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DOI:10.1093/jnci/dju238
First published online September 10, 2014
© The Author 2014. Published by Oxford University Press. All rights reserved.
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Review
Cancer Chemoprevention With Nuts
Marco Falasca, Ilaria Casari, Tania Maffucci
Manuscript received April 28, 2014; revised June 27, 2014; accepted July 1, 2014.
Correspondence to: Marco Falasca, PhD, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4
Newark Street, London E1 2AT, UK (e-mail: [email protected]).
It is well established that increased nut consumption is associated with a reduced risk of major chronic diseases, such as cardiovascular disease and type 2 diabetes mellitus. On the other hand, the association between nut consumption and cancer mortality
is less clear. Recent studies have suggested that nut consumption is associated with reduced cancer mortality. This evidence reinforces the interest to investigate the chemopreventive properties of nuts, and it raises questions about the specific cancer type(s)
and setting that can be more affected by nut consumption, as well as the cellular mechanisms involved in this protective effect.
Here we discuss recent studies on the association of nut consumption and cancer, and we propose specific cellular mechanisms
by which nut components can affect cancer progression.
JNCI J Natl Cancer Inst (2014) 106(9): dju238 doi:10.1093/jnci/dju238
In the last four years, there has been a consistent rise in the number
of diagnosed cancer cases and cancer deaths worldwide. According
to the 2012 World Health Organization data on cancer incidence
in the global population, more than 14 million cases were diagnosed compared to 12.7 million in 2008 and 8.2 million deaths
were recorded compared to 7.6 million in 2008 (1–2). More worryingly, it has been predicted that cancer cases will increase to more
than 19 million a year by 2025.
The reasons for these soaring numbers have been identified
primarily in the increased average life span, lack of prevention,
diagnoses, and adequate treatment in developing countries, and
changes in lifestyle occurring in developing nations, where obesity
and smoking habits are catching up with industrialized countries’
rates. Chemoprevention and early diagnosis are going to be pivotal
to counteract this looming trend (3–4).
It is now well established that lifestyle habits have an impact
in the development of several human cancers (5–6). It has been
estimated that up to 40% of cancer cases are linked to unhealthy
lifestyle habits such as smoking, being overweight, alcohol consumption, low fruit and vegetable intake, occupational hazards, and
exposure to sun and sunbeds. Therefore, there is currently a huge
interest in studying the impact of lifestyle changes on cancer development and progression. Diet in particular has received increasing
attention, with the identification of food that could either increase
or reduce the risk of developing specific types of cancer (7). For
instance, it has been estimated that a Mediterranean diet rich in
fruits, vegetables, fish, and olive oil could reduce the risk of cancer
by 12%, supporting the conclusion that dietary changes could be
highly beneficial in cancer prevention (8–9).
In the past few years, an inverse correlation between nut consumption and major chronic diseases such as cardiovascular diseases, metabolic syndrome, and type 2 diabetes has been established
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(10–14). In addition, studies have suggested that nut consumption
could also have a chemopreventive effect, especially on colorectal
and prostate cancer (15–16). Recent epidemiological studies have
confirmed an inverse association between frequent nut consumption and cancer mortality (17–19). Questions still remain on the
specific cellular mechanisms and the specific cancer types that are
more likely to benefit from this effect (20–22). In this review we
will discuss recent studies on the association of nut consumption
and risk of cancer, and we will suggest specific cellular mechanisms
by which nut components could affect cancer progression.
The Tree Nuts and Nut Composition
By definition, a nut is a dry fruit consisting of a hard or tough shell
around an edible kernel. Walnuts (Juglans regia), hazelnuts (Corylus
avellana), macadamias (Macadamia integrifolia), pecans (Carya illinoiensis), almonds (Prunus amygdalus), cashews (Anacardium occidentale), and pistachios (Pistacia vera) are all tree nuts; Brazil nuts
(Bertholletia excelsa) are seeds but share the same properties of nuts,
and so do peanuts (Arachis hypogaea), which are botanically legumes
but are frequently grouped with nuts because of their similar nutritional properties. Chestnuts (Castanea) are an exception, as they
contain a high amount of starch and little fat and are therefore
considered nutritionally dissimilar even if they are tree nuts (23).
Nuts have a high total fat content, ranging from 46% in cashews
to 76% in macadamia nuts, making them the richest natural plant
foods in fat after vegetable oils (23). However, nuts mainly contain monounsaturated fatty acids (MUFA) or polyunsaturated fatty
acids (PUFA) and a very low content of saturated fatty acids (SFA),
ranging from 4% to 16%. The percentage of MUFA and PUFA
varies between different types of nuts: many nuts contain mostly
MUFA (mainly oleic acid). Brazil nuts have similar proportions of
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MUFA and PUFA, whereas walnuts contain mainly PUFA, both
linoleic acid and α-linolenic acid (23). Nuts also contain proteins,
ranging from 7.9 g in macadamia nuts to 25.8 g in peanuts (per
100 g) and often possess high levels of L-arginine, which is a precursor of nitric oxide (23). Dietary fiber in nuts also ranges from
3.7 g in pine nuts to 10.4 g in hazelnuts (per 100 g). Importantly,
nuts are enriched in several phytochemicals and indeed their beneficial effects have been largely ascribed to the simultaneous presence of these micronutrients, as described below. Amongst the
other micronutrients, nuts contain the B-vitamin folate, ranging
from 22 μg in pecans and Brazil nuts to 145 μg in peanuts (per
100 g), as well as antioxidant vitamins (tocopherols) and phenolic
compounds (23). Almonds are particularly rich in α-tocopherol,
while walnuts are enriched in γ-tocopherol. Finally, nut composition comprises minerals such as calcium, magnesium, potassium,
and selenium, while containing very low sodium concentrations.
