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Ann. N.Y. Acad. Sci.

ISSN 0077-8923

A N N A L S O F T H E N E W Y O R K A C A D E M Y O F SC I E N C E S
Issue: Nutrition and Physical Activity in Aging, Obesity, and Cancer

Combinatorial strategies employing nutraceuticals for


cancer development
Yogeshwer Shukla and Jasmine George
Proteomics Laboratory, Indian Institute of Toxicology Research (CSIR), Lucknow, Uttar Pradesh, India

Address for correspondence: Yogeshwer Shukla, Proteomics Laboratory, Indian Institute of Toxicology Research (CSIR),
Mahatma Gandhi Marg, Lucknow 226001, Uttar Pradesh, India. yogeshwer_shukla@hotmail.com; yshukla@iitr.res.in

Cancer is the second leading cause of death worldwide. Therefore, the fight against cancer is one of the most important
areas of research in medicine, and one that possibly contributes to the increased interest in chemoprevention as an
alternative approach to the control of cancer. Cancer prevention by nutraceuticals present in fruits and vegetables
has received considerable attention because of their low cost and wide safety margin. A substantial amount of
evidence from human, animal, and cell culture studies has shown cancer chemopreventive effects from these natural
products. However, single-agent intervention has failed to produce the expected outcome in clinical trials; therefore,
combinations of nutraceuticals are gaining increasing popularity. Thus, combinations of nutraceuticals that mimic
real-life situations and are competent in targeting multiple targets with very little or virtually no toxicity are needed.
In this review, we summarize the results of those studies that report combinatorial cancer chemopreventive action
of various nutraceuticals and their combinations with anticancer drugs.

Keywords: nutraceuticals; cancer; chemoprevention; anticancer drugs; clinical trials

Introduction prove efficacy with minimized toxicity. Nowadays,


an emphasis has been placed on the development of
Worldwide, about 12.7 million cases of and 7.6 mil-
novel combination therapies/chemoprevention us-
lion deaths from cancer are estimated to have oc-
ing nutraceuticals that are competent in targeting
curred in 2008, with 56% of the cases and 64% of
multiple targets against cancer. Many plant-derived
the deaths in economically developing countries. It
products, in combination with one another, have
is estimated that there will be 16 million new cases
been shown to increase the efficacy of cancer con-
every year by 2020.1 Epidemiological and labora-
trol and have a broader spectrum of activity.4 They
tory data clearly indicate that cancer is linked to not
may act together to give either a synergistic action to
only genetics, but also lifestyle, including dietary
combat tumors through regulation of different sig-
and environmental exposure.2
naling pathways or compensation for the opposite
It has been estimated that more than two thirds of
properties in cancer cell proliferation or apopto-
human cancer cases could be prevented by lifestyle
sis. In this paper, the data for using nutraceuticals
modifications, including dietary habits.3 Substantial
in combination to combat a variety of cancers are
epidemiologic and experimental data exist to sug-
reviewed.
gest that a healthy diet, that is, one high in fruits and
vegetables, decreases the risk of a variety of chronic
Nutraceuticals
diseases, including cancer. To date, hundreds of nat-
ural and synthetic compounds have been shown The term nutraceutical was coined from “nutrition”
to possess promising cancer-preventive properties. and “pharmaceutical” by Stephen DeFelice in 1989.
Despite this, both the incidence and cure rate of A nutraceutical can be defined as “a food (or part
cancer have not improved much and thus have ne- of a food) that provides medical or health bene-
cessitated that some modifications be made to im- fits, including the prevention and/or treatment of a

doi: 10.1111/j.1749-6632.2011.06104.x
162 Ann. N.Y. Acad. Sci. 1229 (2011) 162–175 
c 2011 New York Academy of Sciences.
Shukla & George Nutraceuticals in combination for cancer prevention

Figure 1. Common sources of nutraceuticals known to exhibit cancer-chemopreventive properties along with their chemical
structures.

