Evidence for Anti-Cancer Properties of Blueberries: A Mini-Review

Abstract

Blueberries are a commonly consumed fruit in the United States and are rich in phenolic compounds, which are known for their high antioxidant capacity. Evidence from in vitro, in vivo and a few clinical studies suggest that blueberries and their active constituents show promise as effective anti-cancer agents, both in the form of functional foods and as nutritional supplements. Some of the mechanisms by which blueberries have been shown to prevent carcinogenesis include inhibition of the production of pro-inflammatory molecules, oxidative stress and products of oxidative stress such as DNA damage, inhibition of cancer cell proliferation and increased apoptosis. This review will focus on the preclinical and clinical evidence that supports blueberries as an anti-cancer fruit, as well as expressing the need for more preclinical studies and the need for the conduction of clinical studies with respect to the cancer preventive ability of blueberries.

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1142 Anti-Cancer Agents in Medicinal Chemistry, 2013, 13, 1142-1148
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Evidence for Anti-Cancer Properties of Blueberries: A Mini-Review
Sarah A. Johnson and Bahram H. Arjmandi*
Department of Nutrition, Food and Exercise Sciences, The Florida State University, Tallahassee, FL 32306, USA
Abstract: Blueberries are amongst the most commonly consumed berries in the United States. Berries in general are rich in phenolic
compounds, which are known for their high antioxidant capacity. Specifically, evidence from in vitro,in vivo and a few clinical studies
suggest that blueberries and their active constituents show promise as effective anti-cancer agents, both in the form of functional foods
and as nutritional supplements. Some of the mechanisms by which blueberries have been shown to prevent carcinogenesis include
inhibition of the production of pro-inflammatory molecules, oxidative stress and products of oxidative stress such as DNA damage,
inhibition of cancer cell proliferation and increased apoptosis. This review will focus on the preclinical and clinical evidence that
supports blueberries as an anti-cancer fruit, as well as expressing the need for more preclinical studies and the conduction of clinical
studies with respect to the cancer preventive ability of blueberries.
Keywords: Antioxidant, cancer prevention, carcinogenesis, chemoprevention, DNA damage, functional food, inflammation, oxidative stress,
polyphenol, pterostilbene, tumorigenesis, vaccinium
1. INTRODUCTION
An estimation of the new cancer diagnoses in 2012 was
1,638,910 [1]. In 2008 it was estimated that there were
approximately 11.9 million cancer survivors in the United States
(US) and this number is projected to continue to rise [2]. Despite
advances in medicine, cancer remains to be the second leading
cause of death in the US [3]. According to a recent National
Institutes of Health (NIH) analysis, medical expenditures for cancer
treatment were projected to be approximately $124.6 billion in
2010 and this number is expected to reach $158 billion by the year
2020 [4]. Additionally, one third of all cancer deaths are related to
overweight and obesity, physical inactivity, and malnutrition and
are therefore preventable [1]. The mortality associated with cancer
and the rising costs of cancer care exemplify the importance of
cancer prevention and the necessity of identifying effective and
feasible ways to prevent its occurrence.
Consumption of fruits and vegetables high in bioactive
phytochemicals is associated with a decreased incidence of a
number of cancers, as well as several other chronic diseases [5, 6].
While the role of consuming bioactive food components in cancer
prevention has been investigated for years, questions remain
unanswered regarding their cellular and molecular mechanisms of
action. The term “functional food” refers to foods which contain
bioactive components that provide health benefits that extend
beyond delivering the traditional nutrients required to meet the
basic nutrition needs of the human body [7]. Research has identified
bioactive food components that have great potential in the
prevention of cancer. The anti-cancer abilities of berries have been
demonstrated in numerous preclinical studies. Berries including
blueberries, strawberries, and blackberries and their bioactive
components have been studied for their anti-cancer activities [8, 9].