Nut Consumption and Mortality
Association between nut consumption and total and cause-specific
mortality has been recently investigated in a study (17) comprising
76 464 women from the Nurse’s Health Study (NHS) and 42 498 men
from the Health Professionals Follow-Up Study (HPFS). This study
revealed a statistically significant inverse correlation between frequent nut consumption and total mortality among women and men
(Table 1). The inverse association remained mainly unchanged after
exclusion of participants who had never smoked, or with extremely
high or low body mass index (BMI), or with diabetes at baseline and
after other adjustments. Furthermore, the inverse association persisted in all subgroups in analyses stratified by other potential risk factors for death, with stronger association observed among overweight
or obese participants. Although the authors acknowledged potential
limitations, including the fact that nut intake was self-reported or
the restriction of the study sample to health professionals, this prospective study included a very large sample, 30 years of follow-up,
repeated assessment of diet and lifestyle variables and data on more
than 27 000 deaths for analysis. It is worth mentioning that this study
was conducted in a non-Mediterranean population, which statistically consumes less nuts compared to the European population, and
it is also less likely to follow a Mediterranean diet.
This inverse association has been further confirmed by a recent
study conducted as an observational cohort of the PREDIMED
trial to determine the potential association between total mortality, cardiovascular mortality, or cancer mortality and nut consumption, using baseline nut consumption as the exposure (18). The
PREDIMED was a multicenter trial conducted in Spain for the primary prevention of cardiovascular events (24). Participants at high
risk but with no cardiovascular disease at enrollment were assigned
to a Mediterranean diet supplemented with extra-virgin olive oil,
a Mediterranean diet supplemented with mixed nuts, or a control
diet (participants were advised to reduce dietary fat). While results
of the original trial are discussed later in this review, the recent longitudinal cohort study (18) determined that, in fully adjusted models, participants who ate more than three servings of nuts per week
had a 39% reduction in total mortality risk compared with those
who never or rarely ate nuts (hazard ratio [HR] = 0.61, 95% confidence interval [CI] = 0.45 to 0.83, Ptrend = .012). Interestingly, the
reduction in total mortality risk increased up to 63% (CI = -34%
to -78%) in participants who were in the upper category of nut
consumption before the trial and were allocated to the diet supplemented with nuts during the trial.
Taken together, results from these studies support the conclusion of an inverse association between nut consumption and total
mortality. Additional studies are now required to determine more
specifically the role of different types of nuts, regular quantities to
be consumed, and their potential interaction with other nutrients
Table 1. Hazard ratios for deaths compared with participants who did not eat nuts (17)
Multivariable-adjusted HRs (95% CI)
Frequency of nut consumption
0.93 (0.90 to 0.96)
0.89 (0.86 to 0.93)
0.87 (0.83 to 0.90)
0.85 (0.79 to 0.91)
0.80 (0.73 to 0.86)
< 1 per week
1 per week
2 to 4 times per week
5 or 6 times per week
7 or more times per week
0.84 (0.78 to 0.90)
0.83 (0.76 to 0.89)
0.79 (0.73 to 0.86)
0.75 (0.62 to 0.84)
< 1 per week
1 per week
2 to 4 times per week
5 or more times per week
0.84 (0.77 to 0.91)
0.78 (0.71 to 0.86)
0.75 (0.68 to 0.82)
0.71 (0.63 to 0.81)
< 1 per week
1 per week
2 to 4 times per week
5 or more times per week
0.93 (0.88 to 0.98)
0.93 (0.87 to 1.00)
0.92 (0.85 to 0.98)
0.89 (0.81 to 0.99)
< 1 per week
1 per week
2 to 4 times per week
5 or more times per
week
Total mortality
Ptrend*
<.001
Cardiovascular disease
<.001
Heart disease
<.001
Cancer
.03
* Statistical tests were two-sided, and P values were calculated with the use of the Wald test. HR = hazard ratio.
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and demographic risk factors. In the study analyzing results from
the NHS and HPFS studies (17), a similar inverse association
was detected for consumption of two or more servings per week
of peanuts or tree nuts (pooled multivariable-adjusted HR = 0.88,
CI = 0.84 to 0.93 for peanuts; HR = 0.83, CI = 0.79 to 0.88 for tree
nuts). Similarly, in the cohort of the PREDIMED study, reduced
mortality risk was detected in participants who ate more than three
servings per week of walnuts (HR, fully adjusted model = 0.55,
CI = 0.40 to 0.76, Ptrend < .001) or other nuts, excluding walnuts
(HR, fully adjusted model = 0.66, CI = 0.46 to 0.93, Ptrend = .031).