disease.”5,6 Such products may range from isolated often linked to neoplastic development and acts as a
nutrients, dietary supplements, and specific diets to driving force in premalignant and malignant trans-
genetically engineered designer foods, herbal prod- formation of cells.11 There is now growing evidence
ucts, and processed foods such as cereals, soups, supporting the notion that chronic inflammation
and beverages. In addition, these products are less may lead to malignancies of different organs includ-
expensive, safer, and more readily available than are ing the skin, stomach, colon, breast, prostate, and
synthetic agents.7 Some nutraceuticals are currently pancreas.12–14 One of the most important links be-
under clinical trials, but many have already been tween inflammation and cancer is proinflammatory
approved for clinical use.5,8,9 In the past decade, a transcription factor nuclear factor-kappa B (NF-
number of nutraceuticals have been identified with ␬B).15 NF-␬B is a ubiquitous and evolutionarily
diverse chemical structures to fight against cancer conserved transcription factor that regulates the ex-
(Fig. 1). pression of genes involved in the transformation,
survival, proliferation, invasion, angiogenesis, and
Role of nutraceuticals against neoplastic
metastasis of cancer cells. Many nutraceuticals are
development
shown to exert chemopreventive/anticancer activity
In the last two decades, much evidence has emerged by suppressing the NF-␬B signaling pathway.16–19
indicating that, at the molecular level, most chronic Humans are unknowingly exposed to environ-
diseases, including cancer, are caused by a dysreg- mental insults such as pesticides, fumes, automo-
ulated inflammatory response.10 Inflammation is bile exhaust, ionizing, ultraviolet radiation, etc.,

Ann. N.Y. Acad. Sci. 1229 (2011) 162–175 


c 2011 New York Academy of Sciences. 163
Nutraceuticals in combination for cancer prevention Shukla & George

which cause the formation of oxidants by metabolic cancer incidence by inducing apoptosis with the use
activity within cells. When in excess, these of various mechanisms in multiple types of cancer
oxidants can cause an imbalance, leading to cells.30
production of reactive oxygen species (ROS) or ox-
idative stress.20 Normally, there is equilibrium be- Nutraceuticals in combination
tween ROS generation and antioxidant defense sys- Nutraceuticals have proven very promising in detox-
tems, and any imbalance between them can lead ifying and inhibiting anti-inflammatory and anti-
to oxidative stress. Oxidative stress can alter the cell growth signaling pathways that can culminate
structure of cellular components such as DNA, pro- in apoptosis and/or cell cycle arrest as mentioned
teins, and lipids, which, when left unrepaired, can above. A synergistic therapeutic effect is defined as
induce cell death or cancer development through a stronger effect by the combination of two or more
various mechanisms.21 Imbalance of oxidative stress compounds compared to individual compounds. It
has been shown to be able to trigger the activation is believed that chemotherapeutic/chemopreventive
of multiple signaling pathways, including the acti- combinational approaches have been used to reduce
vation of various transcription factors (e.g., NF-␬B) drug toxicity, to delay the development of cancer
and phosphorylation cascades of mitogen-activated cells, and to reach a greater effect than with one
protein kinases (MAPKs).22 Thus, cancer control active agent alone.
can be achieved by decreasing the rate of oxidative Nutraceuticals may act independently or in
stress and enhancing antioxidant defense mecha- combination as anticancer agents. The additive
nisms. The potential role of dietary antioxidants and synergistic effects of nutraceuticals may be re-
present in nutraceuticals in reducing the risk of can- sponsible for their potent antioxidant and anti-
cer by suppressing the state of oxidative stress has cancer activities, and the benefit of a diet rich in
been well documented in the literature.23–25 fruits and vegetables is attributed to the complex
Another major cause of neoplastic development mixture of nutraceuticals present in whole foods.31
is the dysregulation of body homeostasis, a funda- This hypothesis partially explains why a single an-
mental characteristic of living beings. The balance tioxidant cannot replace the combination of natural
between cell proliferation and apoptosis is a crit- nutraceuticals in achieving health benefits. Lim-
ical step in the maintenance of homeostasis.26,27 ited knowledge is available regarding any interac-
The dysregulation of apoptosis is a hallmark of tion between/among nutraceuticals in suppressing
cancer and is critical for cancer development and neoplastic development. Some of the combinatorial
tumor cell survival.28 Cancer cells can invade effects of nutraceuticals against neoplastic develop-
apoptosis mainly through two signaling pathways: ment are described in the following sections.
extrinsic (receptor mediated) and intrinsic (mi-
tochondria mediated). The extrinsic pathway is Prostate cancer (PCa)
triggered by a complex set of antiapoptotic and PCa is the most prevalent malignancy in men, with
proapototic proteins, including caspase family pro- an expected 217,730 new cases and 32,059 deaths
teins, Bax, B cell lymphoma (Bcl)-2 family proteins, due to this cancer in 2010 in the United States
cytochrome c, apoptotic protease activating factor alone.32 Prostate carcinogenesis has been viewed as
(Apaf)-1, and death receptors (APO-1/TRAIL). The a multistage and complex process consisting of initi-
intrinsic pathway is initiated by cellular develop- ation, promotion, and progression. Despite surgical
mental signals or as a result of severe cellular stress, and diagnostic advances, the incidence of PCa is
including DNA damage. Some antiapoptotic pro- expected to rise in the near future. Both the high
teins, such as Bcl-2 and Bcl-2 extra large (Bcl-xL),29 rate of occurrence and the long latency period to
are overexpressed in many cancer types. There- clinically significant disease make PCa an ideal dis-
fore, selective downregulation of antiapoptotic pro- ease for pharmacologic or nutritional chemopre-
teins and upregulation of proapoptotic proteins in vention.33,34
cancer cells offer promising therapeutic interven- Cruciferous vegetables are a group of vegetables
tions for cancer treatment. A number of nutraceu- named by their cross-shaped flowers and include
ticals, mostly phytochemicals derived from dietary broccoli, Brussel sprouts, watercress, cabbage, kale,
or medicinal plants, have shown potential to reduce cauliflower, kohlrabi, and turnips. Compared with

