Korea. phytochemicals in a cost-effective manner.
Address correspondence to Omer Kucuk, MD, Department of Hematol- Numerous reports suggest a protective role for a diet
ogy and Medical Oncology, Winship Cancer Institute, Emory Univer- rich in fruits and vegetables.5–7 Overall, diets high in
sity, 1365-c Clifton Rd, C-2110, Atlanta, GA 30322. E-mail: okucuk@ vegetables and fruits (⬎400 g/d) may prevent at least
emory.edu
0270-9295/ - see front matter
20% of all cancers. Some of the most convincing evi-
© 2010 Published by Elsevier Inc. dence for the health benefits of fruit and vegetable
doi:10.1053/j.seminoncol.2010.06.014 consumption relates to the reduced risk of gastrointes-

258 Seminars in Oncology, Vol 37, No 3, June 2010, pp 258-281

Phytochemicals and cancer 259

Spices Fruits & Vegetables

Asian ginger (1) Fennel (2) Sesame seed (3) Turmeric (4) Cloves (5)
(Alpinia galanga) (Foeniculum vulgare) (Sesamum indicum) (Curcuma longa) (Eugenia caryophyllu) Cauliflower (1) Mullberry (2) Artichoke (3) Grapes (4) Soybean (5)
(Brassica oleracea) (Morus nigra) (Cynara cardunculus) (Vitis vinifera) (Glycine max)

Traditional Chinese Medicine

Red chili (6) Fenugreek (7) Poppy seed (8) Gamboge (9) Onion (10)
(Capsicum annum) (Trigonella foenum graecum) (Papaver somniferum) (Garcinia hanburyi) (Allium cepa)

Lacquer tree (1) Goldenseal (2) God of thunder vine (3) Smoke tree (4)
((Rhus verniciflua)) ((Hydrastis
y canadensis)) ((Tripterygium
p yg wilfordii)) ((Cotinus coggygria)
ggyg )
Onion seed (11) Holy basil (12) Pomegranate (13)
(Nigella sativa) (Ocimum sanctum) (Punica granatum)

Ayurvedic Medicine
Evodia (5) Song gen (6) Magnolia (7)
(Evodia rutaecarpa) (Phellinus linteus) (Magnolia officinalis)

Others
Aloe (1) Veldt-grape (2) Picroliv (3) Himalayan fir (4) Chitrak (5)
(Aloe vera) (Cissus quadrangularis) (Picrorhiza kurroa) (Abies webbiana) (Plumbago zeylanica)

Cashew nut (1) Horse chestnut (2) Palm (3) Elephant's foot (4) Hop (5)
(Anacardium occidentale)(Aesculus hippocastanum) (Elaeis guineensis) (Elephantopus scaber Linn) (Humulus Iupulus L.)
Boswellia (7) Beauty berry (7) Pink trumpet tree (8) Bloodroot (9) Guggulu (10)
(Boswellia serrata) (Callicarpa macrophylla) (Tabebuia avellanedae) (Sanguinaria canadensis) (Commiphora mukul)

Ginger lily (6) Cork bush (7) Tropical rose mallow (8) Oleander (9)
(Hedychium coronarium) (Mundulea sericea) (Hibiscus vitifolius) (Nerium oleander)
False pepper (11) Rohitukine (12) Ashwagandha (13) Indigo (14) Pinecone ginger (15)
(Embelia ribes) (Dysoxylum binectariferum) (Withania somnifera) (Polygonum tinctorium) (Zingiber zerumbet)

Figure 1. Sources of natural cancer preventative compounds.

tinal cancers, such as those associated with the mouth, lations that migrate from their native countries to other
pharynx, esophagus, stomach, colon, and rectum. Veg- countries, suggesting the importance of environmental
etables are more effective than fruits.5 The mechanisms factors. For example, Japanese who move to Hawaii or
by which vegetables and fruits reduce cancer are mul- California experience a higher rate of cancers of breast
tiple and complex. Various stages of carcinogenesis and prostate. Changes in the incidence of cancer can
may be inhibited, and various in vitro or in vivo systems be seen in one or two generations.10 Approximately
may be used to model these inhibitory effects in pre- one third of all cancers in industrialized societies are
clinical studies. It is logical to acquire compelling attributable to dietary factors and lack of physical ac-
in vitro data prior to performing tests with animal tivity.11
models, and it is generally necessary to isolate and The concept of cancer prevention has been gaining
characterize active chemical principles before moving increasing attention at all levels including the public,
on to the animal model and clinical studies. Figure 1 the media, the government, and the cancer research
shows the sources of some of the commonly used community because it is cost-effective and if successful
botanicals and Figure 2 shows the chemical structures it avoids the toxic side effects of cancer treatment.
of some of the phytochemicals under investigation. Current cost estimates on cancer treatment vary by
Cancer is the leading cause of death for individuals site; however, Shih and Halpern12 discuss various eco-
less than 85 years of age in the United States.8 There is nomic analyses of cancer intervention and cite exam-
a great need for more effective and less toxic therapeu- ples of interventions that result in increased costs such
tic and preventive strategies. Prevention may be more as $1,000 per contrast-enhanced magnetic resonance
effective and less costly because cancer is largely a imaging screening, which is 10 times the cost of
preventable disease that can be attributed to lifestyle screening mammography; $1,800 per positron emis-
factors.9 Epidemiologic studies show changes in the sion tomography scan for cancer staging; $48,000 per
rates of different cancers in genetically identical popu- patient per year for the use of intensity-modulated
260 N.P. Gullett et al

Spices Fruits & Vegetables

O OH
O O O
O O
O H3CO OCH3
O
O H3CO O HO OH OH O
O CH2OH H OH OH
HO OH H2 CH2 OH OH OH O
O H HO O H
O
HO O OCH3
OH HO
1’-Actoxychav- Anethole (2) Sesamin (3) Curcumin (4) Eugenol (5) H OH HO O
OH O O CH2OH
icol acetate (1) H
O O
H Indole 3- Morin (2) Silymarin (3) Resveratrol (4) Genistein (5)
N
O CH3 OH
O H carbinol (1)
O O H
H3C O
O
H H O O
HO H H3C
O
H H O
HO O O
CH3 OH O Traditional Chinese Medicine
Capsaicin (6) Diosgenin (7) Noscapine (8) Gambogic acid (9)
OH O HOOC OH
OH OH O OH
O
OH O CH3 H O H3CO
HO HO HO O
CH3 O
HO O HO OH N
COOH OH
H3C OCH3 HO
OH O OH OH O O
O HO O
OH O
Butein (1) Berberin (2) Celastrol (3) Fisetin (4)
Quercetin (10) Thymoquinone (11) Ursolic acid (12) Ellagic acid (13)
OH O HO
N O HO
Ayurvedic Medicine H N HO
OH
HO H
OH OH OH Evodiamine (5) Hispolon (6) Honokiol (7)
OH O OH OH O O
O CH3
HO OH
HO
O
OH
HO Cinnamoyl O
O O
OCH3 OH OH O
Others
OH HO OH OH
HO OH
OH HO

HO O
OH
O
O O
O
Emodin (1) Piceatannol (2) Picroliv (3) Pinitol (4) Plumbagin (5) OH O HO
O
HO
OH
HO O
O

OH
HO
OH
O
O
O
O
H O
O H3C H CH3
OH

O
H
O
H

O
O

O N+ O
O
O
O O OH
OH
COOH O
O Anacardic acid (1) Escin (2) γ-Tocotrienol (3) Isodeoxyelephan
H3CO H3C CH3 O O -topin (4)
HOOC HO