Additional studies are urgently needed to investigate more in
details the potential role of specific types of nuts.
Nut Consumption, Cardiovascular Disease,
and Other Diseases
Several studies have now established the inverse correlation between
nut consumption and risk of coronary heart disease (CHD) (25).
Indeed, evidence supporting a protective role of nuts was so compelling that it led the US Food and Drug Administration to issue a
health claim for nut consumption because of its link with reduced
risk of cardiovascular diseases. A pooled analysis of four prospective
studies conducted in the United States on healthy individuals with
follow-up ranging from 6 to 18 years reported a 37% reduction
in risk of fatal CHD (relative risk [RR] = 0.63, 95% CI = 0.51 to
0.83) in participants with the highest nut intake after multivariate adjustment (13). The Physicians’ Health Study in particular
reported a 47% reduced risk of sudden cardiac death (RR = 0.53,
95% CI = 0.30 to 0.92) in subjects who ate nuts two or more times
per week compared with those who never or rarely consumed them
(26). The beneficial effect of nuts was independent of age, sex, BMI,
alcohol use, or presence of cardiovascular risk factors. Results from
the PREDIMED trial (24) further showed reduced risk of major
cardiovascular events with a relative risk reduction of approximately 30% (multivariable-adjusted HR = 0.70, CI = 0.54 to 0.92,
P = .01 for the group assigned to the Mediterranean diet with extravirgin olive oil and HR = 0.72, CI = 0.54 to 0.96, P = .03 for the
group assigned to the Mediterranean diet supplemented with nuts).
In a fully adjusted analysis, statistically significant results were
found for the combined cardiovascular end point and for stroke,
but not for myocardial infarction alone (24). Although this study
had several limitations, including losses to follow-up and the fact
that the protocol was changed halfway through the trial, it was
consistent with epidemiological studies showing an inverse association between the Mediterranean diet and incident stroke (27–28).
These results have been further supported by the two recent studies mentioned in the previous paragraph. A more selective analysis
of cause-specific mortality in the study by Bao et al. (17) revealed
a statistically significant inverse association between nut consumption and deaths related to cardiovascular and heart disease in the
pooled analysis of women and men (Table 1). Similarly, in the longitudinal cohort study of the PREDIMED trail (18), a reduced risk
of cardiovascular mortality was observed in participants who ate
more than three servings per week of walnuts (HR, fully adjusted
model = 0.53, CI = 0.29 to 0.98, Ptrend = .047) or other nuts, excluding walnuts (HR, fully adjusted model = 0.42, CI = 0.20 to 0.89,
Ptrend = .031).
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Results from epidemiological studies spurred a wave of clinical studies to identify the mechanisms of the beneficial effects of
nut consumption. Several studies have compared the effects of diets
enriched in nuts and isoenergetic diets on serum lipids and lipoproteins. A pooled analysis of 25 clinical studies reported a doseresponse cholesterol lowering effect independent of the type of nuts
tested and similar across age groups and gender (29). Several other
studies have now confirmed the cholesterol-lowering properties
of nuts (23). Importantly, although the abundance of MUFAs in
nuts is considered the main factor responsible for this action, it has
also been reported that additional factors must contribute to the
cholesterol-lowering activity, likely the presence of other bioactive
phytochemicals, such as tocopherol, squalene, and phytosterol (30).
In recent years, evidence emerged on the protective effect of
nuts against some chronic diseases, including metabolic syndrome
(11) and type 2 diabetes (10,31,32). Nut consumption has also been
shown to improve BMI and adiposity (12) and not to lead to weight
gain (33,34). Accordingly, participants of the PREDIMED study
and the NHS and HPFS studies who ate high amounts of nuts had
lower BMI and less waist circumference (17–18).
Nut Consumption and Cancer
The first indications of a potential protective effect of nut consumption on cancer appeared already in the late 80s/early 90s.