164 Ann. N.Y. Acad. Sci. 1229 (2011) 162–175 


c 2011 New York Academy of Sciences.
Shukla & George Nutraceuticals in combination for cancer prevention

Figure 2. Synergistic inhibitory action of nutraceuticals in combination and with anticancer drugs against various cancers.

other families of vegetables, they contain a signifi- ment with curcumin caused apoptosis and cell
cant amount of isothiocyanates, and strong anticar- cycle arrest but inhibited cell growth, activation
cinogenic activities of cruciferous vegetables have of signal transduction, and transforming activi-
thus been attributed to the high abundance of isoth- ties in both androgen-dependent and androgen-
iocyanates.35 Phenylethylisoathiocyanate (PEITC) independent PCa cells in culture.40 Curcumin has
is one such naturally occurring isothiocyanate com- been shown to inhibit the induction of cancers of the
pound that has attracted a great deal of atten- skin, forestomach, duodenum, and colon in mod-
tion due to its remarkable cancer-chemopreventive els of chemical carcinogenesis in mice and rats.41–43
properties. The mechanisms by which PEITC pro- The combined treatment of low doses of PEITC
tects against cancer have been shown to involve and curcumin has been shown to suppress human
the deletion of preneoplastic cells through induc- PCa cell growth in vitro as well as in immunodefi-
tion of cell cycle arrest and apoptosis36,37 and in- cient (Nu/Nu) mice bearing xenografts of androgen-
hibition of carcinogen activation via modulation of independent human PCa cells (PC-3) and in the
cytochrome P450-dependent monooxygenases and TRAMP mouse model of PCa by inhibition of Akt
enhancement of the antioxidant response element- and NF-␬B signaling pathways (Fig. 2).44,45
dependent carcinogen detoxification enzyme.38 Another nutraceutical from soy, genistein, has
Curcumin (diferuloyl-methane), the yellow pheno- gained popularity in the fight against cancer within
lic pigment found in the spice turmeric, extracted the last decade.46 Epidemiological evidence indi-
from the rhizome of the plant Curcuma longa, cates that there are positive associations between
has been shown to possess strong antioxidant and chemoprevention and the main source of genistein,
anti-inflammatory effects.39 Due to these proper- soy consumption.47,48 Soy has been found to in-
ties, curcumin has been very widely investigated hibit the growth of transplantable human prostate
for its potential chemopreventive activity. Treat- carcinomas and tumor angiogenesis in mice.49

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Nutraceuticals in combination for cancer prevention Shukla & George