Acetyl-11-keto-β- Betulinic acid (7) β-Lapachone (8) Sanguinarine (9) Guggulusterone (10)
boswellic acid (6) O
H 3C CH3 HO O O CH3 HOH2 C
CH3 HO O
N OH OH HO OH
OH OAc O
O O O OH O
O NH4 O
O O
O
O
HO OH HO O
OH O
HO O OH
O NH O OH O
OH3C
OH H O O O
CH3O OH O
O
H3C H O
OH O OAc HO
O
Embelin (11) Flavopiridol (12) Indirubin 3’- Withanolide (14) Zerumbone (15) Xanthohumol (5) Coronarin-D (6) Deguelin (7) Gossypin (8) Oleandrin (9)
monoxime (13)

Figure 2. Structures of natural cancer preventative compounds.

radiation therapy to treat prostate cancer; $50,000 per The involvement of multiple factors and develop-
patient per year for trastuzumab in the treatment of mental stages, and our increased understanding of can-
HER-2–positive breast cancer; $1,800 per month for cer at the epigenetic, genetic, molecular, and cellular
gefitinib for the treatment of lung cancer; and more levels is opening up enormous opportunities to inter-
than $8,000 for a 6-day course of palifermin in the rupt and reverse the initiation and progression of the
treatment of oral mucositis.12 disease and provide scientists with numerous targets to
With the current price tag on cancer treatment, arrest by physiological and pharmacological mecha-
many people turn to natural compounds for chemopre- nisms, with the goal of impeding or delaying the devel-
vention, as well as for treatment of disease and ameliora- opment of cancer and preventing end-stage, invasive
tion of side effects of therapy. National Health Statistics disease.15 In the 2008 inaugural issue of Cancer Preven-
reports on the use of complementary and alternative tion Research, Lippman provides an overview of the
medicine (CAM) completed for 2002 and 2007 show that field of chemoprevention stating that major advances
US adults were more likely to use CAM when concerns include the concept of intraepithelial neoplasia and mo-
about cost delayed use of conventional medical care. In lecular cancer risk assessment.16 Specifically, he discusses
2007, the most commonly used natural products by adults the way in which oncology research now views prema-
for health reasons in the past 30 days were fish oil or lignancy and carcinogenesis as heterogeneous processes
omega 3 fatty acids or docosahexaenoic acid (DHA; involving tissue injury, genetic and epigenetic alterations,
37.4%), glucosamine (19.9%), echinacea (19.8%), flaxseed signal transduction abnormalities, clonal patches, inflam-
oil or pills (15.9%), and ginseng (14.1%).13 The National mation, and angiogenesis. Another major technological
Health Statistics reports acknowledge that a limitation in advance is the increasing sophistication of genetically
identifying the population’s use of CAM is the reliance on engineered mouse models that can facilitate the elucida-
self-reporting, noting that in general less than 30% of tion of molecular mechanisms of potential cancer preven-
patients disclose their CAM use to their physician.14 tive compounds.16
Phytochemicals and cancer 261

Natural compounds have been presumed to be safer 13-cRA, alpha-interferon, and alpha-tocopherol ap-
than synthetic compounds due to their presence in the peared to be effective in delaying SPTs.27
diet, wide availability, and tolerability. Historically, ep- Discovery of biomarkers such as epidermal growth
idemiologic studies showed that individuals with lower factor receptor (EGFR), cyclooxygenase-2 (COX-2), and
serum levels of certain micronutrients (such as vitamin Ras, and the development of inhibitors of these biomar-
E, vitamin D, calcium, selenium, etc) had a higher risk kers have been useful strategies in cancer chemopre-
of cancer. Subsequently, vitamins and micronutrients vention.15 Several targeted agents such as EGFR inhib-
became the agents of choice for early cancer chemo- itors erlotinib and gefitinib, COX-2 inhibitors celecoxib
prevention trials. The underlying assumption was that and rofecoxib, and farnesyltransferase inhibitors (FTIs)
“more” of these vitamins/micronutrients equaled “bet- have been investigated.28 –31 However, safety has been
ter” and dosing in subsequent trials was not based on a major concern with these pharmaceutical agents.
biological activity or oral bioavailability but increased Safety is always a primary consideration in studies in-
pharmacologic dosing (often 10 –20 times physiologic volving human subjects who have no evidence of can-
levels).17 An example of high dosing is the Selenium cer who are potential candidates for chemoprevention.
and Vitamin E Cancer Prevention Trial (SELECT), An ideal chemopreventive agent is expected to be
which investigated chemoprevention of prostate can- nontoxic, effective at low doses, orally taken, and in-
cer in more than 35,000 men with average risk. The expensive. Dietary compounds have drawn a great deal
SELECT trial was based on the premise that daily sele- of attention because of their safety and potential ability
nium (200 ␮g of L-selenomethionine) or daily vitamin E to reduce the risk of cancer. Multiple epidemiological
(400 IU of all rac-a-tocopheryl acetate), used alone or in and animal model studies show that consumption of
combination, could reduce the incidence of prostate fruit and vegetables decreases the occurrence of a
cancer. SELECT had a median follow-up of 5.5 years. variety of cancers.7,32–35 Below we discuss the cancer
Neither selenium, nor vitamin E, nor the combination preventive properties and mechanisms of action of
of both agents prevented prostate cancer. Secondary selected natural compounds.
analyses showed no effect on the risks of lung, colo-
rectal, or overall cancer incidence; no effect on cardio-
GREEN TEA
vascular events; and no effect on overall survival. Re-
views of SELECT including comparisons to other Next to water, tea is the most popular beverage
selenium clinical trials as well as animal studies indi- consumed in the world and is distinguished by the
cated that the selenium supplement L-selenomethi- presence of a group of polyphenols called catechins. A
onine and high initial levels of selenium in the study growing body of evidence from laboratory animal stud-
subjects may have negatively affected the results.18 In a ies demonstrates that tea consumption has an inhibi-
recent editorial, Klein stated that it may be difficult to tory effect on carcinogenesis at various organ sites. For
precisely assess the health benefit of an individual nu- example, oral administration of tea infusion can inhibit
tritional agent, noting that dietary or nutrient supple- the development of experimental rodent skin tumors,36
mentation for the prevention of cancer may be best growth of implanted tumor cells,37 invasion and metas-
achieved by lifelong healthy eating habits.19 These rec- tasis of malignant tumors,38,39 and angiogenesis.40,41
ommendations should be kept in mind by those who The bioavailability and biotransformation of tea poly-
are involved in or interested in chemoprevention re- phenols, however, are the key factors for the above-
search. They serve as a reminder of the need for not mentioned chemopreventive effects of tea against tu-
only multimodality cancer treatment but also multimo- morigenesis. At present, epidemiological studies have
dality prevention. The natural compounds discussed not yielded conclusive evidence of the protective ef-
herein are individual components of an overall health- fect of tea consumption against the development of
ier environment and dietary pattern. human cancers.42– 44 However, limited epidemiological
The clinical chemoprevention trials first started with studies suggest that people drinking more cups of tea
carotenoids and their analogs, including 13-cis-retinoic regularly have a lower risk of prostate45,46 and breast
acid (13-cRA), which showed a significant decrease in cancer.47 Four major green tea components are epigal-
the size of oral premalignant lesions and reversal of locatechin-3-gallate (EGCG), epigallocatechin (EGC),
dysplasia.20 A phase III trial in patients with leukoplakia epicatechin-3-gallate (ECG), and epicatechin (EC), all of
with high-dose 13-cRA followed by low-dose 13-cRA or which are also present in black and other teas.
beta-carotene suggested that low-dose 13-cRA was bet- The mechanisms by which tea polyphenols may act
ter than beta-carotene for prevention of recurrence.21 A include inhibition of mutagenesis,48 –50 genotoxicity,51,52
phase III trial with high doses of 13-cRA showed sig- transformation,53–55 cell proliferation,56 – 65 and angiogene-
nificant reduction in the incidence of second primary sis.40,41 Each mechanism involves multiple potential mo-
tumors (SPTs) after 1 year of treatment.22,23 After these lecular targets, which will be discussed below. Many
successful results, a number of retinoid trials were studies have suggested that EGCG (Figure 3A) pos-
conducted with mixed results.24 –26 The combination of sesses the most potent activity against all stages of
262 N.P. Gullett et al