A case-control study of stomach cancer found a dose-response
relationship for seven dietary items, including nuts (35). Similarly,
a cohort study conducted on 14 000 Adventist men found a statistically significant reduction of prostate cancer risk associated
with increasing consumption of beans, lentils, peas, tomatoes, raisins, dates, and other dried fruits (36). It must be noted, however,
that only age-adjusted relative risks were statistically significant,
whereas no statistically significant association was found in the
multivariate models (36). The hypothesis that grains, cereals and
nuts may be protective against prostate cancer was later supported
by a study on prostate cancer in a Canadian population that discovered a 31% risk reduction (odds ratio [OR] = 0.69, 95% CI = 0.53
to 0.91), although in this study nuts were mixed with legumes and
seeds (37). Evidence of a protective role of nuts on colorectal cancer in women also appeared with a prospective study conducted
in Taiwan that recruited almost 24 000 people and followed them
annually for 10 years (38). Beneficial effects of peanut consumption
were observed in women, although the authors acknowledged some
limitations of the study, including the lack of detailed information
on other potential factors. Nevertheless, the European Prospective
Investigation into Cancer and Nutrition (EPIC), which was one
of the largest prospective cohort studies on diet and cancer, also
showed a reduced incidence of colon cancer in women who had
an average intake of 16 g of nuts and seeds daily, compared with
nonconsumers (39). No observable effect was detected in men or
on rectal cancer, although this might reflect the smaller number of
rectal vs colon cancer case patients in the study and the fact that
more women were recruited. In addition, according to a study conducted on Greek women, there appears to be a 27% reduced risk
of endometrial cancer because of a diet rich in nuts, legumes, and
seeds, although it has to be considered that this is a low-risk population for this type of cancer, and the study only had 84 cases of
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women with confirmed endometrial cancer and 84 control patients
(40). Taken together, these studies were all indicative of an inverse
association between nut consumption and cancer.
The recent investigation of the association between nut consumption and total and cause-specific mortality assessed in the
NHS and in HPFS (17) confirmed a statistically significant inverse
association between nut consumption and deaths related to cancer
in the pooled analysis of women and men (Table 1). Similarly, the
recent longitudinal cohort study from the PREDIMED trial (18)
also indicated that participants with a frequency of total nut consumption of more than three servings per week had a 40% reduction in cancer death (HR = 0.60, 95% CI = 0.37 to 0.98, Ptrend was
not statistically significant [.064]). Interestingly, the hazard ratio in
participants who specifically ate walnuts more than three servings
per week was 0.46 (95% CI = 0.27 to 0.79, Ptrend = .005).
Taken together, these studies have provided some very strong
support to the hypothesis of a beneficial effect of nut consumption
on all cancer-related mortality. It must be noted, however, that these
two studies analyzed the association between nut intake and cancer
mortality. It would be important to establish now if the benefits are
because of a reduction of cancer risk or survival or a combination
of both. Furthermore, it would be interesting to assess whether nuts
have stronger preventive effect on specific cancer types and possibly
on specific subsets of certain cancer types. Some studies have already
started to investigate this aspect. For instance, a prospective cohort
study followed 75 690 women in the NHS and evaluated the association between nut consumption and pancreatic cancer risk (19).
During a follow up from 1980 to 2010, the authors documented
466 cases of pancreatic cancer, and they identified an inverse association between frequent nut consumption and risk of pancreatic
cancer. Specifically, women who consumed a 28-g serving size of
nuts two times or more per week had an age-adjusted relative risk
of pancreatic cancer of 0.65 (95% CI = 0.47 to 0.90; Ptrend = .005)
and a multivariable relative risk of 0.65 (95% CI = 0.47 to 0.92;
Ptrend = .007), compared with nonconsumers. Importantly, similar
results were obtained after controlling for BMI and history of diabetes, for other dietary variables (such as alcohol consumption, multivitamin use, intakes of red meats, fruits, vegetables, and vitamin
D) or after adjusting for the Mediterranean diet score. An inverse
association also remained when the multivariate analyses were performed within subgroups of BMI, physical activity, smoking, and
intakes of red meat, fruits, and vegetables or after adding a fouryear lag period between nut intake assessment and each follow-up
period, supporting the conclusion that frequent nut consumption
was associated with reduced risk of pancreatic cancer (19). Recent
results from a population-based case-control study involving 2865
case patients with 3299 control patients revealed an inverse association between nut consumption during adolescence and breast cancer risk in adult life (41). Specifically, adjusted odds ratios were 0.86
(95% CI = 0.71 to 1.04) for total nuts servings of one to three per
month; 0.86 (95% CI = 0.72 to 1.04) for total nuts servings of one
to six per week; 0.76 (95% CI = 0.61 to 0.95) for total nuts servings of one or more per day, compared with consumption of less
than once per month (Ptrend = .04). The inverse association between
total intake of nuts during adolescence and breast cancer risk was
stronger for postmenopausal than for premenopausal breast cancer.
These results were consistent with a previous study that analyzed
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the association between adolescent fiber and nuts intake and proliferative benign breast disease (BBD), a marker of increased breast
cancer risk (42). This study showed that total nut intake of two or
more servings per week during adolescence was inversely associated
with proliferative BBD (multivariable HR = 0.64, 95% CI = 0.48
to 0.85, Ptrend < .01), compared with an intake of less than one serving per month. Statistically significant inverse association was also
observed for peanuts intake alone.
Although some of these studies could not support a direct
cause-effect association, they have definitely provided evidence of
the beneficial effects of nut consumption and of their inverse association with cancer-related mortality. Questions remain on the cellular mechanisms responsible for their anticancer activity.