Resveratrol, a polyphenolic phytoalexin found in Apples are widely and commonly consumed and
red wine and grape-derived products, has also re- are one of the main contributors of phytochemicals
cently received much attention in regards to can- in the human diet. They are rich in hydroxycinnamic
cer prevention. Reports have shown that resvera- acids, dihydrochalcones, flavan-3-ols/procyanidins,
trol suppressed chemically induced mammary can- anthocyanins, and flavonols. Quercetin 3-glycosides
cer in rats.50–52 Genistein and resveratrol, alone and (Q3G), chlorogenic acid, catechin, epicatechin and
in combination, suppress PCa development in the their dimers, phloridzin, and cyanidin 3-glycosides
SV-40 Tag rats by reducing cell proliferation and are the main individual phenolics in apples. Ap-
insulin-like growth factor-1 protein expression and ple consumption has been linked to a lowered risk
by increasing apoptosis in the prostate (Fig. 2).53 of cancer, coronary heart disease, asthma and pul-
Tea from the Camellia sinensis species of the monary function problems, and type II diabetes.58
Theaceae family is one of the most ancient and, af- The synergistic effects of apple extracts and Q3G
ter water, is the most widely consumed beverage in were assessed by measurement of the inhibition of
the world. Tea is rich in polyphenolic constituents, MCF-7 human BC cells proliferation (Fig. 2).59
which have strong anti-inflammatory, antioxidant, The chemopreventive potential of genistein, as
anticarcinogenic, as well as antimutagenic proper- mentioned above, has attracted considerable in-
ties in a variety of biological systems. Tea polyphe- terest because of its inhibitory activity on cellu-
nols are also reported to inhibit proliferation and lar events associated with carcinogenesis. On the
increase apoptosis in PCa cells in in vitro.54 Soy basis of its potential anticancer activity, genistein
phytochemical concentrate, black tea, and green tea has been extensively studied for exerting its ef-
combinations at low doses are reported to have ficacy through regulation of various cell signal-
significantly reduced tumorigenicity rate, primary ing pathways.60 Genistein, in combination with
tumor growth, tumor proliferation index and mi- capsaicin, exerts anti-inflammatory and anticar-
crovessel density, serum androgen level, and metas- cinogenic properties through the modulation of
tases to lymph nodes in androgen-sensitive human MAPK family proteins and COX-2 synergistically or
prostate tumors in mice than either or their alone nonsynergistically (Fig. 2).61
doses.55 Combination of epigallocatechin gallate
(EGCG) and genistein, derived from green tea and Colon cancer
soy products, with quercetin, present in abundance Colon cancer (CC) is a malignant tumor with
in fruits and vegetables, exert synergy in control- high morbidity and mortality. With 639,000 deaths
ling the proliferation and expression of androgen worldwide per year, it is the fourth most common
receptor and tumor suppressor p53 gene expression form of cancer and the third leading cause of
in CWR22Rv1 PCa cells.56 These studies thus show cancer-related death worldwide.62 Epidemiological
that the intake of whole foods could significantly studies have demonstrated that CC development is
affect PCa tumorigenesis and that the combination closely associated with dietary habits and lifestyle,
of whole foods may be superior in slowing cancer that is, the consumption of food high in fat and
growth. carbohydrates, which could promote the growth of
tumors.63
Breast cancer Curcumin, which is widely used as a food ad-
Breast cancer (BC) is the most frequently diag- ditive, inhibits proliferation and metastasis and in-
nosed cancer in women. Approximately one million duces apoptosis in various malignant tumors, in-
women are estimated to be newly diagnosed with BC cluding CC, by modulating several different signal
each year worldwide. Although a great deal of work pathways.64–66 Epidemiologic studies suggest that
has been done on the prevention and treatment of the consumption of tea, especially green tea, is linked
BC, the results are not satisfactory and need to be to a decreased incidence of various cancers includ-
greatly improved. For example, one drug, tamox- ing CC.67–69 Over 40 experimental studies in ro-
ifen, has been demonstrated to be effective in only dents have shown that green tea or its constituents
one third of BC patients.57 Therefore, exploring new can either inhibit carcinogenesis or the growth of
approaches in the prevention and treatment of BC established cancers at various organ sites, including
is of great interest. the colon.70 Green tea contains several polyphenolic