The majority of berry-related cancer preclinical studies demonstrate
the effectiveness of berries in inhibiting tumorigenesis in a wide
range of cancers including oral [10], esophageal [11, 12], colon
[13], lung [14], and skin cancer [15]. However, there are studies
that have shown no such effect. For instance, a study by Carlton
et al. [16] noted the ineffectiveness of 10% lyophilized strawberries
*Address correspondence to this author at the Department of Nutrition,
Food and Exercise Sciences, The Florida State University, Tallahassee, FL
32306, USA; Tel: 1-850-645-1517; Fax: 1-850-645-5000;
E-mail: barjmandi@fsu.edu
in the diet of mice to inhibit 4-(methylnitrosamino)-1-(3-pyridyl)-1-
butanone- and benzo[a]pyrene-induced lung tumorigenesis. The
authors believe that the lack of effectiveness of strawberries in this
case was due to the degradation of bioactive compounds, namely
ellagic acid (EA), due to lyophilization, as well as reduced
bioavailability. In terms of blueberries, they have been identified as
a rich source of potent phytochemicals which work to counteract
oxidative damage and inflammation and have antioxidant and
scavenging effects on carcinogens [17-19]. The intent of this article
is to review the preclinical (presented in Table 1) and clinical
evidence that supports the role of blueberries as an anti-cancer
berry, as well as expressing the need for more preclinical studies
and clinical studies with respect to the cancer preventive ability of
blueberries.
2. PHYTOCHEMICAL COMPOSITION, ABSORPTION,
METABOLISM AND ANTIOXIDANT CAPACITY OF
BLUEBERRIES
Blueberries are rich in phenolic compounds, particularly
anthocyanins which are responsible for their color, flavonoids
(catechin, epicatechin, myricetin, quercetin, kaempferol, and
chlorogenic acid), shown in Fig. (1), phenolic acids (gallic acid,
caffeic acid, ferulic acid, and ellagic acid), shown in Fig. (2), and
stilbenes (pterostilbene), shown in Fig. (3) [19, 20]. Total phenolic
content of blueberries vary greatly among species and cultivars but
all are rich sources of phenolic compounds with average content of
300 mg/100g fresh weight [21]. On a dry weight basis, total
phenolic content is about 2500 mg/100g and is one of the highest
among fruits and vegetables [22].
Polyphenol absorption and bioavailability varies among
different polyphenols and this is an important fact given that their
anti-cancer properties depend on their consumption and subsequent
bioavailability [23, 24]. Their bioavailability, which has been
described in two review papers, one reviewing bioavailability and
bioefficacy of polyphenols in humans, and the other reviewing
bioavailability of polyphenols in general [23, 24]. The readers are
referred to these reviews for details on the bioavailability of
polyphenols. In reference to anthocyanins, their absorption and
metabolism in both animals and humans have been reviewed [25].
It has been suggested that anthocyanins are absorbed from the
stomach and the small intestine rapidly after their consumption and
are excreted into the bile as intact glycosides and in their
metabolized forms shortly after their absorption [25, 26]. While
anthocyanins may be rapidly absorbed and excreted, their

Anti-Cancer Properties of Blueberries Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 8 1143
absorption is not efficient and varies depending on their chemical
structures, other food components present in the gastrointestinal
tract and the food matrix [25, 26]. It has also been suggested that
the microbes found in the lower gastrointestinal tract further
metabolize anthocyanins to phenolic acids and therefore may play a
substantial role in their absorption and metabolism [23, 25]. It has
shown that the blood levels of anthocyanins in humans after their
consumption is significantly less than what has been shown in
in vivo studies to be the level required to exhibit anti-cancer effects
[26]. This suggests that it may not only be the intact anthocyanins
that exert anti-cancer properties but their hydrolyzed aglyconic
metabolites may also play a role.
Phenolic compounds have been shown to have biological
activity and have high antioxidant capacity [17-19]. Total
antioxidant capacity, as measured by oxygen radical absorbance
capacity (ORAC), may range from 13.9 to 45.9 mol Trolox
equivalents (TE)/g of fresh berries and these values vary among
Table 1. Summary of in vivo studies investigating the anti-cancer properties of blueberries.