Figure 3. Selected natural cancer preventative compounds.

multistage carcinogenesis.66 – 68 After supplementation other low-grade lymphomas who used over-the-
EGCG, plasma concentration has increased up to 4,400 counter (OTC) products containing tea polyphenols
pmol/mL.69 –71 Such concentrations of EGCG would be had evidence of clinical benefit from these products.83
enough to exert antioxidant activity in the blood Phase I trials also have been conducted to define the
stream. Previously, Nam et al reported that EGCG po- biodistribution pattern, pharmacokinetic parameters,
tently and specifically inhibits the chymotrypsin-like and safety profile for short-term oral administration of
activity of the proteasome in vitro (50% inhibitory con- green tea preparations.84 – 86 Up to 1 g of green tea
centration [IC50] ⫽ 86 –194 nmol/L) and in cultured solids (equivalent of ⬃900 mL of green tea) could be
tumor cells (1–10 ␮mol/L) at the concentrations found safely consumed by patients.87 EGCG also may increase
in the serum of green tea drinkers.72 Understanding the efficacy of anticancer drugs in cell culture and
how daily tea consumption and its cancer chemopre- animal models; it increased the efficacy of erlotinib in
vention mechanisms in humans is an important issue to head and neck cancer models88 and sensitized erlotinib-
elucidate the beneficial potential of tea beverage on resistant lung cancer cells to erlotinib. EGCG also
cancer prevention. sensitized the TRAIL (tumor necrosis factor [TNF]-
Although both black tea and green tea have been related apoptosis-inducing ligand)-resistant LnCaP
studied for their chemopreventive potential, green tea prostate cancer cells to TRAIL-mediated apoptosis.89
showed greater efficacy against multiple types of can-
cer. EGCG is the most abundant polyphenol in green
CURCUMIN
tea. Epidemiological and animal model studies have
yielded promising results of green tea and its constitu- The Zingiberaceae is a well-known plant family in
ents in cancer prevention.73–78 In xenograft models, Southeast Asia, and numerous species are being used in
green tea polyphenols (GTPs) inhibited growth and traditional medicine for the treatment of several dis-
metastasis of mouse mammary carcinoma cells79 and eases. The representative chemopreventive agent is
reduced tumor blood vessel formation.80 Polyphenolic curcumin. This compound has been shown to exert
extract (PPE) from green tea reduced the risk of colon anti-carcinogenic effects in a diverse array of animal
carcinogenesis in rats.81 Esophageal cancer risk was and cell culture models. Surh and Chun have summa-
inversely associated with green tea consumption.82 Pa- rized mechanistic and anti-carcinogenesis studies con-
tients with chronic lymphocytic leukemia (CLL) and ducted with curcumin.90 Inhibition of tumor promo-
Phytochemicals and cancer 263

tion is predominant. Curcumin (Figures 2 and 3B) sides its well-defined antioxidant potential, resveratrol
inhibits 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-in- also has substantial anti-inflammatory activity.115
duced inflammation, hyperplasia, proliferation, ornithine Piceatannol (3,3=,4,5=-tetrahydroxy-trans-stilbene), a
decarboxylase (ODC), reactive oxygen species (ROS) gen- hydroxylated analog of resveratrol, also has been re-
eration, COX, and lipoxygenase in mice. The proposed ported to possess anti-inflammatory properties. Piceat-
molecular mechanism relates to activator protein-1 (AP-1) annol significantly reduced lipopolysaacharide (LPS)-
binding with DNA. Suppression of TPA-induced activa- induced production of nitric oxide (NO) in murine
tion of c-Jun/AP-1 in cultured NIH3T3 cells, and inhibi- macrophages116,117 or microglia.118 The LPS-induced ex-
tion of nuclear factor-␬B (NF-␬B) in cultured human pression of inducible NO synthase (iNOS) also was sup-
leukemia cells stimulated with TPA, were observed. pressed by piceatannol.117–119 Like resveratrol, piceatan-
Curcumin (Figures 2 and 3B), isolated from the roots nol was reported to possess an anti-tumorigenic
(rhizomes) of the plant Curcuma longa (Figure 1), is potential.120
the major yellow pigment present in turmeric, widely Resveratrol prevented the development of carcino-
used as a spice. Although turmeric and its chemical gen induced skin cancer in mice and was effective in all
components have been used in Ayurvedic medicine stages of carcinogenesis.113 Topical application of res-
(ancient Indian medicine including massage, medita- veratrol both before and after UVB exposure decreased
tion, and complementary medication) for thousands of skin cancer incidence in mice.121 Prophylactic use of
years, it was not until the 1980s that the anti-tumori- resveratrol reduced the number and the size of esoph-
genic activity of curcumin was reported. Turmeric ex- ageal, intestinal, and colon tumors.121,122 Resveratrol
tract inhibited the growth of Chinese hamster ovary was effective in the prevention of DMBA-induced mam-
cells, and was cytotoxic to lymphocytes and Dalton’s mary carcinogenesis, and it inhibited the growth of
lymphoma cells in vivo.91 Ethanol extract of turmeric and MDA-MB-231 xenografts, induced apoptosis of pros-
curcumin ointment gave good results in patients with tate cancer cell lines PC-3, DU145, and LNCaP and
external cancerous lesions.92 Curcumin interrupts the suppressed the progression of prostate cancer in
carcinogenesis process by inhibiting the initiation step TRAMP mice.112,123–126 Resveratrol was also effective
or suppressing the promotion and progression stages in against a number of other cancers, including the
animal models.93,94 Several studies in rodent models tumors of liver, pancreas, gastrointestinal tract, lung,
demonstrated the inhibitory effects of curcumin on and soft tissues.77,127–131 Besides its in vitro effects,
colon carcinogenesis.95,96 Curcumin inhibits the initia- resveratrol also exerts antitumor activity in vivo and
tion and promotion of chemically induced skin can- enhances the therapeutic effects of 5-FU in a murine
cer97 and 7,12-dimethylbenz[a]anthracene (DMBA)-in- model of liver cancer.132 Resveratrol may inhibit DNA
duced oral carcinogenesis.98 Curcumin also inhibits the adduct formation by benzo[a]pyrene (B[a]P) in the
growth of cancer cells from multiple organ sites in vitro lungs of BALB/c mice.133 Clinical safety of oral resvera-
and in xenograft models by inducing cell cycle arrest trol up to 5 g was observed in a phase I study.134
and apoptosis.77,90,99,100
Curcumin has synergistic activity with genistein,101
LYCOPENE
green tea,102 and embelin,103 and enhances the efficacy
of the anti-cancer drugs 5-fluorouracil (5-FU)104 and Lycopene (Figure 3D) is a carotenoid that gives
gemcitabine,105 and the vinca alkaloid vinorelbine.106 In tomato its red color. It is also found in guava, water-
a pilot study, 100% of patients showed a decreased melon, and pink grapefruit, but it is most abundant in
polyp number and size after a mean of 6 months of red tomatoes and processed tomato products, espe-
treatment with curcumin and quercetin.107 A phase I cially tomato paste. Because of its potent antioxidant
clinical trial showed that curcumin was safe up to 8 effect, lycopene has drawn much attention as a cancer
g/d.108 A pharmacodynamic and pharmacokinetic study preventive agent. Population studies have shown that
of oral Curcuma extract was also performed in patients high intake of lycopene is inversely associated with the
with colorectal cancer.109 incidence of certain types of cancers, including those
of the digestive tract, prostate, and cervix.135–139 Con-
sumption of tomato products may prevent disease pro-
RESVERATROL AND PICEATANNOL
gression in benign prostate hyperplasia (BPH) and pros-
Resveratrol (3,5,4=-trihydroxy-trans-stilbene) (Fig- tate cancer.140,141 A combination of vitamin E, selenium,
ures 1, 2, and 3C), a naturally occurring polyhydroxy- and lycopene dramatically inhibited prostate cancer
lated stilbene, is widely present in grapes, red wine, development and increased disease-free survival in an
mulberries, and other edible plants. This naturally oc- animal model.142 Dunning R-3327H prostate cancer
curring stilbene exerts protective effects against exper- growth rate was reduced in rats fed broccoli, tomato,
imentally induced carcinogenesis.110 –114 However, the and a combination of tomato plus broccoli.143 We con-
molecular mechanisms underlying chemopreventive ducted a phase II randomized clinical trial of lycopene
activity of resveratrol remain largely unresolved. Be- supplementation before radical prostatectomy which
264 N.P. Gullett et al