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c 2011 New York Academy of Sciences.
Shukla & George Nutraceuticals in combination for cancer prevention

compounds including the following catechins: that the combination of PFE and DAS synergisti-
EGCG, (–)-epigallocatechin (EGC), epicatechin-3- cally inhibited mouse skin tumor growth, which was
gallate (ECG), and epicatechin (EC). EGCG is one of accompanied by a reduction in nick formation, re-
the major constituents of green tea, and it seems to gression of tumor volume, decrease in proliferation
be the most potent compound in tea with respect to markers, inhibition of MAPKs and NF-␬B signal-
inhibiting cell proliferation and inducing apoptosis ing, and induction of apoptotic cell death (Fig. 2).86
in cancer cells.71,72 Recently, the chemopreventive Therefore, we assert that the use of combination
effects of curcumin and green tea catechins individ- therapy in the management of skin cancer proves to
ually and in combination on 1,2-dimethylhydrazine be more beneficial over individual agents.
(DMH)-induced colon carcinogenesis were studied
in male Wistar rats by inhibiting the total number Lung cancer
of aberrant crypt foci (ACF) per rat suggest that the Among various cancers, lung cancer is the lead-
combination of curcumin and catechins may pro- ing cause of cancer-related mortality in the United
duce a synergistic CC-preventative effect that would States, and it is also one of the most common can-
be more potent than each of the compounds alone cers worldwide.1 Although new advancements have
(Fig. 2).73 Ohishi et al. demonstrated that sulindac, a been made in lung cancer diagnosis and treatment,
promising cancer-preventive agent for CC, synergis- the overall 5-year survival rate is still less than 5%.
tically suppressed ACF formation without notable The poor lung cancer survival statistics suggest that,
side effects when used in combination with EGCG in addition to smoking cessation, there is an urgent
(Fig. 2).74 The combination of only 1 mg/mL of EC need for additional approaches for the prevention
and 10 mg/mL of EGCG showed synergistic effects of this deadly disease.
on growth inhibition and induction of apoptosis in Luteolin, 3 ,4 ,5,7-tetrahydroxyflavone, is a nat-
human CC cells (Fig. 2). Mechanistic studies showed ural antioxidant that usually occurs in its
that this is due to the inhibition of transcriptional glycosylated form in several green vegetables such
activity of the activator protein 1 (AP-1), c-fos, NF- as artichoke, celery, broccoli, cauliflower, green pep-
␬B, and cyclinD1 promoters.75 per, cabbage, and spinach.87 It exhibits a wide range
of pharmacological properties ranging from anti-
Skin cancer inflammation to anticancer effects.88 Studies have
Our laboratory is also actively investigating the hy- shown that the combination of luteolin and EGCG
pothesis that combinations of food-based cancer more effectively induced apoptosis of both lung can-
prevention strategies will be a highly effective strat- cer and squamous cell carcinoma of the head and
egy for the reduction/prevention of carcinogenesis. neck cancer cell lines and inhibited tumor growth in
We have chosen to focus our experimental efforts nude mice xenograft models (Fig. 2). Their combi-
on pomegranate fruit extract (PFE) and garlic con- nation activated both mitochondria-dependent and
stituent (diallyl sulfide [DAS]), two foods widely -independent pathways of apoptosis to varying de-
consumed and frequently cited to have potential grees in the cell lines tested. Moreover, lung cancer
human health benefits.76–79 cell lines expressing wild-type p53 showed higher
Pomegranate (Punica granatum Linn.; Puni- sensitivity to the combination than those with mu-
caceae) fruit is widely consumed fresh and in bev- tant or no p53. Moreover, knockdown of p53 using
erage forms as juice and wines.80 The juice and shRNA strongly inhibited apoptosis, suggesting ac-
peel of pomegranates possess marked antioxidant tivation of p53-dependent apoptotic pathways by
capacity80,81 with high content of polyphenols, in the combination of luteolin and EGCG.89
particular, ellagitannins, condensed tannins, and Inhibitory effects of N -acetyl-S-(PEITC)-l-
anthocyanins, 80,82 and both have been shown cysteine (PEITC-NAC), myo-inositol (MI), and
to have chemopreventive, chemotherapeutic, and indole-3-carbinol (I3C) or 3,3 -diindolylmethane
anti-inflammatory efficacy.83,84 DAS, a organosul- (DIM), alone and in combination, have been studied
fur component of garlic (Allium sativum; Alliaceae) by Kassie et al.90 on 4-(methylnitrosamino)-1-(3-
has been demonstrated to exert a potential chemo- pyridyl)-1-butanone (NNK) plus benzo[a]pyrene-
preventive activity against human cancers, such as induced A/J mouse lung tumorigenesis and
that of the colon and lung.85 Recently, we reported proliferation of A549 cells and human bronchial