Author(s)/Year/
Reference Number
Carcinogen and
Cancer Type
Model Treatment Treatment
Duration
Results
Aiyer et al., 2008
[34]
Endogenous DNA
damage
CD-1
mice
400 ppm EA or 5% dehydrated
berries ( BB, SRB, or RR)
3 weeks BB group had a non-significant reduction (25%) in endogenous
DNA adducts.
Aiyer et al., 2008
[43]
E2-induced DNA
damage
ACI rats 0.5% each of mixed berries
(SRB, BB, BL B, RR, and BR),
2.5% BB, or 400 ppm EA
14 weeks BB group had reduced levels of P-1 (77%), P-2 (43%), and
PL-1 (68%) adduct subgroups (P< 0.001).
Stoner et al., 2010
[12]
NMBA-induced
esophageal cancer
Fisher
344 rats
0.5% of either BR, RR, SRB,
BB, noni, acai, or wolfberry
35 weeks BB group had significant reductions in tumor incidence
(P < 0.05) and tumor multip licity (P < 0.05).
Wang et al., 2010
[44]
NMBA-induced
esophageal cancer
Fisher
344 rats
5% and 10% of either BR, SRB,
or BB residues or whole berry
powder
32 weeks All treatment groups were equally effective in reducing tumor
number (P< 0.05) and tumor volume (P< 0.05) when
compared with the control group.
Boateng et al., 2007
[45]
AOM-induced
ACF
Fisher
344 rats
5% BLK, 5% BB, 5% plums, or
5% mangos or 20%
pomegranate juice, watermelon
juice, or cranberry juice
13 weeks BB group had lower ACF in the proximal colon (P < 0.05) and
the results were significantly different wh en compared with the
other treatment groups (P< 0.05).
BB group had a 93% reduction in number of ACF and results
were significantly different when compared with the other
treatment groups (P < 0.05).
Suh et al., 2007 [46] AOM-induced
ACF
Fisher
344 rats
40 ppm of pterostilbene 8 weeks Pterostilbene group had a reduction in ACF formation
(57% inhibition, P < 0.001), multiple clusters of aberrant crypts
(29% inhibition, P < 0.01), colonic cell proliferation (P < 0.01)
and iNOS expression.
Paul et al., 2010 [47] AOM-induced
ACF
Fisher
344 rats
40 ppm of pterostilbene 45 weeks Pterostilbene group had 67.8% tumor incidence compared to
87.5% in the control g roup and reduced tumor multiplicity by
40.2% (P = 0.04).
Pterostilbene group had reduced PCNA and decreased
expression on -catenin and cyclin D1.
Simmen et al., 2009
[48]
AOM-induced
ACF
Sprague-
Dawley
rats
10% BB powder 33 weeks BB group had increased ACF numbers in the distal colon of
female rats (P < 0.05).
BB tended (P < 0.1) to reduce the total number of ACF in the
colon and intestinal tumor incidence in males.
Ayier et al., 2008
[49]
E2-induced
mammary cancer
ACI rats 2.5% powdered BR or BB or
400 ppm EA
26 weeks BB group had a non-significant reduction (40%) in tumor
volume.
Aiyer et al., 2010
[50]
E2-induced
mammary cancer
ACI rats 1% or 2.5% powdered berries
(BR or BB) or 400 ppm EA
26 weeks 2.5% BB group had reduced tumor incidence (P < 0.05) and
multiplicity (38% reduction, P < 0.05).
2.5% BB group had significantly reduced expression of phase 1
E2 metabolizing enzymes.
Adams et al., 2011
[51]
MDA-MB-231-
induced mammary
tumor metastasis
BALB/c
Nu-Nu
athymic
mice
5% or 10% freeze-dried whole
BB powder
8 weeks 5% BB had 75% lower tumor volume and 10% BB had 60%
lower tumor volume (P 0.05).
Tumor cell proliferation was lower in both 5% and 10% BB
groups and cell death was greater in the 10% BB group
(P 0.05).
5% BB group had 70% fewer liver metastases (P = 0.04) and
25% fewer lymph node metastases (P = 0.09).