suggested that lycopene may decrease the growth of LUTEOLIN

prostate cancer.144 In a lycopene supplementation trial
Luteolin (Figure 3E) is a flavonoid found in a variety
we also observed stabilization of serum prostate spe-
of vegetables, especially in broccoli, celery, cabbage,
cific antigen (PSA) levels in men with prostate can-
spinach, green pepper, and cauliflower. It has anti-
cer.145 Lycopene strongly inhibited in vitro cell growth
inflammatory and anti-cancer effects.168 Luteolin has
and induced apoptosis in breast and prostate cancer
been found to induce cell cycle arrest and apoptosis
cells.146 –148 Lycopene treatment reduced the incidence
in a variety of cancer cells including oral squamous
of aberrant crypt foci and may have a role in colon
cancer,169 esophageal cancer,170 lung cancer,171 co-
cancer prevention.149 Lycopene also suppressed the
lon cancer,172 and hepatoma.173 Luteolin inhibited
growth of lung cancer cells and was more potent than
cell growth and induced apoptosis in prostate cancer
alpha-carotene or beta-carotene.150 In an animal model
cells both in vitro and in vivo.174 It also increased the
study151,152 and in two large cohort studies lycopene
efficacy of cisplatin in gastric cancer cells175 and
intake was significantly associated with a lower risk of
inhibited tumor promotion in a DMBA-induced mam-
lung cancer.153 We also observed decreased incidence
mary tumor model.176 Colon cancer development in
and size of leiomyomas in the oviducts of Japanese
both initiation and the post-initiation stages of carcino-
quail fed lycopene supplement.154
genesis was decreased in an animal model.177

POMEGRANATE
SOY ISOFLAVONES
The fruit of the tree Punica granatum (Figure 1),
grown mainly in the Mediterranean region, has been Soy isoflavones include genistein, daidzein, and gly-
shown to possess many medicinal properties such as citein. Genistein is the most active and abundant isofla-
being anti-oxidant and anti-inflammatory.155 The anti- vone (Figures 2 and 3F) found in soybeans (Figure 1)
oxidant activity of flavonoids obtained from pomegran- and soy products. It has selective estrogen receptor
ate juice was observed to be close to that of butylated modulator (SERM) properties similar to tamoxifen and
hydroxyanisole and green tea and significantly greater raloxifene.178 Epidemiological studies show an inverse
than red wine.156 –158 The polyphenol-rich fractions of association between dietary soy consumption and the risk
pomegranate inhibited growth of breast cancer cells159 of prostate,179 breast,180,181 and endometrial182 cancers.
and decreased new blood vessel formation in the Dietary genistein supplementation decreased the devel-
chicken chorioallantoic membrane model.160 In cell opment of mammary cancers in an animal model.183 Con-
culture studies, the pomegranate constituents cyanidin, sumption of a soy isoflavone mixture consisting of
delphinidin, and petunidin inhibited the growth of genistein and daidzein inhibited DMBA-induced prostate
breast cancer cells.161 Inhibition of skin tumor promo- cancer formation.184 Genistein inhibited prostate cancer
tion in CD1 mice was observed with topical application cell growth in culture by inducing G2/M arrest and apo-
of pomegranate seed oil.162 Pomegranate fruit extract ptosis, inhibited the secretion of PSA, and increased the
induced cell cycle arrest and apoptosis of human lung radiation effect against prostate cancer in cell culture
carcinoma A549 cells, significantly inhibited A549 tu- and in orthotopic and metastatic in vivo models.185,186
mor growth in nude mice,163 and decreased carcino- Genistein also potentiated the anti-tumor activity of
gen-induced lung carcinogenesis in A/J mice.164 cisplatin in BxPC-3 tumor xenografts.187 On the basis of
Malik et al165 observed growth inhibition in PC-3 these observations, several early clinical trials either
prostate cancer cells and CWR22Ru1 xenografts and with genistein or soy products have been completed. A
decreased serum level of PSA. Pomegranate extract also pilot study conducted in patients with prostate cancer
inhibited the proliferation of LNCaP and human umbil- and rising serum PSA levels suggested that soy isofla-
ical vein endothelial cells (HUVEC) cells and decrease vones may benefit some patients with prostate can-
the xenografted prostate cancer size, tumor microves- cer.188 Another phase II trial in biochemically relapsed
sel density, vascular endothelial growth factor (VEGF) prostate cancer patients showed a significant decrease
levels, and hypoxia-inducible factor (HIF)-1alpha ex- in the serum PSA level.189
pression.166 Pantuck et al167 conducted a phase II study We and others have previously reported that soy
in patients with rising PSA and gave 8 ounces of pome- isoflavones exert anti-cancer effects188,190 –192 and en-
granate juice daily until disease progression. PSA dou- hance the efficacy of chemotherapy193 and radiation
bling time increased from 15 months to 54 months therapy186,194 –198 in prostate cancer. Moreover, soy
after pomegranate juice supplementation (P ⬍.001). isoflavones have shown potent anti-oxidant and anti-
Statistically significant prolongation of PSA doubling inflammatory properties,199 –202 and therefore could po-
time suggested a potential role for pomegranate in tentially protect normal tissues from radiation toxicity,
prostate cancer prevention.167 Pomegranate consump- thereby decreasing urinary, intestinal, and sexual ad-
tion may retard prostate cancer progression and im- verse effects in patients receiving radiation therapy for
prove patient’s quality of life. prostate cancer. We conducted a pilot study to inves-
Phytochemicals and cancer 265