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c 2011 New York Academy of Sciences. 167
Nutraceuticals in combination for cancer prevention Shukla & George

epithelial cells (HBECs) (Fig. 2). Combinatorial and curcumin was also seen in the inhibition of
treatment with these agents caused marked re- chemically induced oral carcinogenesis in hamsters
ductions in mice lung tumor multiplicity. Com- through suppression of cell proliferation, induction
binatorial treatment also caused reduction in ac- of apoptosis, and inhibition of angiogenesis.102 The
tivation of Akt, ERK, and NF-␬B in lung tumor combinations of these nutraceuticals may be ex-
tissues; CSC-pretreated HBEC; and A549 cells. This plored as chemopreventive agents for humans at
study demonstrated the promise of combinations of high risk of oral cancer, such as those with erythro-
PEITC-NAC, I3C/DIM, and MI for the chemopre- plakia and leukoplakia.
vention of lung carcinogenesis.
Ovarian cancer
Oral cancer Ovarian cancer accounts for nearly 3% of all cancers
Oral cancer is a major health problem in develop- among women. It is the ninth most common cancer
ing countries such as India. The high incidence of and the fifth most common cause of cancer-related
oral cancer and oral precancerous lesions in India deaths in women. In 2010, an estimated 21,880 new
have long been linked with the habit of betel quid cases and 13,850 deaths in women in the United
chewing incorporating tobacco.91 Oral leukoplakia States were due to ovarian cancer.32
is the most common premalignant lesion of oral I3C is a compound present in cruciferous vegeta-
cancer, and up to 20% of the patients with leuko- bles such as broccoli, cabbage, and cauliflower. Its
plakia develop invasive carcinoma.92 There is in- ability to cause G1 arrest of cell cycle, induce apop-
creasing evidence for an association between a high tosis, and interfere with signal transduction path-
consumption of fruits and vegetables and reduced ways has been demonstrated in a variety of cancers,
risk of oral cancer.93,94 including that of prostate, melanoma, and BC cell
Epidemiologic studies have provided evidence lines.103–105 Due to its broad spectrum of activi-
that increased intake of tomato and garlic are ties combined with its low toxicity, I3C has been
associated with decreased cancer risk.95,96 Toma- acclaimed as a potent chemopreventive and anti-
toes and tomato products contain rich sources cancer agent.106 Another nutraceutical, resveratrol,
of an antioxidant carotenoid called lycopene, re- is a powerful antioxidant present in the skin and
ported to be the most powerful of all the di- seeds of grapes. These two compounds belong to
etary carotenoids. Recently, researchers have found a group of potential chemopreventive agents of di-
that dietary intake of lycopene was linked to a etary origin. For the first time, Raj et al.107 demon-
lower risk of cell proliferation in prostate and strated the effects of I3C on ovarian cancer cells
oral cancer.97,98 Bhuvneswari et al.99 showed that (SK-OV-3 cells) and its synergism with resveratrol
a combination treatment of tomato and garlic in- (Fig. 2). SK-OV-3 cells underwent profound mor-
hibits 7,12-dimethylbenz[a]anthracene (DMBA)- phological changes upon combination treatment
induced bone marrow nuclei, genotoxicity, and with I3C or resveratrol, inhibited cell proliferation,
oxidative stress in Swiss albino mice. The same and caused cell contraction and apoptosis. Analysis
group also showed that this combined treatment of apoptosis-associated genes revealed an inhibition
synergistically suppressed the incidence and mean of retinoblastoma protein and survivin gene expres-
tumor burden of DMBA-induced hamster buccal sion. This was accompanied by elevation of p21, a
pouch carcinomas at lower doses by modulating tumor suppressor. The cell cycle was inhibited at
xenobiotic-metabolizing enzymes in the pouch and both G1 and G2/M by individual treatments and
liver with a decreased incidence of bone marrow was accentuated by a combination. This will pro-
micronuclei (Fig. 2).100 vide a foundation for the use of these compounds
As stated above, curcumin is traditionally well in combination for chemoprevention of ovarian
known to have therapeutic effects on various types cancers.
of diseases.64–66 The combination of EGCG and cur-
Other combinatorial effects: nutraceuticals
cumin showed synergistic interactions in growth
and anticancer drugs
inhibition and increased sigmoidicity of the dose-
effect curves in human oral epithelial cells (Fig. It has been suggested that chemotherapy could
2).101 Synergism between a combination of EGCG favorably be combined with dietary agents in