Gordillo et al., 2009
[52]
EOMA cell-
induced
endothelial cell
neoplasm
129P/3
mice
10, 20, or 1000 mg/kg BBE
5, 20, or 200 mg/kg BBE
20 mg/kg BBE for survival
study
Tumor
volume
(7 days)
Blood tests
(7 days)
Survival
(35 days)
Tumor volume was decreased (P < 0.01) in group fed 10 mg/kg
BBE and additional doses had no further effects.
BBE at all three doses reduced (P < 0.01) MDA.
There was a dose-dependent increase in the ratio of
GSH/GSSG up to a dose of 20 mg/kg of BBE.
Survival curve showed an increase in survival time of mice fed
20 mg/kg BBE (P < 0.02).
Abbreviations: ACF, aberrant crypt foci; AOM, azoxymethane; BB, blueberries; BLB, blackberries; BR, black raspberries; EA, ellagic acid; EOMA, neoplastic endothelial cells;
iNOS, nitric acid synthase; MDA, malondialdehyde; NMBA, N-nitrosomethylbenzylamine; PCNA, proliferating cell nuclear antigen; RR, red raspberries; SRB, strawberries.

1144 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 8 Johnson and Arjmandi
species and cultiv ars of the Vaccinium species [17, 22]. Blueberry
extract ranks as one of the highest in antioxidant capacity in
comparison with other fruits and reference compounds such as
vitamin C [22].
In the US, the most common species of blueberries include
lowbush “wild” blueberries (Vaccinium angustifolium Aiton) which
are grown in the wild, highbush “cultivated” blueberries (Vaccinium
corymbosum L.) which are commercially grown on plantations and
are bred for their production and characteristics, and rabbiteye
blueberries (Vaccinium ash ei Reade) which are grown in the
southern region of the US [18, 22]. Evidence suggests that lowbush
blueberries contain higher amounts of anthocyanins, total phenolic
compounds, and have greater antioxidant capacity when compared
with that of highbush blueberries as well as other commonly
consumed fruits in the US [18, 27]. The phytochemical composition
and antioxidant capacity of blueberries support its potential role in
reducing inflammation and oxidative stress, as well as other
processes that may contribute to the development of cancer.
OH
OH
O
O
RO
OH
HO
(a) Quercetin
OOH
OHO
RO
HO
HO
OH
(c) Myricetin
HO
OH
O
OH
OH
HO
(b) D-(+)-Catechin
(d) L-Epicatechin
O
HO
OH
OH
HO
HO
HO
O
HO
OOH
OH
(e) Kaempferol (f) Chlorogenic acid
HO
HO O
O
OH
OH
HO OH
O
Fig. (1). Flavonoids in blueberries.
O
OH
O
(a) Pterostilbene
CH3
CH3
Fig. (3). Stilbenes in blueberries.
O
O
O
O
OH
OH
HO
HO
(a) Ellagic Acid
OH
HO
HO OH
O
(b) Gallic Acid
OH
HO
OHO
(c) Caffeic acid
O
CH
3
HO
OH
O
(d) Ferulic acid
Fig. (2). Phenolic acids in blueberries.

Anti-Cancer Properties of Blueberries Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 8 1145
3. EVIDENCE FOR ANTI-CANCER ACTIVITY OF
BLUEBERRIES AND THEIR BIOACTIVE COMPONENTS
3.1. Cell Culture Studies
Findings from in vitro studies suggest that the anti-cancer
effects of blueberries work through several mechanisms. For
instance, chronic inflammation has been implicated in the
development of a variety of cancers [28] and it has been shown that
blueberries and their constituents reduce inflam mation by inhibitin g
the activation of nuclear factor-kappa B (NFB) [29, 30] and the
p38 mitogen-activated protein kinase (MAPK) cascade [31].
Oxidative stress and subsequent oxidative DNA damage have also
been shown to be involved in the initiation and the development of
all types of cancers [32] and there have been reports [33-35] that
blueberries can prevent this in cell culture studies in vitro. In
addition to suppressing inflammatory and oxidative processes,
blueberries have been shown to inhibit cancer cell proliferation and
cause apoptosis of cancer cells [36-39]. Furthermore, blueberries
appear to be effective in reducing the metastatic and angiogenic
potential of cancer cells in cell cultu re studies in vitro [40-42].