Mechanisms Involved in the Anticancer
Properties of Nuts
Different hypotheses have been proposed to explain the protective
effects of nuts, including the direct anticancer properties of several
nut components, which can act in a synergistic way to block cancer cell proliferation. Furthermore, nuts contain many antioxidant
and anti-inflammatory substances, and indeed some of the beneficial effects on cardiovascular diseases have been ascribed to the
action of these components. With the growing evidence indicating
the key role for inflammation and oxidative stress in the development of specific cancer types, it is very likely that the antioxidative
and anti-inflammatory properties of some nut components also
contribute to their anticancer activity. Finally, since reprogramming of energy metabolism has been recently recognized as a key
feature of cancer cells, it can be hypothesized that nuts can affect
cancer progression through their ability to alter lipid profiles and
cell metabolism.
Anticancer Properties of Nut Phytochemicals
Over the last 20 years, epidemiological studies have indicated an
inverse relationship between diet and development of cancer with
a regular intake of fruits and vegetables clearly associated with a
decreased risk of the disease. As a result, there has been a huge
interest in studying the components responsible for this chemopreventive activity, which has led to the identification of several
phytochemicals or bioactive compounds with different chemical structures and functions (43). Bioactive compounds or nutraceuticals are extranutritional constituents that typically occur in
small quantities in food and are associated with beneficial effects
on health (43). Nuts contain many bioactive compounds that have
been found to affect several cellular processes involved in tumor
development and progression, including cell survival, cell proliferation, cell invasion, and angiogenesis (43) and therefore can account
for the anticancer properties of nuts. A few representative examples
of some of these compounds, some of their anticancer activities and
mechanisms of actions are listed in Table 2.
Polyphenols. Polyphenols are metabolites containing benzene
rings with one or more attached hydroxyl groups, which include
phenolic acids, flavonoids, stilbenes, and curcuminoids (44). In
vitro and in vivo anticancer activity has been reported for some
phenolic acids, such as anacardic acid, found in cashew shells
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Table 2. Examples of phytochemicals present in nuts and their potential anticancer properties
Phytochemical and
type of nuts
Biological effects
In vivo models
Molecular targets
MDA-MB-231 breast cancer
xenografts (52)
PANC1 pancreatic cancer
xenografts (53)
PC3 prostate cancer
xenografts (49)
Inhibits: NF-κB pathway (50); COX2, cyclin
D1, MMP-9, PDGF, VEGF expression (50)
Increases: p21/WAF1, p53 (50,53)
Ellagic acid
(Walnuts and pecans)
Cell cycle arrest
Apoptosis
Anacardic acid
(Cashews shells)
Inhibits cell proliferation (43,48) and
increases survival (43)
Genistein
(Hazelnuts, peanuts)
Induces apoptosis and cell cycle
arrest; inhibits cell growth, migration,
invasion, angiogenesis and
metastasis
Subrenal capsule xenograft
transplant (55)
PC3 bone tumor growth (55)
Resveratrol
(Peanuts)
Induces apoptosis, inhibits cell invasion,
angiogenesis (43)
Ins
(1,3,4,5,6)P5
(Cashews, peanuts)
Induction of apoptosis (68), inhibition of
angiogenesis (69)
Several models of
breast, colorectal, liver,
pancreatic and prostate
cancer (60)
SKOV3 ovarian cancer
xenografts (69)
(43,45–49) and ellagic acid, contained in walnuts and pecans
(44,50–53). Similarly, genistein, a flavonoid mainly found in soybeans but also in nuts (54), has shown in vitro anti-invasive and in
vivo antimetastatic activity (55–59). Within the group of stilbenes,
resveratrol has been extensively studied for its anticancer properties, and it has been shown to be able to inhibit the three major
stages of carcinogenesis: initiation, promotion, and progression, as
well as tumor angiogenesis and cell invasion (60–64). Importantly,
an inverse association was observed for resveratrol from grapes
and risk of breast cancer (65). Interestingly, anacardic acid and resveratrol seem also to be able to counteract cancer-related epigenetic alterations (66).
Carotenoids. Carotenoids are naturally occurring fat-soluble
pigments belonging to the group of tetraterpenes. Although they
are present only in small amounts in nuts, it has been proposed that
they can exert anticancer properties because of their antioxidant
effect or, as in the case of lycopene, their direct effect on cancer
cells (44).
Phytosterols. Phytosterols are chemically classified as 4-desmethylsterols, and they include β-sitosterol, campesterol, and
stigmasterol, principally found in nuts, whole grains, seeds, and
corresponding oils (44). β-sitosterol has been reported to possess
antiproliferative and proapoptotic properties towards several cancer cells (44).
Phytoestrogens. Phytoestrogens are nonsteroidal compounds,
structurally similar to estradiol (17-β-estradiol), which can act as
estrogen’s antagonists. Accumulating evidence suggests that phytoestrogens may have protective action in some hormone-dependent diseases, including prostate, breast, and bowel cancer. It is
worth noticing that some studies have found an inverse correlation
between nut consumption and risk of colon and colorectal cancer,
specifically in the female population (38,39), and therefore it is
tempting to speculate that this could be, at least partially, because
of the anti-estrogen activity of phytoestrogens.