tigate if soy isoflavone supplementation during radia- authors concluded that the use of low doses of a COX-2
tion therapy would alleviate urinary, intestinal, and inhibitor in combination with DHA could be a strategy
sexual adverse effects in patients with localized pros- for prostate cancer chemoprevention.212
tate cancer.203 At 3 months, soy-treated patients had
less urinary incontinence, less urgency, and better erec-
THYMOQUINONE
tile function as compared to the placebo group. At 6
months, the symptoms in soy-treated patients were The anti-tumor activity of thymoquinone (TQ)
further improved as compared to the placebo group. seems promising both for chemoprevention and pre-
Soy isoflavones taken in conjunction with radiation venting drug-induced toxicity. Additionally, this com-
therapy could reduce the urinary, intestinal, and sexual pound exhibits some selectivity to cancer cells, since
adverse effects of treatment in patients with prostate normal human pancreatic ductal epithelial cells (HPDEs)
cancer. and mouse keratinocytes are resistant to the apoptotic
effects of.213,214 TQ also has been shown to have anti-
inflammatory activities in pancreatic ductal adenocarci-
OMEGA-3 FATTY ACIDS
noma (PDA) cells, and these activities are paralleled by
The benefits of omega-3 fatty acids have been cited inhibition of NF-␬B.215
for a variety of medical conditions,204,205 including can- Gali-Muhtasib et al216 evaluated the therapeutic po-
cer prevention and cancer-induced cachexia.206 The tential of TQ in two different murine colon cancer
ability of omega-3 fatty acids (eicosapentaenoic acid models, the 1,2-dimethyl hydrazine (DMH) and xeno-
[EPA], and docosahexaenoic acid [DHA]) to reduce graft models. In the DMH model, TQ significantly re-
inflammatory cytokines has generated much interest in duced the numbers and sizes of aberrant crypt foci by
the possibility of their modifying the acute phase re- 86%, and tumor multiplicity at week 20 was reduced by
sponse in cachectic patients—specifically to decrease 76%. In the xenograft model of HCT116 colon cancer
the production of acute-phase proteins. Fish oil supple- cells, TQ significantly (P ⬍.05) delayed the growth of
ments rich in omega-3 fatty acids have been shown to the tumor with increased evidence of apoptosis, sup-
reduce production of the cytokines interleukin (IL)-1, porting the potential use of TQ as a therapeutic agent
IL-6, and TNF in normal volunteers.207,208 EPA also has in human colorectal cancer.216 In another study, Al-
been shown to inhibit fat and protein breakdown in Johar et al reported modulation by TQ of aberrant crypt
animal models of cancer cachexia.209 Among the poly- foci in rats induced by azoxymethane.217
unsaturated fatty acids (PUFAs), the n-3 PUFAs (linoleic Kaseb et al218 observed in a xenograft prostate tu-
acid and its derivatives) have been extensively studied mor model that TQ inhibited growth of C4 –2B– de-
and exhibited chemopreventive potential in animal rived tumors in nude mice. This was associated with a
models of prostate, breast, and colon carcinogenesis, dramatic decrease in androgen receptor, transcription
and currently several preventive trials are ongoing factor E2F-1, and cyclin A as determined by Western
against these cancers.210 In a phase II study of high-dose blot analysis. Their findings clearly suggest that TQ may
fish oil capsules (7.5 g EPA plus DHA) in cachectic prove to be an effective agent in treating hormone-
patients a small subset of patients had weight stabiliza- sensitive as well as hormone-refractory prostate can-
tion or weight gain, which provided the promise that cers with a reasonable degree of selectivity.
omega-3 fatty acids may have therapeutic value at the
high dose used in the study.211
OTHER NATURAL AGENTS
The interest in modulating the acute-phase response
and inflammatory reaction to tumor cells has involved There are many other dietary and medicinal botani-
not only natural compounds such as omega-3 fatty cals and other natural compounds that are currently
acids but also synthetic anti-inflammatory drugs such as under investigation for their potential cancer chemo-
nonsteroidal anti-inflammatory drugs (NSAIDs) and preventive effects. These include ellagic acid, some
COX-2 inhibitors. Narayanan et al212 assessed the effi- triterpenes (such as lupeol, betulinic acid, ginsen-
cacy of both DHA and celecoxib, individually and in osides, oleanolic acid, etc), and ginkolide B. Ellagic acid
combination at low doses, in three prostate cancer cell (Figure 3I) is an antioxidant polyphenol present in
lines. They measured cell growth inhibition and induc- many fruits and vegetables including grapes, strawber-
tion of apoptosis, and expression of COX-2, NF-␬B, and ries, raspberries, pomegranate, and nuts, which ex-
retinoid X receptor (RXR). A 48-hour incubation of hibited chemopreventive activity against skin, lung,
prostate cancer cells with DHA or celecoxib induced esophageal, colon, bladder, prostate, and breast can-
apoptosis, and altered the expression of the above cers.219,220 Among the triterpenes, lupeol221 and betu-
proteins. Interestingly, the modulation of expression linic acid222 have been extensively investigated for
was more pronounced in cells treated with low doses their chemopreventive activities221 and showed a
of DHA and celecoxib in combination than in cells broad spectrum of activity against multiple cancer
treated with the higher doses of individual agents. The types in both cell culture and animal models. Ginko
266 N.P. Gullett et al