Nonetheless, cell culture findings cannot be extrapolated to in vivo
conditions. Therefore, there is a need to confirm these cell culture
findings in animal and clinical studies.
3.2. Animal Studies
3.2.1. Blueberries and DNA Damage
In vivo studies have demonstrated the potential for blueberries
and their chemical constituents to inhibit carcinogenesis at multiple
sites and through different mechanisms. In a 2008 study, Aiyer
et al. [34] examined the ability for whole berries, a rich source of
the anthocyanin EA, and pure EA to reduce endogenous oxidative
DNA damage, an important factor involved in the initiation of
cancer. Female CD-1 mice were fed a control diet or diet
supplemented with 400 ppm of ellagic acid or 5% w/w dehydrated
berries (blueberries, strawberries, and red raspberries). The
blueberry supplemented diet group showed a moderate but non-
significant reduction in endogenous DNA adducts (25%), whereas
the EA diet showed a significant reduction (48%) as well as a 3-8
fold over-expression of genes involved in DNA repair. In another
2008 study, Aiyer and colleagues [43] investigated the potential for
a diet supplemented with 2.5% each of mixed berries (0.5% each of
blueberries, blackberries, strawberries, red raspberries, and black
raspberries), blueberries alone (2.5%), or EA (400 ppm) to reduce
17-estradiol (E2)-induced oxidative DNA damage in female ACI
rats, a rat model of E2-induced mammary tumorigenesis. The EA
supplemented group had significantly reduced levels of oxidative
DNA damage (79%), as measured by 8-oxo-7,8-dihydroguanine,
whereas the groups with berry supplemented diets did not show a
significant reduction. However, the blueberry supplemented group
had significantly reduced levels of P-1 (77%), P-2 (43%), and PL-1
(68%) adduct subgroups and the EA supplemented group had
significantly reduced levels of P-1 (63%), P-2 (44%), and
PL-1 (67%) adducts. These results suggest that both EA and
anthocyanins from blueberries may be effective in preventing E2-
induced mammary tumorigenesis, as well as overall carcinogenesis,
through their ability to reduce oxidative DNA damage and DNA
adducts.
3.2.2. Blueberries and Gastrointestinal Cancers
Evidence suggests that blueberries and their bioactive
constituents show promise in the prevention of several cancers of
the gastrointestinal (GI) tract. Stoner and colleagues [12] have
reported the effects of multiple berries, including blueberries, on the
prevention of N-nitrosomethylbenzylamine (NMBA)-induced
esophageal tumorigenesis in rats. They found that a diet containing
5% blueberries was effective in reducing esophageal tumor
incidence and multiplicity. However, a 2010 study conducted by
Wang et al. [44] suggested that blueberry ellagitannins may not be
the constituent in blueberries responsible for their chemopreventive
properties but rather may be due to other phytochemicals found in
blueberries or their synergistic effects. Their results showed that
berry residues (black raspberries, strawberries, and blueberries)
were equally effective in reducing NMBA-induced esophageal
tumorigenesis in rats despite their varying ellagitannin content.