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Inhibits: NF-κB pathway (43); cyclinD1,
COX2 and c-Myc expression (43,48); Bcl2, Bcl-xL, c-FLIP, cIAP-1, survivin (43)
Inhibits: NF-κB pathway (50,55); Akt,
AP-1 (50); cyclinB1, VEGF and FGF-2
expression (43)
Increases: p21/WAF1, caspase 12 and
glutathione peroxidase (50)
Inhibits: NF-κB pathways (43,50); COX2,
JNK, MEK, survivin, MMP-2/9, VEGF, FGF,
IL-1, IL-6 expression (43) etc
Inhibits: PI3K/Akt pathway (68,69)
Inositol Polyphosphates. A new interesting class of bioactive compounds is represented by inositol polyphosphates, the
water-soluble head groups of phosphoinositides. Phytic acid or
inositol(1,2,3,4,5,6)hexakisphosphate (InsP6), naturally found in
legumes, wheat bran, soy foods, and nuts, possesses antitumor activity in vitro and in vivo (59). However, the very high concentrations
required for InsP6 to be active (1–5 mM) suggest a lack of selectivity of this compound, although it is noteworthy that, even at these
concentrations, inositol polyphosphates do not appear to have toxic
effects (67). We reported the anticancer activity of the pentakisphosphate, Ins(1,3,4,5,6)P5 both in vitro and in vivo (68,69).
Diet Fiber. Fiber is one of the main components of all types of
nuts. Although the role of a diet rich in fiber is yet to be clarified, evidence suggests a preventive action on cancer. A 21% risk
reduction of colorectal cancer was observed among high fiber
consumers in the EPIC study (70). A large case-control study on
pancreatic cancer in Italy found an inverse correlation between
soluble and insoluble fiber intake from fruit and risk of pancreatic
cancer, and no association with grain fiber (71). Total, insoluble,
and legume fiber intake was linked to a reduction of prostate cancer risk in a French prospective study, whereas no correlation was
observed with soluble, vegetable, and fruit fiber intakes (72). In
contrast, fruit fiber intake was inversely associated with prostate
cancer risk in men participating in the EPIC study (73). Also in
the EPIC study, a protective effect of vegetable fiber against breast
cancer was found (74), which has been confirmed by the SU.VI.
MAX study, but no correlation with fiber from other food sources
emerged (75).
Vitamin and Micronutrients. Nuts are very rich in antioxidants
such as tocopherols, magnesium, and selenium. The anticancer
properties of vitamin E—a group of fat-soluble compounds that
includes tocopherols—seem to be strictly related to their antioxidant properties (76). Magnesium plays a key role in many essential cellular processes, and its deficiency may be associated with
inflammation. Magnesium homeostasis impairment is frequently
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observed in tumor cells (77). Selenium has been linked to many
health benefits in humans, including decreasing the incidence of
cancer (78).
Potential Synergy of Nut Phytochemicals
The use of bioactive compounds in cancer prevention and treatment has attracted increasing attention in recent years (79–81).
Although extensively studied, the precise mechanism of action of
most of them has not been completely elucidated yet. It is also
important to underline that bioactive compounds are usually present in food at lower concentrations than those used in in vitro
studies and reported to be effective. This observation may raise
doubts about the effectiveness of a diet enriched in foods containing these compounds in cancer therapy. Some concerns also come
from their actual bioavailability and bioactivity. In this respect, the
possibility to enhance their activity by combining different compounds or, more importantly, by using specific foods that already
contain a combination of these compounds, is very intriguing
(16,82). It is worth mentioning that, although phytochemicals have
been demonstrated to possess preventive effects on cardiovascular disease, cancer, and other chronic conditions (83–85), studies
on single compounds have not reached the same positive results
(86). This leads to the hypothesis that the protective effect could
be because of a synergistic action of phytochemicals’ combinations
normally found in these foods (16,82,87).
Anti-inflammatory and Antioxidant Properties of Nuts in
Cancer Prevention
Inflammation. Inflammation has been associated with many of
the cellular mechanisms involved in tumor progression, such as
deregulated cell proliferation and survival, genome destabilization,
and induction of migration and invasion (88). Inflammation has also
been linked to genomic instability through several mechanisms, and
it has been associated with all different steps that are involved in
metastasis development (89). For instance, tumor-associated macrophages are critical for invasion and for intravasation of cancer cells
into blood and lymphatics vessels, a process which is also facilitated
by tumor necrosis factor–induced increase in vascular permeability,
prostaglandin production, and matrix metalloproteinases–mediated
tissue remodeling (90). Inflammatory mediators further enhance
the survival of circulating cancer cells and promote their extravasation by inducing the upregulation of adhesion molecules.
Nuts possess several components with potential anti-inflammatory properties, including MUFA, magnesium, fiber, α-linolenic
acid, and L-arginine (91–94). Quercetin and resveratrol also exhibit
anti-inflammatory properties by acting on the formation of prostaglandins and proinflammatory cytokines involved in inflammatory
response (95,96). Epidemiologic studies have suggested an inverse
association between nut consumption and inflammation (91–94).