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Shukla & George Nutraceuticals in combination for cancer prevention

anticancer strategies, since combination treatment and neck squamous cell carcinoma lines, YCU-N861
enhances the therapeutic ratio of chemotherapy and YCU-H891, by inhibiting the epidermal growth
by targeting both tumor cells and tumor vessels. factor receptor signaling pathway.122 Interestingly,
Moreover, these combined treatment modalities are YCU-H891 cells that are resistant to 5-fluorouracil
achieved without increased toxicity compared with became sensitive to the drug when combined with
chemotherapy alone.108,109 EGCG.122 They also reported that treatment with
Honokiol, an active compound purified from EGCG inhibited the growth of both YCU-H891
magnolia, has drawn much attention for its an- cells and BC cell line BT-474 more strongly than
tiangiogenesis and apoptosis properties. Previous that with taxol alone.123 Liang et al.124 reported
reports have demonstrated that honokiol inhibited that treatment with EGCG significantly reduced the
mouse skin tumor promotion in an in vivo two- IC50 value for doxorubicin (DOX) from 36 to 1.9
stage carcinogenesis110 and induced apoptosis of ␮g/mL, and that for ECG to 2.3 ␮g/mL in human
human CC cell RKO via p53-independent path- hepatocellular carcinoma cells BEL-7404/DOX. Ad-
ways.111 Adriamycin (ADR), a DNA-intercalating ditionally, the combination of EGCG and DOX
agent, is a significant active chemotherapy medicine clearly enhanced the reduction of tumor volumes
for the treatment of a variety of human and murine in an in vivo xenograft model inoculated with BEL-
tumors.112,113 ADR could induce the apoptosis 7404/DOX cells. Furthermore, combination treat-
of tumor cells by inhibiting DNA polymerases, ment with EGCG and tamoxifen was synergistically
topoisomerases, and RNA synthesis.114–117 When cytotoxic and enhanced apoptosis in MDA-MB-231
combined with ADR, Honokiol encapsulated with human BC cells and decreased tumor growth in a
liposome inhibited the proliferation of mouse 4T1 MCF-7 cell xenograft model (Fig. 2).125,126
BC cells via apoptosis and significantly decreased tu- Milk thistle (Silybum marianum) has a long his-
mor growth through increased apoptosis in mouse tory of use in humans and is commonly used in the
breast tumor model also as compared with either treatment of liver disease.127 Silymarin, the name
treatment alone (Fig. 2).118 of the crude milk thistle extract, is composed of
Atorvastatin, an inhibitor of 3-hydroxy- 3- several stereoisomers including silibinin (or sily-
methylglutaryl CoA (HMG-CoA) reductase, is bin), silychristin, and silydianin.128 Silibinin and
a commonly used drug for the treatment of silymarin have been shown to have anticancer ef-
hypercholesterolemia. In addition to inhibiting fects in several in vitro and in vivo cancer mod-
cholesterol biosynthesis, atorvastatin also inhibits els.129–134 Silibinin’s antineoplastic actions appear to
the biosyntheses of farnesyl pyrophosphate and work through several different pathways.135 One of
geranyl pyrophosphate, which are required in the most prominent effects seen in preclinical stud-
higher amounts by malignant cells than nor- ies of silibinin is G1 arrest and apoptosis136 with an
mal cells for their growth.119,120 A synergistic in- increase of the cyclin-dependent kinase inhibitors
hibitory effect of a novel combination of polyphe- kip1/p27 and cip1/p21.134 Further study has shown
non E (PPE, a standardized green tea polyphe- that silibinin causes decreased phosphorylation of
nol preparation) and atorvastatin was studied in retinoblastoma protein leading to stability of the
a mouse 4-(methylnitrosaminao)-1-(3-pyridyl)-1- complex formed with E2F.137 Silibinin increases the
butanone–induced lung tumorigenesis and in hu- efficacy of several chemotherapy agents both in vitro
man lung cancer H1299 and H460 cell lines (Fig. and in vivo. It acts synergistically with DOX to in-
2). PPE and atorvastatin at low doses synergistically hibit growth via apoptosis in the human PCa cells
inhibited lung tumorigenesis in mice as well as the (DU145)138 and sensitizes these same cells to the an-
growth of lung cancer cells, possibly through en- tineoplastic effects of cisplatin and carboplatin.139
hanced apoptosis.121 Additional studies are needed The combination of silibinin and mitoxantrone
to determine whether lower levels of PPE and ator- (anthracenedione and topoisomerase II inhibitor)
vastatin can prevent lung cancer in animal models exhibits a pattern of synergy in reducing cell via-
and humans. bility with increased apoptosis in human PCa cells
In 2001, Weinstein’s group reported that EGCG PC-3.140
at 0.1 ␮g/mL markedly enhanced the growth in- Shpitz et al.141 examined the chemopreventive
hibitory effects of 5-fluorouracil on human head effects of celecoxib, a specific COX-2 inhibitor,