In a 2007 study, Boateng and associates [45] examined the
effects of blueberries on azoxymethane (AOM)-induced aberrant
crypt foci (ACF) in Fisher 344 rats. Blueberry (5% of diet)
significantly reduced the formation of AOM-induced ACF. In a
similar study conducted by Suh et al. [46], pterostilbene, an active
constituent of blueberries, significantly suppressed AOM-induced
ACF formation (27%), as well as th e formation of multiple clusters
of aberrant crypts (29%) in Fisher 344 rats. Pterostilbene also
suppressed colon cell proliferation and nitric oxide synthase (iNOS)
expression. Because the inflammatory gene iNOS is usually
overexpressed in human colon tumors and in colon tumors of rats
treated with AOM, the authors suggest that the suppression of ACF
formation by blueberries may be mediated through the inhibition
of colon cell proliferation and iNOS expression. In 2010, Paul
et al. [47] further investig ated the chemopreventive potential of
pterostilbene on colon carcinogenesis by evaluating its ability to
reduce colonic tumor formation and by evaluating the mechanistic
action of pterostilbene during colon carcinogenesis. They found that
the group treated with pterostilbene had significantly reduced colon
tumor multiplicity of non-invasive adenocarcinomas. Additionally,
it was determined that the m echanisms by which pterostilbene m ay
exert its chemopreventive effects is through its ability to regulate
the Wnt/-catenin-signaling pathways, as well as by reducing
inflammatory responses of mucosal and tumor cells. A study by
Simmen and colleagues [48] investigated the effect of 10% whole
blueberry powder in the prevention of AOM-induced colon ACF
and intestinal tumors in rats. Overall, blueberry supplementation
tended to reduce gastrointestinal tumor incidence in males but had
no significant effects on tumor incidence in females, suggesting
there may have been a gender-diet interaction.
In summary, a diet containing 5% blueberries rather than
10% blueberries, as well as pterostilbene rather than blueberry
ellagitannins, may be most effective in reducing the development of
esophageal and colon cancers. Some of the ways in which
blueberries reduce the development of ACF may include the
inhibition of inflammatory responses of mucosal and tumor cells
including the inflammatory gene iNOS, reducing colonic cell
proliferation, as well as through the regulation of the Wnt/-
catenin-signaling pathways.
3.2.3. Blueberries and Breast Cancer
Blueberries also show promise as a chemopreventive agent for
mammary tumors. Using ACI rats, which are known for their
susceptibility to E2-induced mammary tumors, Aiyer et al. [49]
examined the efficacy of powdered berries (2.5% wt/wt black
raspberries or blueberries) versus ellagic acid (400 ppm) in
reducing mammary tumor incidence in rats treated with implants
containing 27 mg 17-estradiol for 24 weeks. While there were no
significant differences in tumor incidence between the groups,
blueberry treated groups showed a 40% reduction in tumor volume,
albeit not significant. In a 2010 study with a similar design with the
addition of a mechanistic component, Aiyer and associates [50]
showed that blueberry supplementation significantly reduced
the expression of phase 1 E2 metabolizing enzymes, though to a
lesser extent than that of black raspberries. However, blueberry
supplementation did significantly reduce tumor incidence, tumor
volume, and tumor multiplicity when given at a dose of 2.5%
wt/wt. These data suggest that one of the ways in which blueberries
may inhibit the formation of mammary tumors is through
modulation of enzymes involved in estrogen metabolism.

1146 Anti-Cancer Agents in Medicinal Chemistry, 2013, Vol. 13, No. 8 Johnson and Arjmandi
Adams et al. [51] demonstrated the ability of daily consumption
of whole blueberry powder to protect against tumor growth and
metastasis in mice. In the first part of the study, mice fed 5% wt:wt
whole blueberry powder had a 75% lower tumor volume and mice
fed 10% wt:wt whole blueberry powder had a 60% lower tumor
volume when compared with the control m ice (P 0.05).
Additionally, tumor cell (Ki-67) proliferation was lower in both
groups and cell death was greater in the mice fed 10% wt:wt whole
blueberry powder when compared to the control group (P 0.05).
When they analyzed tissues taken from the tumor sites they found
altered expression of the genes involved in Wnt signaling,
thrombospondin-2, interleukin 13 (IL-13), and interferon gamma
(IFN) which are important in the regulation of inflammation,
cancer, and metastasis (P 0.05). In the second part of the study,
they showed the ability of 5% whole blueberry powder to inhibit
MDA-MB-231-luc-D3H2LN metastasis in mice. Their results
showed a 70% reduction in liver metastases (P = 0.04) and a 25%
reduction in lymph node metastases (P = 0.09) when compared to
the control mice.