In the PREDIMED study, a decrease in plasma concentrations of
some inflammatory markers (IL-6, ICAM-1 and VCAM-1) was
observed in the two interventional groups with Mediterranean
diets compared with the control group after three months (97).
Acute studies have also suggested a role for nut consumption in
modulation of inflammatory response.
6 of 10 Review | JNCI
Oxidative stress. Oxidative stress has been observed in many
cancers, both in solid tumors and hematopoietic malignancies.
Evidence suggests that the accumulation of reactive oxygen species
(ROS) could promote cell proliferation, cell survival, migration,
and metastasis through several mechanisms. For instance, ROS can
oxidize PUFA and activate lipid peroxidation, which in turn can
alter membrane fluidity and increase membrane permeability, leading to leakage of intracellular enzymes and recruitment of inflammatory cells (98). In addition, lipid peroxidation can generate other
free radicals and products that directly regulate gene expression
and cell proliferation. ROS can also oxidize proteins, have been
shown to induce oxidative modification to DNA bases, which
can lead to mispair/mutagenic potential or affect DNA methylation, and are directly involved in the regulation of several cellular
functions by activating key signaling pathways, including NF-kB,
phosphoinositide 3-kinase (PI3K)/Akt, heat shock proteins, and
mitogen-activated protein kinase (98). It is also important to note
that some anticancer agents are able to induce cancer cell apoptosis
by increasing ROS levels (99). Therefore, free radicals can play a
dual role as both accelerator or inhibitor in carcinogenesis.
Nuts contain several antioxidant components, such as phytosterols, carotenoids, phenols (proanthocyanidins, flavonoids,
resveratrol), and vitamin E (α-tocopherol, β-tocopherol and
γ-tocopherol) (100–102). Selenium and magnesium are also key
components of antioxidant enzymes (78,103). It has been suggested
that a reduced susceptibility to low density lipoprotein (LDL) oxidation contributes to the protective effect of nut consumption on
cardiovascular risk. A review of studies investigating the effect of
nuts on oxidation concluded that, although results from animal
studies and human clinical trials did not show consistent positive
effects on oxidation status, there was no deleterious effect on oxidation (100). Therefore, the authors concluded that the antioxidant
components may counteract the effect of the unsaturated fats (100).
Among these components, resveratrol is one of the most studied
for its anticancer activity. Interestingly, it has been shown that resveratrol can act both as oxidant and antioxidant, and it can reduce
the expression of oncogenes.
Nuts, Energy Metabolism, and Cancer
Alteration of metabolic pathways is very common in cancer cells,
and indeed reprogramming of metabolism has been recently recognized as an emerging hallmark of cancer (104). Although many
studies have been focused on glucose metabolism and in particular
on the ability of cancer cells to use aerobic glycolysis, there is currently an increasing interest in studying lipid metabolism and it is
becoming overtly evident that the alteration of lipid metabolism is
critical for cancer development (105). Several enzymes involved in
lipogenesis and lipolysis have been found overexpressed in cancer,
including fatty acid synthase that catalyzes the final steps during
fatty acids synthesis (106), or monoacylglycerol lipase that releases
free fatty acids from monoacylglycerols (107). Similarly, increased
activity of the sterol regulatory element-binding protein (SREBP),
or overexpression of its downstream targets, has been observed in
several cancers (108). In addition, increasing evidence suggest that
cholesterol plays a key role in cancer (109).
Consistent with the emerging role of lipid metabolism, the
accumulation in specific lipid droplets (LDs) has been observed in
Vol. 106, Issue 9 | dju238 | September 10, 2014
several cancers where they are thought to act as storage of triacylglycerols and cholesteryl ethers (CE) (110). A recent study has
reported the specific role of these LDs in cancer cell proliferation,
indicating their potential use as both biomarkers and molecular
targets (111). Specifically, it has been shown that loss of the tumor
suppressor phosphate and tensin homolog (PTEN) in prostate
cancer and consequent activation of the PI3K/Akt pathway results
in activation of SREBP and accumulation of CE in LDs. The
mechanism of this accumulation involves uptake of LDL through
an LDL receptor and the conversion of excess free cholesterol into
CE by the action of the enzyme acyl coenzyme A:cholesterol acyltransferase (ACAT). In a normal cell, accumulation of free cholesterol would inhibit SREBP and LDL receptors, thereby reducing
LDL uptake. Prostate cancer cells appear to use ACAT to remove
the excess cholesterol and store it as CE into LDs in order to maintain uptake of LDL and associated fatty acids, including the key
arachidonic acid that is involved in cell proliferation and growth.