biloba extracts and its constitutent ginkolide B also also can sensitize tumors to radiation232 and to chemo-
have been tested for their chemopreventive activities therapeutic agents233 and thus has the potential to be
and showed some promise against several cancer used not only for prevention but also for treatment.
types.223,224 They showed that capsaicin derived from red chili,
TQ-derived black cumin, anethole from fennel, eugenol
from cloves, and zerumbone derived from ginger also
MECHANISMS OF NATURAL
exhibit similar activity. The potential of these com-
CHEMOPREVENTIVE COMPOUNDS
pounds is self-evident not only in cell culture models
Recent entire genomic sequencing results revealed but also in animal models of human cancers. Various
that a lung tumor carried more than 23,000 mutations. clinical trials have revealed that these agents are quite
A smoker develops one mutation for every 15 ciga- safe and well tolerated even at very high doses. For
rettes smoked. This indicates the complexity of human example, curcumin tested even at 15 g/d for 3 months
cancers. Furthermore, there are approximately 25,431 had no dose-limiting toxicity. The cell signaling path-
human genes, and out of these 2,995 genes have been ways activated by natural dietary agents are diverse.
linked with 153 cell signaling pathways and about 350 Moreover, the same compound may activate different
genes have been linked directly with any given cancer. signaling pathways on different cell types. Some of the
Thus, targeting a single gene is unlikely to treat or important signaling pathways targeted by botanicals
prevent any cancer. There has been a paradigm change are shown in Figure 4 and described below.
in the area of drug development moving from mono-
targeted drugs to multi-targeted drugs. Most natural p53 Family
products are naturally designed to be multi-targeted.
The tumor-suppressor p53 plays a pivotal role in
Thus, promiscuity is becoming a virtue in drug devel-
controlling the cell cycle, apoptosis, genomic integrity,
opment.225
and DNA repair.234,235 Activated p53 binds to regulatory
Among all drug targets, transcription factors NF-␬B
DNA sequences and activates certain genes resulting in
and STAT3 that regulate the expression of more than
cell cycle inhibition, apoptosis, genetic stability and
400 gene products appear to be vital for both preven-
inhibition of angiogenesis.236 –238 Furthermore, acti-
tion and treatment of cancer.226 –230 They regulate trans-
vated p53 can behave both as transactivator and tran-
formation of normal cells to tumor cells, survival of
srepressor.239,240 Certain botanical compounds may in-
tumor cells, proliferation of tumor cells, invasion, an-
duce cell cycle arrest or apoptosis by activating p53.
giogenesis, epithelial–mesenchymal transition (EMT),
For example, EGCG induces the expression of p53 and
and metastasis. Most tumor cells appear to express
its targets p21 and BAX in prostate cancer and breast
constitutively active forms of these transcription fac-
cancer cells.241,242 Induction of cell cycle arrest and
tors.226 –229 Additionally, most risk factors for cancer
apoptosis was observed with luteolin which activated
such as grilled meat, high fat, stress, alcohol, tobacco,
p53 and its targets p21, BAX and PUMA.175,243 Apopto-
radiation, environmental pollutants, and infectious
sis through p53-dependent BAX induction was ob-
agents (eg, human papilloma virus [HPV], human im-
served in breast and bladder cancer cells exposed to
munodeficiency virus [HIV], hepatitis B [HBV] and C
curcumin.244,245 Induction of p53-mediated apoptosis
[HCV] viruses, Helicobacter pylori) all have been
by activating its mitochondrial translocation has also
shown to activate NF-␬B. Similarly, most growth factor
been observed with curcumin.246 Resveratrol induced
receptors that have been linked with cancer, such as
apoptosis only in cells expressing wild-type p53247 and
EGFR, HER2, TNF receptor (TNFR), fibroblast growth
activated the expression of p21, p27, BAX, PUMA,
factor receptor (FGFR), and platelet-derived growth
MDM2, and cyclin G.248 Soy isoflavone genistein acti-
factor receptor (PDGFR), all have been found to acti-
vated p53 and p21 and induced G2/M arrest and apo-
vate NF-␬B. Thus, suppression of NF-␬B and STAT3
ptosis in human malignant glioma cell lines.249 Botani-
pathways may be an ideal strategy for both prevention
cals may also induce cell cycle arrest and apoptosis in
and treatment of cancer.230
mammalian cells containing two closely related pro-
Aggarwal and coworkers have identified compounds
teins, p63 and p73.250,251 For example, EGCG induced
from vegetables, fruits, cereals, legumes, spices and
apoptosis by activating p73-dependent expression of
nuts which can suppress NF-␬B and STAT3 pathways
p21, reprimo, cyclin G1, PERP, MDM2, WIG1, and
and their downstream gene products. They have also
PIG11252 and activated p73 in multiple myeloma cells
found compounds from traditional Chinese medicine
in vitro.253
and Indian medicine that can abrogate both constitu-
tive and inducible NF-␬B and STAT3 pathways. For
example, they have shown that curcumin can suppress Nuclear Factor-␬B
both NF-␬B and STAT3 pathways in a variety of tumor NF-␬B is a master transcription factor that promotes
cells, leading to inhibition of survival of tumor cells, transcription of target genes through the recruitment of
suppression of proliferation, and invasion.231 This agent coactivators and corepressors.254 There are many activa-
Phytochemicals and cancer 267

Figure 4. Some of the important molecular pathways affected by phytochemicals.

tors of NF-␬B, including free radicals, inflammatory cy- may be one of the important factors for the proapop-
tokines, carcinogens, tumor promoters, gamma-radi- totic function of curcumin and induction of apoptosis
ation, and UV light. NF-␬B target genes are important in glioma cells.263
for cellular growth and transformation, inflamma-
tion, apoptosis, invasion, metastasis, and sensitivity
Signal Transducers and
to chemotherapy and radiation. Natural compounds
Activators of Transcription
such as curcumin,255,256 resveratrol,257 EGCG,258 lyco-
pene,259 genistein,193 and luteolin171 are potent inhibi- The STAT pathway was discovered during the
tors of NF-␬B. These compounds may block NF-␬B study of transcriptional activation in response to
signaling pathways that activate the NF-␬B signaling interferon.265 Seven STAT family members (STAT1,
cascade, translocation of NF-␬B to the nucleus, DNA STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6)
binding of the dimers, or interactions with the basal have been cloned in mammalian cells. Constitutive acti-
transcriptional machinery. The inhibition of NF-␬B re- vation of STAT3 and STAT5 has been reported in certain
sults in inhibition of its target genes including Bcl-2, solid tumors as well as multiple myeloma, lymphoma and
cyclin D1, matrix metalloproteases, VEGF, and others. leukemia suggesting its importance in cancer cells.266
Green tea cathecins,267 resveratrol,268 genistein,269 and
Activator Protein-1 curcumin270 have been shown to modulate STAT activa-
AP-1 is a group of proteins that activate transcription tion in cancer cells. Green tea polyphenols inhibited
and mediate gene repression.260 The target genes of STAT3 expression in TRAMP mice contributing to
AP-1 include modulators of survival, metastasis, angio- growth inhibition and apoptosis,271 and inhibited an-
genesis, proliferation, invasion, and differentiation.260 giogenesis by inhibiting the expression of VEGF and
Botanicals such as green tea,261 resveratrol,262 and cur- matrix metalloproteinase-9 (MMP-9) mediated through
cumin263 have been reported to suppress AP-1 activa- STAT3 suppression in breast cancer.267 Luteolin inhib-
tion. EGCG inhibits the transcriptional activity of AP-1 ited phosphorylation of STAT3 and inhibited the ex-
in cancer cells.261,264 Resveratrol inhibits TPA-induced pression of cyclin D1, survivin, Bcl-x(L), and VEGF in
AP-1 DNA binding by inhibiting the nuclear expression hepatoma cells.173 Resveratrol modulated IL-6 –induced
of c-Jun and c-Fos.262 Suppression of AP-1 activity also ICAM-1 gene expression by attenuating STAT3 phos-
268 N.P. Gullett et al