In summary, these studies have demonstrated that doses of
2.5% wt/wt powdered blueberries is effective in reducing tumor
incidence, tumor volume, and tumor multiplicity while 5% wt/wt
powdered blueberries is effective in reducing tumor volume and
10% wt/wt powdered blueberries are effective in reducing tumor
cell proliferation and increasing cell death. Some of the suggested
mechanisms of action include the reduction of the expression of
phase 1 E2 metabolizing enzymes and altering the expression of the
genes involved in Wnt signaling, thrombospondin-2, IL-13, and
IFN.
3.2.4. Blueberries and Endothelial Cell Neoplasms
Endothelial cell neoplasms are the most common type of soft
tissue tumor found in infants with hemangioenthothelioma (HE)
being the most common type of endothelial cell neoplasm occurring
in infants. Gordillo and colleagues [52] studied the effects of a
blueberry extract on management of hemangioenthothelioma (HE)
in mice. They found that mice receiving oral gavage feedings of
blueberry extract had a dose-dependent decrease in tumor size and
enhanced survival when compared to the control mice. While these
results demonstrate potential in preventing endothelial cell
neoplasms, there is only one known animal study that has been
done in this area and findings from this study should not be
considered conclusive until additional studies are conducted.
3.3. Human Studies
3.3.1. Blueberries and DNA Damage
To date there are no published clinical studies that have
evaluated the role of blueberries as an anti-cancer agent. Two
studies have, however, examined the potential for a quercetin-rich
blueberry/apple juice mixture to protect against induction of
oxidative DNA damage. A pilot study by Wilms et al. [33]
investigated the ability of a quercetin-rich blueberry/apple juice
mixture to protect against ex vivo induced lymphocytic oxidative
DNA damage in humans. Subjects consumed the blueberry/apple
juice mixture for four weeks and their lymphocytes were treated ex
vivo with H2O2 and benxo(a)pyrene at 0, 2, and 4 weeks. Their
findings showed a non-significant decrease in oxidative DNA
damage after exposure to H2O2 ex vivo by 41% (P = 0.07) and a
non-significant decrease in the ex vivo-induced BPDE-DNA adduct
level by 11%. In a later study, Wilms and associates [53] studied
the impact of a 4-week blueberry juice intervention on ex vivo
induced lymphocytic DNA damage in humans. The subjects
consumed 1 liter of a quercetin-rich blueberry/apple juice mixture
per day (16 mg ascorbic acid and 97 mg quercetin) for 4 weeks.
The intervention resulted in significantly increased plasma
concentrations of quercetin and ascorbic acid, as well as trolox
equivalent antioxidant capacity (TEAC). They also saw a 20%
reduction in ex vivo H2O2-induced oxidative DNA damage (P < 0.01).
Conversely, there was a 28% increase in ex vivo induced
benzo[a]pyrene-diol-epoxide (BPDE)-DNA adducts (P < 0.01).
Overall, these two studies demonstrate the potential for blueberries
to reduce oxidative DNA damage in humans, which is known to be
involved in the initiation and development of cancer.
4. CONCLUSION
Despite advances in medicine, cancer continues to be a major
public health threat to the US, as well as the rest of the world.
Identifying natural and cost-effective ways to reduce the risk of
cancer is essential in lowering the overall prevalence of cancer.
Blueberries are a commonly consumed fruit in the US and contain a
wide variety of bioactive phenolic compounds known for their
antioxidant and anti-cancer properties. In vitro, and a limited
number of in vivo studies, have provided a great deal of evidence
supporting the potential for blueberries and their constituents to be
used as chemopreventive agents in th e prevention of a wide variety
of cancers. While a few human studies have investigated the effects
of blueberries on the prevention of oxidative DNA damage, further
clinical research is needed to establish the extent to which blueberry
consumption, both as a functional food and as a nutritional
supplement, reduces the incidence of various types of cancer.
Furthermore, considering the strong possibility that the phyto-
chemicals present in blueberries work additively or synergistically,
studies comparing the chemopreventive effects of whole blu eberries
to their individual constituents, such as pterostilbene, are merited.
CONFLICT OF INTEREST
The author(s) confirm that this article content has no conflict of
interest.
ACKNOWLEDGEMENTS
Declared none.
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Received: July 27, 2012 Revised: January 07, 2013 Accepted: January 09, 2013