One of the most accepted mechanisms responsible for the
protective effect of nuts on cardiovascular diseases is their wellestablished lipid-lowering activity. A systematic review of studies published up to August 2004 reported that three studies on
almonds, two studies on peanuts, one study on pecan nuts, and
four studies on walnuts had consistently shown a decrease in
total cholesterol (between 2% and 16%) and LDL cholesterol
(between 2% and 19%) in people who ate nuts compared with
people who ate control diets (112). A recent pooled analysis of
1284 observations by 583 participants from 25 clinical studies
revealed a dose-response cholesterol-lowering effect, with a mean
estimated reduction of total cholesterol and LDL-cholesterol
of 5% and 7%, respectively, and no effect on HDL-cholesterol
or triglycerides (except in subjects with serum triglycerides
>150 mg/dL). The effect was dose related, similar by gender and
across age groups and independent of the type of nuts tested.
Importantly, the effect was greater for subjects with higher baseline values of LDL-cholesterol and those with lower baseline
BMI (113). Similarly, a recent meta-analysis of 13 clinical trials
showed that walnut-rich diets reduced LDL-cholesterol concentrations with no effect on HDL-cholesterol or triglycerides, compared with control diets (114). Recent intervention studies using
walnuts, almonds, hazelnuts, pistachios, macadamias, and peanuts
have all confirmed the LDL-cholesterol lowering effects (23).
Interestingly, although this property has been mainly ascribed to
the fact that nuts are rich in unsaturated fatty acids, it was also
reported that the cholesterol-lowering effect was 25% higher
than predicted on the basis of the nuts’ fatty acids profiles (23).
Therefore, it has been suggested that other nut components, such
as fibers, vitamins, folic acid, magnesium, copper, plant proteins
and sterols, and phenolic components can also contribute to the
cholesterol-lowering profile.
Since it is well documented that nuts have a cholesterol-lowering effect and they can modify lipid profiles in humans, it is tempting to speculate that some of their anticancer properties can be
directly ascribable to their effect on lipid profiles. For instance, by
lowering cholesterol levels they can reduce the accumulation of CE
in cancer cells and therefore possibly reduce uptake of LDL and
essential fatty acids, ultimately resulting in inhibition of cancer cell
proliferation and tumor growth.
jnci.oxfordjournals.org
Despite the high fat content of nuts, their consumption has been
shown to induce a decrease in body weight. In addition, nut consumption has also been shown to reduce visceral adiposity, hyperglycemia, insulin resistance, and endothelial dysfunction. These
data suggest that nut consumption may affect cell metabolism.
Since cancer cells have been shown to induce a specific metabolism
reprogramming, it is tempting to hypothesize that nut effect on
metabolism could counteract the cancer-specific cell metabolism.
Pressing Questions
Unwinding the tangle of nut consumption and cancer survival will
require studies specifically designed to investigate this correlation.
Throughout the review, we have attempted to provide some explanations for the protective role of nut consumption in cancer survival. Several questions still remain to be addressed.
1.Are there specific cancer types where nut consumption is
more effective than others? Within a specific cancer type, are
there specific subsets where nut consumption is more beneficial? Is there a potential association with specific mutations,
signaling pathways alteration, etc.?
2. Are some nut species more effective than others?
3.Can nut consumption be used in combination with
chemotherapy?
4.What are the best methodological approaches and animal
models to study nut effects?
5. What are the amounts of nuts to be consumed to get a beneficial effect?
Future directions in order to get a stronger correlation between
nut consumption and cancer chemoprevention involve epidemiologic research that narrows the focus on specific cancer types or
types of nuts. It would be also interesting to perform studies in specific cancer settings and to investigate the association between nut
consumption and cancer recurrence or metastasis in populations
at high risk. Another key aspect to be investigated is the amount
of nuts to be consumed and the potential interaction with other
nutrients and demographic risk factors.
Conclusion
Since the publication of our review on cancer chemoprevention
by nuts (16), research on the effects of nut consumption on cancer survival has substantially increased the evidence of an inverse
correlation. In this review, we have focused our attention on the
potential mechanisms responsible for the chemopreventive properties of nuts. This is a very interesting topic that further requires
future investigation specifically designed to address this question. Population-based studies on the association between nuts
and cancer have often been limited by the fact that they grouped
nuts, legumes, and seeds, they measured dietary intake at baseline, or had insufficient statistical power because of limited cancer
cases and distribution of nut intake. Therefore, better epidemiological studies, in particular large prospective cohort studies to
assess the association between nut consumption and cancer, are
urgently needed. The compelling evidence that increased nut
consumption is associated with statistically significant reduction
JNCI | Review 7 of 10
of mortality risk, including cancer, suggest that nut consumption
should be considered a tool of intervention to reduce the burden
of cancer. More importantly, this reinforces the rationale that nuts
should be included as a serving in the fruit and vegetables serving
recommendation.
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Funding
This work was supported by Pancreatic Cancer Research Fund and Prostate
Cancer UK (PG12-23 and PG13-029).
Notes
The funders had no role in the decision to write the manuscript, the contents, or
the decision to submit it for publication.
Affiliation of authors: Queen Mary University of London, Barts and The
London School of Medicine and Dentistry, Blizard Institute, Inositide
Signalling Group.
Vol. 106, Issue 9 | dju238 | September 10, 2014