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c 2011 New York Academy of Sciences. 169
Nutraceuticals in combination for cancer prevention Shukla & George

and curcumin alone and in combination using the support the hypothesis that Se and vitamin E are
DMH-induced CC in rats (Fig. 2). Curcumin and effective agents for PCa chemoprevention.
celecoxib decreased the average number of ACF per Recently, a study by Vidlar et al.153 demonstrated
rat colon, and the most efficient effect was ob- that the combination of 570 mg of silymarin and
served when rats received both agents. Curcumin 250 ␮g of Se daily for 6 months significantly reduced
potentiates the antitumor effects of gemcitabine in two markers of lipid metabolism known to be asso-
pancreatic cancer by suppressing proliferation, ciated with PCa progression, low-density lipopro-
angiogenesis, NF-␬B, and NF-␬B–regulated gene teins and total cholesterol in the blood of men after
products.142 Curcumin synergistically augments the radical prostatectomy, with no adverse effects. These
growth inhibition inserted by celecoxib in pan- findings suggest that a dietary intervention with a
creatic cancer cells (P-34, MIAPaCa, and Panc-1) SM–Se combination could benefit both patients af-
expressing COX-2. This synergistic effect was me- ter radical prostatectomy and those who are at risk
diated through inhibition of COX-2.143 This may of PCa progression.
enable the use of gemcitabine and celecoxib at lower
Conclusions and future directions
and safer concentrations and may pave the way for a
more effective treatment in this devastating disease. Clearly, research on the combined action of nu-
The synthetic isothiocyanate derivative traceuticals and with anticancer drugs is influencing
indole-3-ethyl isothiocyanate (ITC), a popular the processes involved in the progression and metas-
chemopreventive agent present in cruciferous tasis of common cancers. Many of these nutraceu-
vegetables, exerts synergy to stimulate apoptosis ticals are reported to act synergistically, which may
in combination with the chemotherapeutic drug explain why some food items or diets may show
cisplatin in human ovarian carcinoma cells.144 cancer-preventive effects that cannot be explained
Thus, there may be worth in future studies in based on individual bioactive ingredients. It is in-
assessing the value of ITC in the treatment of teresting to note that many of these nutraceuticals
ovarian cancer and in elucidating the mechanisms are already commercially available as dietary herbal
of its action. supplements or in the form of pills. Still many of
these nutraceuticals have not been approved by the
Clinical trials
Food and Drug Administration (FDA) and are not
To date, very few nutraceuticals in combination indicated for specific diseases, but are being sold
or with anticancer drugs have been successful simply as nutritional supplements for general health
in clinical trials for the treatment of cancer. In and immune function maintenance. This under-
the recent past, vitamin E and selenium (Se) scores an immediate need to further establish the
have received attention for the management of efficacy and toxicity profiles of combinations of ac-
PCa.145–147 Present in a variety of food products tive compounds and use them based on logically
and available as dietary supplements, Se is an es- derived synergistic combinations. The development
sential micronutrient that occurs predominantly as of new supplement regimens, cancer therapies, and
selenomethionine (SeMet), whereas vitamin E nutraceuticals may especially benefit from improved
(or ␣-tocopherol) is a fat-soluble physiological insight into the mechanisms behind synergistic ef-
antioxidant, and both are required for normal fects of both natural and synthetic chemopreventive
health.148–150 The ongoing Se and vitamin E chemo- compounds.
prevention trial (SELECT), sponsored by the Na- Conflicts of interest
tional Cancer Institute, is an intergroup phase III,
randomized, double-blind, placebo-controlled, The authors declare no conflicts of interest.
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