phorylation,268 while tumor-induced T-cell apoptosis (IFN)-gamma may enhance the development of can-
by STAT5A was prevented by curcumin.272 cer.281 Thus, activation of T cells or production of
cytokines such as IFN-gamma or IL-12 may have a
Ubiquitin-Proteasome Pathway cancer preventive effect. Immunomodulating effects of
Dou has reported proteasome inhibition by vitamin A, zinc, vitamin E, green tea, and omega-3 fatty
genistein.273 Nam et al72 observed that EGCG potently and acids have been well described. Green tea polyphenols
specifically inhibits the chymotrypsin-like activity of the prevented UV radiation-induced mouse skin carcino-
proteasome in vitro (IC50⫽ 86 –194 nmol/L) and in genesis by a number of mechanisms: inducing IL-12–
cultured tumor cells (1–10 ␮mol/L) at the concentra- dependent DNA repair; activating cytotoxic (CD8⫹) T
tions found in the serum of green tea drinkers.72 Re- cells; inducing tumor cell apoptosis and inhibiting an-
cently proteasome inhibition has become increasingly giogenic factors;282,283 and enhancing CD8⫹ T-cell–me-
important in cancer and drug resistance research. The diated anti-tumor immunity induced by DNA vaccina-
vast majority of regulated proteolysis in eukaryotic cells tion.284 Curcumin restored progenitor, effector, and
occurs through the actions of the ubiquitin–protea- circulating T cells in tumor-bearing animals.272 Genistein
some pathway.273 Although it would seem disastrous to increased host resistance to B16F10 tumor by increasing
alter the activity of this crucial protein degradation activities of cytotoxic T cells and nautral killer (NK)
system, proteasome inhibition has been well estab- cells.285 Resveratrol enhanced IFN-gamma expression
lished as a rational strategy for multiple myeloma, non- in CD8⫹ T cells, leading to immune stimulation, and
Hodgkin lymphoma, and some other solid tumors.273 suppressed the CD4⫹CD25⫹ cell population, which has
Understanding the involved mechanism of action has tumor-derived regulatory effects.286
led to integration of this class of drugs into combina-
tion regimens that use both proteasome inhibitors and Inhibition of Angiogenesis
standard chemotherapeutics. Angiogenesis plays an important role in cancer de-
velopment, progression, and metastasis, as well as con-
Growth Factors tributing to resistance to chemotherapy and radiation.
Growth factors such as EGF, PDGF, FGF, tumor EGCG inhibited viability, capillary tube formation, and
growth factor (TGF), insulin-like growth factor (IGF), migration of HUVEC, and inhibited the expression of
and colony-stimulating factor (CSF) are important in the angiogenic and metastasis markers (von Willebrand fac-
development of cancer. Activation of signaling pathways tor, VEGF, CD31, MMP-2, MMP-7, MMP-9, and MMP-12)
by these molecules results in increased cell growth, sup- in a xenograft model of pancreatic cancer.287 Luteolin
pression of apoptosis, and invasion by cancer cells. inhibited VEGF-induced angiogenesis and tumor
Growth factor receptor activation results in the activa- growth in a murine xenograft model.288 A number of
tion of several downstream signaling pathways such as studies suggest that angiogenesis is also inhibited by
PI3K-AKT and Ras-MAPK. Natural compounds may tar- curcumin,289,290 genistein,291,292 rutin,292 naringin,292
get these signaling pathways and inhibit cancer devel- apigenin,292 and vitamin E.292
opment. For example, curcumin inhibits the EGFR and
IGF receptor pathways and enhances the efficacy of Antiviral Effects
5-FU and oxaliplatin.274,275 Curcumin may enhance FOL- Clinical trials have suggested that antioxidant ther-
FOX (folinic acid, 5-fluorouracil, and oxalipatin) treat- apy may have a beneficial effect in patients with
ment by inhibiting EGFR, HER-2, HER-3 and IGF-1R as chronic hepatitis C (CHC) infection. Melhem et al293
well as AKT and COX-2.275 EGCG potentiated the ef- conducted a phase I clinical trial assessing 50 CHC
fects of erlotinib in head and neck cancer by inhibiting patients treated with seven antioxidant oral prepara-
the activation of EGFR, AKT, and ERK88,276 and inhib- tions along with four different intravenous prepara-
ited the activation of IGF-1 receptor in colon cancer tions daily for 10 weeks and monitoring HCV-RNA
cells.277 Inhibition of EGFR by EGCG was associated levels, liver enzymes, and liver histology. The results
with altered order of fatty acids and fluidity changes in showed normalization of liver enzymes in 44% of pa-
the colon cancer cell membrane.278 Luteolin inhibited tients, a decrease in viral load in 25% of patients, and
IGF-1–induced activation of IGF-1R and AKT in PC-3 histologic improvement in 36% of patients. In another
and DU145 prostate cancer cells and suppressed acti- study, 23 CHC patients refractory to IFN-alpha therapy
vation of EGFR and MAPK/ERK signaling.279 Luteolin were treated with high-dose alpha-tocopherol for 12
inhibited EGFR and induced growth inhibition and ap- weeks. In 11 of 23 patients, aminotransferases ALT and
optosis in pancreatic cancer cells.280 AST were lowered by 46% and 35%, respectively, but
this initial response was followed by a rapid relapse
Immunologic Effects upon cessation of treatment with vitamin E.294
It has been reported that the absence of functional T Chronic infection with HCV and/or HBV is associ-
cells or T-cell– derived cytokines such as interferon ated with the majority of hepatocellular carcinoma
Phytochemicals and cancer 269

(HCC) cases. Recent estimates for the United States plastic lesions in the colon and liver of rats.303 Brassica
have attributed 47% of cases to HCV alone, 15% to HBV juice increased CYP1A2 and GST in the human hepa-
alone, and 5% to co-infection with both viruses.295 The toma cell line HepG2.303 In recent human intervention
remaining 33% of cases appear to be due to non-viral studies, brussels sprouts and red cabbage induced
causes. Once HCV infection develops into cirrhosis, GSTs.303 Constituents of brussels sprouts can protect
HCC develops at an annual rate of 5% to 7%.296 To date, DNA by direct scavenging, eg, hydroxyl radical and
there have been few randomized clinical trials testing other oxidants, without pro-oxidant effects, at concen-
the chemopreventive effect of antioxidants on hepato- trations potentially achieved by modest intake of the
carcinogenesis. In one clinical trial, Takagi et al297 di- vegetables.304 Dietary broccoli induced CYP1A1 en-
vided 83 patients with liver cirrhosis and chronic HCV zyme activities in rat liver,305 as well as phase II en-
infection into two groups and treated one group with zymes, QR and GST, in human prostate cells.306 Broc-
vitamin E. After a follow-up of 5 years, cumulative coli supplements induced GST activity in blood
tumor-free survival and cumulative overall survival lymphocytes and colon mucosa of ICR(Ha) mice.307
rates were higher in the vitamin E group compared to
the control group, but this difference was not statisti- RANK/RANKL/Osteoprotegerin
cally significant.
In an animal model of hepatocarcinogenesis in rats, The most important cytokine machinery that is in-
lycopene decreased the size of preneoplastic foci in volved in bone metastasis of cancer cells is the osteo-
liver induced by diethylnitrosamine but did not reduce protegerin (OPG)/receptor activator of NF-␮B (RANK)/
the number of lesions.298 Lycopene reduced the num- RANK ligand (RANKL)/MMP-9 system.193 The molecular
ber of liver tumor-bearing rats by 50% and reduced the triad OPG/RANK/RANKL plays important roles in bone
average number of tumors per animal by 88%.299 Since remodeling. RANKL is expressed by osteoblasts and is
lycopene has anti-viral and anti-carcinogenic effects the necessary and sufficient for osteoclastogenesis.308
potential of prevention of HCC by administering lyco- RANKL binds to its receptor RANK, present at the
pene along with anti-viral treatment in HCV infection is surface of osteoclast precursors and mature osteoclasts,
an attractive concept. Previous studies have shown that inducing osteoclast formation and activation.308,309 It
increased lycopene levels have been associated with has been reported that RAW264.7 cells, one of the
increased clearance of oncogenic HPV infection.300 osteoclast precursor macrophages, can differentiate to
Other anti-oxidants have shown similar anticarcino- osteoclasts when cultured with 25 to 200 ng/mL
genic effects. Beck et al301 has demonstrated that sele- RANKL.309 The main features of osteoclasts include the
nium-deficient mice are more prone to develop muta- abilities to absorb bone, express tartrate-resistant acid
tions in the viral genome of both the coxsackie and phosphatase (TRAP), and express proteases, including
influenza viruses resulting in conversion of non-virulent MMP-9.309,310 RANKL activity can be blocked by the
strains of virus to virulent strains. soluble decoy receptor OPG, resulting in prevention of
bone resorption.311 The expression of OPG/RANK/
RANKL also has been found in some cancer cells and
Modulation of Phase I and Phase II Enzymes active T cells, suggesting their effects on cancer bone
One of the most important mechanisms of chemo- metastasis.312–314 RANKL also enhances expression and
prevention by cruciferous plants appears to be induc- activity of MMP-9,310 which is a well-known protease
tion of phase II enzymes and inhibition of phase I for cancer cell invasion and metastasis. Thus, OPG/
enzymes. Blocking carcinogen metabolite activation RANK/RANKL/MMP-9 system is believed to be a ther-
and enhancing carcinogen detoxification are two meth- apeutic target for the treatment of cancer bone metas-
ods of decreasing carcinogenicity. Many isothiocya- tasis.314
nates (ITCs) mediate one or both of these responses Genistein could enhance antimetastasis activity of
and they are effective inhibitors of tumorigenesis in docetaxel by regulation of osteoclast differentiation
various animal models, most strikingly in lung and and formation. It has been known that metastatic can-
esophagus cancer. The major mechanism for prevent- cer cells release RANKL and OPG, which act on oste-
ing carcinogenesis appears to be selective inhibition of oclast precursor cells to regulate the production of
cytochrome P450 enzymes. Numerous ITCs are induc- functioning osteoclasts in the bone microenviron-
ers of phase II detoxification enzymes such as glutathi- ment.315,316 RANKL stimulates the formation and differ-
one S-transferase (GST) and NAD(P)H: quinone oxi- entiation of osteoclasts via binding to its receptor,
doreductase (QR). Some compounds are remarkably RANK, expressed in osteoclast precursors and mature
potent, such as sulforaphane and PEITC, components osteoclasts.315,316 OPG is a decoy receptor that prevents
of broccoli and watercress, respectively.302 binding of RANKL to RANK by competitive binding to
The juices of watercress and brussels sprouts con- RANKL, leading to the inhibition of osteoclast forma-
tain high concentrations of glucotropeolin and sinigrin, tion and osteoclast activity308,316 in the presence of
respectively, and attenuated DNA-damage and preneo- cancer cells. Yonou et al317 reported that OPG de-
270 N.P. Gullett et al

creased human prostate cancer burden in human adult binding activity in prostate cancer cells. This is a novel
bone implanted into SCID mice. In support of these epigenetic pathway that activates tumor-suppressor
investigators, we found that genistein upregulated the genes by modulating either H3–K9 methylation or
expression of OPG in PC-3 culture and PC-3 prostate deacetylation at gene promoters leading to inhibition
cancer bone tumors.193 Genistein also inhibited RANKL of the AKT signaling pathway.
expression and secretion from PC-3 cancer cells, sug- Majid et al323 also reported that BTG3 mRNA expres-
gesting an inhibitory effect of genistein on osteoclast sion was downregulated in cancer tissues and cells.
formation. In contrast, docetaxel inhibited the expres- Genistein and 5-Aza-cytidine (5Aza-C) induced BTG3
sion of OPG and the inhibition of OPG could promote mRNA expression in all PC cell lines. Complete meth-
the formation and the activity of osteoclasts.193 More ylation of BTG3 promoter in tumor samples and cancer
importantly, we found that genistein inhibited differen- cell lines was observed. Genistein and 5Aza-C treat-
tiation and formation of osteoclasts, suggesting that ment significantly decreased promoter methylation, re-
genistein has an inhibitory effect on osteolysis.193 In- activating BTG3 expression. Genistein and 5Aza-C in-
deed, from ex vivo bone tumor x-rays, we observed creased levels of acetylated histones 3, 4, histone 3
much less osteolysis in genistein-treated bone tumor dimethylated at lysine 4, histone 3 trimethylated at
than in control bone tumor. Osteoclastic activity is lysine 4, and RNA polymerase II, decreased DNA
believed to be a critical target for therapy against bone methyl transferase and methyl-binding domain protein
metastasis. Recent reports also showed that genistein 2 activity, and increased histone acetyl transferase (HAT)
supplementation decreased the ratio of RANKL/OPG in activity. Thus, they showed that BTG3 is silenced in pros-
healthy human serum and negatively regulated RANKL- tate cancer and can be reactivated by genistein-induced
induced osteoclastic differentiation, supporting our promoter demethylation and active histone modification.
findings.318,319 Thus, regulation of the ratio of RANKL/ Genistein showed similar effects to that of 5Aza-C.
OPG could be a mechanism by which genistein en-
hanced the anti-tumor and antimetastatic activity of MicroRNAs
docetaxel in PC-3 prostate cancer bone metastasis.
MicroRNAs (miRNAs) constitute an evolutionarily
conserved class of small noncoding RNAs that are en-
DNA Methylation, Histone dogenously expressed with crucial functions in funda-
Acetylation, Chromatin Structure mental cellular processes such as cell cycle, apoptosis
Methylation of promoter regions of tumor-suppres- and differentiation.324 Disturbance of miRNA expres-
sor genes leads to their silencing and has been reported sion and function leads to deregulation of basic cellular
in many cancers.320 In addition, methylation of certain processes leading to tumorigenesis.324 A growing body
genes has been associated with resistance to chemo- of experimental evidence suggests that human tumors
therapy and radiation.321 Inhibition and reversal of have deregulated expression of microRNAs, which
DNA methylation may be one of the mechanisms for have been proposed as novel oncogenes or tumor sup-
the chemopreventive activity of natural compounds. pressors. Studies have shown that microRNA expres-
Genistein has been reported to prevent and reverse sion patterns may serve as phenotypic signatures of
DNA methylation, increase histone acetylation and different cancers and could be used as diagnostic, prog-
modify chromatin structure in prostate cancer nostic, and therapeutic tools. Saini et al324 reviewed the
cells.322,323 role of microRNAs in prostate carcinogenesis and di-
Kikuno et al322 tested the hypothesis that genistein etary factors that may play an important role in the
activates expression of several aberrantly silenced tu- process of carcinogenesis through modulation of
mor-suppressor genes that have unmethylated promot- miRNA expression. It has been proposed that dietary
ers such as PTEN, CYLD, p53, and FOXO3a. They modulation of miRNA expression may contribute to the
reported that genistein activated tumor-suppressor cancer-protective effects of dietary components.
genes through remodeling of the heterochromatic do-
mains at promoters in prostate cancer cells by modu-
CONCLUSIONS
lating histone H3-Lysine 9 (H3–K9) methylation and
deacetylation. Genistein activation involved demethyl- The results of epidemiological, preclinical, and early
ation and acetylation of H3–K9 at the PTEN and the clinical studies suggest that selected dietary products
CYLD promoter, while acetylation of H3–K9 at the p53 may play a role in cancer prevention and treatment.
and the FOXO3a promoter occurred through reduction Many of these agents target multiple signal transduc-
of endogenous SIRT1 activity. There was a decrease of tion pathways. The key challenge to researchers is how
SIRT1 expression and accumulation of SIRT1 in the best to use this information for effective cancer preven-
cytoplasm from the nucleus. Increased expression of tion and treatment. Development of synthetic analogues
these tumor-suppressor genes was also reciprocally re- of natural compounds and/or using nanotechnology
lated to attenuation of phosphorylated-AKT and NF-␬B approach may increase the potency and bioavailability
Phytochemicals and cancer 271

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